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Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by covalent bonds, and are found in the bacterial capsule, the outermost membrane of cell envelope of Gram-negative bacteria, such as E. coli and Salmonella.^[1] Today, the term endotoxin is often used synonymously with LPS,^[2] although there are a few endotoxins (in the original sense of toxins that are inside the bacterial cell that are released when the cell disintegrates) that are not related to LPS, such as the so-called delta endotoxin proteins produced by Bacillus thuringiensis.^[3]

Lipopolysaccharides can have substantial impacts on human health, primarily through interactions with the immune system. LPS is a potent activator of the immune system and pyrogen (agent that causes fever).^[4] In severe cases, LPS can play a role in causing septic shock.^[5] In lower levels and over a longer time period, there is evidence LPS may play an important and harmful role in autoimmunity, obesity, depression, and cellular senescence.^[6]^[7]^[8]^[9]

Discovery

The toxic activity of LPS was first discovered and termed endotoxin by Richard Friedrich Johannes Pfeiffer. He distinguished between exotoxins, toxins that are released by bacteria into the surrounding environment, and endotoxins, which are toxins "within" the bacterial cell and released only after destruction of the bacterial outer membrane.^[10] Subsequent work showed that release of LPS from gram negative microbes does not necessarily require the destruction of the bacterial cell wall, but rather, LPS is secreted as part of the normal physiological activity of membrane vesicle trafficking in the form of bacterial outer membrane vesicles (OMVs), which may also contain other virulence factors and proteins.^[11]^[1]

Functions in bacteria

LPS is a major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria and protecting the membrane from certain kinds of chemical attack. LPS is the most abundant antigen on the cell surface of most Gram-negative bacteria, contributing up to 80% of the outer membrane of E. coli and Salmonella.^[1] LPS increases the negative charge of the cell membrane and helps stabilize the overall membrane structure. It is of crucial importance to many Gram-negative bacteria, which die if the genes coding for it are mutated or removed. However, it appears that LPS is nonessential in at least some Gram-negative bacteria, such as Neisseria meningitidis, Moraxella catarrhalis, and Acinetobacter baumannii.^[12] It has also been implicated in non-pathogenic aspects of bacterial ecology, including surface adhesion, bacteriophage sensitivity, and interactions with predators such as amoebae. LPS is also required for the functioning of omptins, a class of bacterial protease.^[13]

Composition

The saccharolipid Kdo₂-Lipid A. Kdo residues in red (core), glucosamine residues in blue, acyl chains in black and phosphate groups in green.

Lipopolysaccharides are composed of three parts: the O antigen (or O polysaccharide), the core oligosaccharide, and Lipid A.

O-antigen

The repetitive glycan polymer contained within an LPS is referred to as the O antigen, O polysaccharide, or O side-chain of the bacteria. The O antigen is attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. The composition of the O chain varies from strain to strain; there are over 160 different O antigen structures produced by different E. coli strains.^[14] The presence or absence of O chains determines whether the LPS is considered "rough" or "smooth". Full-length O-chains would render the LPS smooth, whereas the absence or reduction of O-chains would make the LPS rough.^[15] Bacteria with rough LPS usually have more penetrable cell membranes to hydrophobic antibiotics, since a rough LPS is more hydrophobic.^[16] O antigen is exposed on the very outer surface of the bacterial cell, and, as a consequence, is a target for recognition by host antibodies.

Core

The core domain always contains an oligosaccharide component that attaches directly to lipid A and commonly contains sugars such as heptose and 3-Deoxy-D-manno-oct-2-ulosonic acid (also known as KDO, keto-deoxyoctulosonate).^[17] The LPS cores of many bacteria also contain non-carbohydrate components, such as phosphate, amino acids, and ethanolamine substituents.

Lipid A

Lipid A is, in normal circumstances, a phosphorylated glucosamine disaccharide decorated with multiple fatty acids. These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane, and the rest of the LPS projects from the cell surface. The lipid A domain is responsible for much of the toxicity of Gram-negative bacteria. When bacterial cells are lysed by the immune system, fragments of membrane containing lipid A are released into the circulation, causing fever, diarrhea, and possible fatal endotoxic shock (also called septic shock). The Lipid A moiety is a very conserved component of the LPS.^[18] However Lipid A structure varies among bacterial species. Lipid A structure largely defines the degree and nature of the overall host immune activation.^[19]

Lipooligosaccharides

The "rough form" of LPS has a lower molecular weight due to the absence of the O polysaccharide. In its place is a short oligosaccharide: this form is known as Lipooligosaccharide (LOS), and is a glycolipid found in the outer membrane of some types of Gram-negative bacteria, such as Neisseria spp. and Haemophilus spp.^[6]^[20] LOS plays a central role in maintaining the integrity and functionality of the outer membrane of the Gram negative cell envelope. LOS play an important role in the pathogenesis of certain bacterial infections because they are capable of acting as immunostimulators and immunomodulators.^[6] Furthermore, LOS molecules are responsible for the ability of some bacterial strains to display molecular mimicry and antigenic diversity, aiding in the evasion of host immune defenses and thus contributing to the virulence of these bacterial strains. In the case of Neisseria meningitidis, the lipid A portion of the molecule has a symmetrical structure and the inner core is composed of 3-deoxy-D-manno-2-octulosonic acid (KDO) and heptose (Hep) moieties. The outer core oligosaccharide chain varies depending on the bacterial strain.^[6]^[20]

LPS detoxification

A highly conserved host enzyme called acyloxyacyl hydrolase (AOAH) may detoxify LPS when it enters, or is produced in, animal tissues. It may also convert LPS in the intestine into an LPS inhibitor. Neutrophils, macrophages and dendritic cells produce this lipase, which inactivates LPS by removing the two secondary acyl chains from lipid A to produce tetraacyl LPS. If mice are given LPS parenterally, those that lack AOAH develop high titers of non-specific antibodies, develop prolonged hepatomegaly, and experience prolonged endotoxin tolerance. LPS inactivation may be required for animals to restore homeostasis after parenteral LPS exposure.^[21] Although mice have many other mechanisms for inhibiting LPS signaling, none is able to prevent these changes in animals that lack AOAH.

Dephosphorylation of LPS by intestinal alkaline phosphatase can reduce the severity of Salmonella tryphimurium and Clostridioides difficile infection restoring normal gut microbiota.^[22] Alkaline phosphatase prevents intestinal inflammation (and "leaky gut") from bacteria by dephosphorylating the Lipid A portion of LPS.^[23]^[24]^[25]

Biosynthesis and transport

**LPS final assembly:** O-antigen subunits are translocated across the inner membrane (by Wzx) where they are polymerized (by Wzy, chain length determined by Wzz) and ligated (by WaaL) on to complete Core-Lipid A molecules (which were translocated by MsbA).^[26]

**LPS transport:** Completed LPS molecules are transported across the periplasm and outer membrane by the lipopolysaccharide transport (Lpt) proteins A, B, C, D, E, F, and G.^[27]

The entire process of making LPS starts with a molecule called lipid A-Kdo2, which is first created on the surface of the bacterial cell's inner membrane. Then, additional sugars are added to this molecule on the inner membrane before it's moved to the space between the inner and outer membranes (periplasmic space) with the help of a protein called MsbA. The O-antigen, another part of LPS, is made by special enzyme complexes on the inner membrane. It is then moved to the outer membrane through three different systems: one is Wzy-dependent, another relies on ABC transporters, and the third involves a synthase-dependent process.^[28]

Ultimately, LPS is transported to the outer membrane by a membrane-to-membrane bridge of lipolysaccharide transport (Lpt) proteins.^[27]^[29] This transporter is a potential antibiotic target.^[30]^[31]

Biological effects on hosts infected with Gram-negative bacteria

Immune response

LPS acts as the prototypical endotoxin because it binds the CD14/TLR4/MD2 receptor complex in many cell types, but especially in monocytes, dendritic cells, macrophages and B cells, which promotes the secretion of pro-inflammatory cytokines, nitric oxide, and eicosanoids.^[32] Bruce Beutler was awarded a portion of the 2011 Nobel Prize in Physiology or Medicine for his work demonstrating that TLR4 is the LPS receptor.^[33]^[34]

As part of the cellular stress response, superoxide is one of the major reactive oxygen species induced by LPS in various cell types that express TLR (toll-like receptor).^[35] LPS is also an exogenous pyrogen (fever-inducing substance).^[4]

LPS function has been under experimental research for several years due to its role in activating many transcription factors. LPS also produces many types of mediators involved in septic shock. Humans are much more sensitive to LPS than other animals (e.g., mice). A dose of 1 μg/kg induces shock in humans, but mice will tolerate a dose up to a thousand times higher.^[36] This may relate to differences in the level of circulating natural antibodies between the two species.^[37]^[38] Said et al. showed that LPS causes an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L1.^[39]

Endotoxins are in large part responsible for the dramatic clinical manifestations of infections with pathogenic Gram-negative bacteria, such as Neisseria meningitidis, the pathogens that causes meningococcal disease, including meningococcemia, Waterhouse–Friderichsen syndrome, and meningitis.

Portions of the LPS from several bacterial strains have been shown to be chemically similar to human host cell surface molecules; the ability of some bacteria to present molecules on their surface which are chemically identical or similar to the surface molecules of some types of host cells is termed molecular mimicry.^[40] For example, in Neisseria meningitidis L2,3,5,7,9, the terminal tetrasaccharide portion of the oligosaccharide (lacto-N-neotetraose) is the same tetrasaccharide as that found in paragloboside, a precursor for ABH glycolipid antigens found on human erythrocytes.^[6] In another example, the terminal trisaccharide portion (lactotriaose) of the oligosaccharide from pathogenic Neisseria spp. LOS is also found in lactoneoseries glycosphingolipids from human cells.^[6] Most meningococci from groups B and C, as well as gonococci, have been shown to have this trisaccharide as part of their LOS structure.^[6] The presence of these human cell surface 'mimics' may, in addition to acting as a 'camouflage' from the immune system, play a role in the abolishment of immune tolerance when infecting hosts with certain human leukocyte antigen (HLA) genotypes, such as HLA-B35.^[6]

LPS can be sensed directly by hematopoietic stem cells (HSCs) through the bonding with TLR4, causing them to proliferate in reaction to a systemic infection. This response activate the TLR4-TRIF-ROS-p38 signaling within the HSCs and through a sustained TLR4 activation can cause a proliferative stress, leading to impair their competitive repopulating ability.^[41] Infection in mice using S. typhimurium showed similar results, validating the experimental model also in vivo.

Effect of variability on immune response

O-antigens (the outer carbohydrates) are the most variable portion of the LPS molecule, imparting antigenic specificity. In contrast, lipid A is the most conserved part. However, lipid A composition also may vary (e.g., in number and nature of acyl chains even within or between genera). Some of these variations may impart antagonistic properties to these LPS. For example, diphosphoryl lipid A of Rhodobacter sphaeroides (RsDPLA) is a potent antagonist of LPS in human cells, but is an agonist in hamster and equine cells.^[42]

It has been speculated that conical lipid A (e.g., from E. coli) is more agonistic, while less conical lipid A like that of Porphyromonas gingivalis may activate a different signal (TLR2 instead of TLR4), and completely cylindrical lipid A like that of Rhodobacter sphaeroides is antagonistic to TLRs.^[43]^[44] In general, LPS gene clusters are highly variable between different strains, subspecies, species of bacterial pathogens of plants and animals.^[45]^[46]

Normal human blood serum contains anti-LOS antibodies that are bactericidal and patients that have infections caused by serotypically distinct strains possess anti-LOS antibodies that differ in their specificity compared with normal serum.^[47] These differences in humoral immune response to different LOS types can be attributed to the structure of the LOS molecule, primarily within the structure of the oligosaccharide portion of the LOS molecule.^[47] In Neisseria gonorrhoeae it has been demonstrated that the antigenicity of LOS molecules can change during an infection due to the ability of these bacteria to synthesize more than one type of LOS,^[47] a characteristic known as phase variation. Additionally, Neisseria gonorrhoeae, as well as Neisseria meningitidis and Haemophilus influenzae,^[6] are capable of further modifying their LOS in vitro, for example through sialylation (modification with sialic acid residues), and as a result are able to increase their resistance to complement-mediated killing ^[47] or even down-regulate complement activation^[6] or evade the effects of bactericidal antibodies.^[6] Sialylation may also contribute to hindered neutrophil attachment and phagocytosis by immune system cells as well as a reduced oxidative burst.^[6] Haemophilus somnus, a pathogen of cattle, has also been shown to display LOS phase variation, a characteristic which may help in the evasion of bovine host immune defenses.^[48] Taken together, these observations suggest that variations in bacterial surface molecules such as LOS can help the pathogen evade both the humoral (antibody and complement-mediated) and the cell-mediated (killing by neutrophils, for example) host immune defenses.

Non-canonical pathways of LPS recognition

Recently, it was shown that in addition to TLR4 mediated pathways, certain members of the family of the transient receptor potential ion channels recognize LPS.^[49] LPS-mediated activation of TRPA1 was shown in mice^[50] and Drosophila melanogaster flies.^[51] At higher concentrations, LPS activates other members of the sensory TRP channel family as well, such as TRPV1, TRPM3 and to some extent TRPM8.^[52] LPS is recognized by TRPV4 on epithelial cells. TRPV4 activation by LPS was necessary and sufficient to induce nitric oxide production with a bactericidal effect.^[53]

Testing

Lipopolysaccharide is a significant factor that makes bacteria harmful, and it helps categorize them into different groups based on their structure and function. This makes LPS a useful marker for telling apart various Gram-negative bacteria. Swiftly identifying and understanding the types of pathogens involved is crucial for promptly managing and treating infections. Since LPS is the main trigger for the immune response in our cells, it acts as an early signal of an acute infection. Therefore, LPS testing is more specific and meaningful than many other serological tests.^[54]

The current methods for testing LPS are quite sensitive, but many of them struggle to differentiate between different LPS groups. Additionally, the nature of LPS, which has both water-attracting and water-repelling properties (amphiphilic), makes it challenging to develop sensitive and user-friendly tests.^[54]

The typical detection methods rely on identifying the lipid A part of LPS. However, this method has limitations because Lipid A is very similar among different bacterial species and serotypes. LPS testing techniques fall into six categories, and they often overlap: in vivo tests, in vitro tests, modified immunoassays, biological assays, and chemical assays.^[54]

Pathophysiology

LPS is a powerful toxin that, when in the body, triggers inflammation by binding to cell receptors. Excessive LPS in the blood can lead to endotoxemia, potentially causing a harmful condition called septic shock. This condition includes symptoms like rapid heart rate, quick breathing, temperature changes, and blood clotting issues, resulting in blood vessels widening and reduced blood volume, leading to cellular dysfunction.^[54]

Recent research indicates that even small LPS exposure is associated with autoimmune diseases and allergies. High levels of LPS in the blood can lead to metabolic syndrome, increasing the risk of conditions like diabetes, heart disease, and liver problems.^[54]

LPS also plays a crucial role in symptoms caused by infections from harmful bacteria, including severe conditions like Waterhouse-Friderichsen syndrome, meningococcemia, and meningitis. Certain bacteria can adapt their LPS to cause long-lasting infections in the respiratory and digestive systems.^[54]

Recent studies have shown that LPS disrupts cell membrane lipids, affecting cholesterol and metabolism, potentially leading to high cholesterol, abnormal blood lipid levels, and non-alcoholic fatty liver disease. In some cases, LPS can interfere with toxin clearance, which may be linked to neurological issues.^[54]

Health effects

In general the health effects of LPS are due to its abilities as a potent activator and modulator of the immune system, especially its inducement of inflammation.

Endotoxemia

The presence of endotoxins in the blood is called endotoxemia. High level of endotoxemia can lead to septic shock,^[55] while lower concentration of endotoxins in the bloodstream is called metabolic endotoxemia.^[56] Endotoxemia is associated with obesity, diet,^[57] cardiovascular diseases,^[57] and diabetes,^[56] while also host genetics might have an effect.^[58]

Moreover, endotoxemia of intestinal origin, especially, at the host-pathogen interface, is considered to be an important factor in the development of alcoholic hepatitis,^[59] which is likely to develop on the basis of the small bowel bacterial overgrowth syndrome and an increased intestinal permeability.^[60]

Lipid A may cause uncontrolled activation of mammalian immune systems with production of inflammatory mediators that may lead to septic shock.^[20] This inflammatory reaction is mediated by Toll-like receptor 4 which is responsible for immune system cell activation.^[20] Damage to the endothelial layer of blood vessels caused by these inflammatory mediators can lead to capillary leak syndrome, dilation of blood vessels and a decrease in cardiac function and can lead to septic shock.^[61] Pronounced complement activation can also be observed later in the course as the bacteria multiply in the blood.^[61] High bacterial proliferation triggering destructive endothelial damage can also lead to disseminated intravascular coagulation (DIC) with loss of function of certain internal organs such as the kidneys, adrenal glands and lungs due to compromised blood supply. The skin can show the effects of vascular damage often coupled with depletion of coagulation factors in the form of petechiae, purpura and ecchymoses. The limbs can also be affected, sometimes with devastating consequences such as the development of gangrene, requiring subsequent amputation.^[61] Loss of function of the adrenal glands can cause adrenal insufficiency and additional hemorrhage into the adrenals causes Waterhouse-Friderichsen syndrome, both of which can be life-threatening.

It has also been reported that gonococcal LOS can cause damage to human fallopian tubes.^[47]

Auto-immune disease

The molecular mimicry of some LOS molecules is thought to cause autoimmune-based host responses, such as flareups of multiple sclerosis.^[6]^[40] Other examples of bacterial mimicry of host structures via LOS are found with the bacteria Helicobacter pylori and Campylobacter jejuni, organisms which cause gastrointestinal disease in humans, and Haemophilus ducreyi which causes chancroid. Certain C. jejuni LPS serotypes (attributed to certain tetra- and pentasaccharide moieties of the core oligosaccharide) have also been implicated with Guillain–Barré syndrome and a variant of Guillain–Barré called Miller-Fisher syndrome.^[6]

Link to obesity

Epidemiological studies have shown that increased endotoxin load, which can be a result of increased populations of endotoxin-producing bacteria in the intestinal tract, is associated with certain obesity-related patient groups.^[7]^[62]^[63] Other studies have shown that purified endotoxin from Escherichia coli can induce obesity and insulin-resistance when injected into germ-free mouse models.^[64] A more recent study has uncovered a potentially contributing role for Enterobacter cloacae B29 toward obesity and insulin resistance in a human patient.^[65] The presumed mechanism for the association of endotoxin with obesity is that endotoxin induces an inflammation-mediated pathway accounting for the observed obesity and insulin resistance.^[64] Bacterial genera associated with endotoxin-related obesity effects include Escherichia and Enterobacter.

Depression

There is experimental and observational evidence that LPS might play a role in depression. Administration of LPS in mice can lead to depressive symptoms, and there seem to be elevated levels of LPS in some people with depression. Inflammation may sometimes play a role in the development of depression, and LPS is pro-inflammatory.^[8]

Cellular senescence

Inflammation induced by LPS can induce cellular senescence, as has been shown for the lung epithelial cells and microglial cells (the latter leading to neurodegeneration).^[9]

Role as contaminant in biotechnology and research

Lipopolysaccharides are frequent contaminants in plasmid DNA prepared from bacteria or proteins expressed from bacteria, and must be removed from the DNA or protein to avoid contaminating experiments and to avoid toxicity of products manufactured using industrial fermentation.^[66]

Ovalbumin is frequently contaminated with endotoxins. Ovalbumin is one of the extensively studied proteins in animal models and also an established model allergen for airway hyper-responsiveness (AHR). Commercially available ovalbumin that is contaminated with LPS can falsify research results, as it does not accurately reflect the effect of the protein antigen on animal physiology.^[67]

In pharmaceutical production, it is necessary to remove all traces of endotoxin from drug product containers, as even small amounts of endotoxin will cause illness in humans. A depyrogenation oven is used for this purpose. Temperatures in excess of 300 °C are required to fully break down LPS.^[68]

The standard assay for detecting presence of endotoxin is the Limulus Amebocyte Lysate (LAL) assay, utilizing blood from the Horseshoe crab (Limulus polyphemus).^[69] Very low levels of LPS can cause coagulation of the limulus lysate due to a powerful amplification through an enzymatic cascade. However, due to the dwindling population of horseshoe crabs, and the fact that there are factors that interfere with the LAL assay, efforts have been made to develop alternative assays, with the most promising ones being ELISA tests using a recombinant version of a protein in the LAL assay, Factor C.^[70]

Testing: Lipopolysaccharide, is a significant factor that makes bacteria harmful, and it helps categorize them into different groups based on their structure and function. This makes LPS a useful marker for telling apart various Gram-negative bacteria. Swiftly identifying and understanding the types of pathogens involved is crucial for promptly managing and treating infections. Since LPS is the main trigger for the immune response in our cells, it acts as an early signal of an acute infection. Therefore, LPS testing is more specific and meaningful than many other serological tests. The current methods for testing LPS are quite sensitive, but many of them struggle to differentiate between different LPS groups. Additionally, the nature of LPS, which has both water-attracting and water-repelling properties (amphiphilic), makes it challenging to develop sensitive and user-friendly tests. The typical detection methods rely on identifying the lipid A part of LPS. However, this method has limitations because Lipid A is very similar among different bacterial species and serotypes. LPS testing techniques fall into six categories, and they often overlap: in vivo tests, in vitro tests, modified immunoassays, biological assays, and chemical assays. ^[54]
Pathophysiology: LPS is a powerful toxin that, when in the body, triggers inflammation by binding to cell receptors. Excessive LPS in the blood can lead to endotoxemia, potentially causing a harmful condition called septic shock. This condition includes symptoms like rapid heart rate, quick breathing, temperature changes, and blood clotting issues, resulting in blood vessels widening and reduced blood volume, leading to cellular dysfunction. Recent research indicates that even small LPS exposure is associated with autoimmune diseases and allergies. High levels of LPS in the blood can lead to metabolic syndrome, increasing the risk of conditions like diabetes, heart disease, and liver problems. LPS also plays a crucial role in symptoms caused by infections from harmful bacteria, including severe conditions like Waterhouse-Friderichsen syndrome, meningococcemia, and meningitis. Certain bacteria can adapt their LPS to cause long-lasting infections in the respiratory and digestive systems. Recent studies have shown that LPS disrupts cell membrane lipids, affecting cholesterol and metabolism, potentially leading to high cholesterol, abnormal blood lipid levels, and non-alcoholic fatty liver disease. In some cases, LPS can interfere with toxin clearance, which may be linked to neurological issues.^[54]

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External links

Lipopolysaccharides at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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[Wang_2010-26] Wang X, Quinn PJ (April 2010). "Lipopolysaccharide: Biosynthetic pathway and structure modification". Progress in Lipid Research. 49 (2): 97–107. doi:10.1016/j.plipres.2009.06.002. PMID 19815028.

[Ruiz_2009-27] Ruiz N, Kahne D, Silhavy TJ (September 2009). "Transport of lipopolysaccharide across the cell envelope: the long road of discovery". Nature Reviews. Microbiology. 7 (9): 677–683. doi:10.1038/nrmicro2184. PMC 2790178. PMID 19633680.

[Romano_2003-28] Romano KP, Hung DT (March 2023). "Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance". Biochimica et Biophysica Acta. Molecular Cell Research. 1870 (3): 119407. doi:10.1016/j.bbamcr.2022.119407. PMC 9922520. PMID 36543281.

[29] Sherman DJ, Xie R, Taylor RJ, George AH, Okuda S, Foster PJ, et al. (February 2018). "Lipopolysaccharide is transported to the cell surface by a membrane-to-membrane protein bridge". Science. 359 (6377): 798–801. doi:10.1126/science.aar1886. PMC 5858563. PMID 29449493.

[30] Pahil KS, Gilman MS, Baidin V, Clairfeuille T, Mattei P, Bieniossek C, et al. (January 2024). "A new antibiotic traps lipopolysaccharide in its intermembrane transporter". Nature. 625 (7995): 572–577. doi:10.1038/s41586-023-06799-7. PMC 10794137. PMID 38172635.

[31] Zampaloni C, Mattei P, Bleicher K, Winther L, Thäte C, Bucher C, et al. (January 2024). "A novel antibiotic class targeting the lipopolysaccharide transporter". Nature. 625 (7995): 566–571. doi:10.1038/s41586-023-06873-0. PMC 10794144. PMID 38172634.

[32] Abbas A (2006). Basic Immunology. Elsevier. ISBN 978-1-4160-2974-8.

[33] Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. (December 1998). "Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene". Science. 282 (5396): 2085–2088. Bibcode:1998Sci...282.2085P. doi:10.1126/science.282.5396.2085. PMID 9851930.

[34] "The 2011 Nobel Prize in Physiology or Medicine - Press Release". www.nobelprize.org. Archived from the original on 23 March 2018. Retrieved 28 April 2018.

[35] Li Y, Deng SL, Lian ZX, Yu K (June 2019). "Roles of Toll-Like Receptors in Nitroxidative Stress in Mammals". Cells. 8 (6): 576. doi:10.3390/cells8060576. PMC 6627996. PMID 31212769.

[36] Warren HS, Fitting C, Hoff E, Adib-Conquy M, Beasley-Topliffe L, Tesini B, et al. (January 2010). "Resilience to bacterial infection: difference between species could be due to proteins in serum". The Journal of Infectious Diseases. 201 (2): 223–232. doi:10.1086/649557. PMC 2798011. PMID 20001600.

[37] Reid RR, Prodeus AP, Khan W, Hsu T, Rosen FS, Carroll MC (July 1997). "Endotoxin shock in antibody-deficient mice: unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide". Journal of Immunology. 159 (2): 970–975. doi:10.4049/jimmunol.159.2.970. PMID 9218618.

[38] Boes M, Prodeus AP, Schmidt T, Carroll MC, Chen J (December 1998). "A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection". The Journal of Experimental Medicine. 188 (12): 2381–2386. doi:10.1084/jem.188.12.2381. PMC 2212438. PMID 9858525.

[39] Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, et al. (April 2010). "Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection". Nature Medicine. 16 (4): 452–459. doi:10.1038/nm.2106. PMC 4229134. PMID 20208540.

[Chastain_2012-40] Chastain EM, Miller SD (January 2012). "Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease". Immunological Reviews. 245 (1): 227–238. doi:10.1111/j.1600-065X.2011.01076.x. PMC 3586283. PMID 22168423.

[41] Takizawa H, Fritsch K, Kovtonyuk LV, Saito Y, Yakkala C, Jacobs K, et al. (August 2017). "Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness". Cell Stem Cell. 21 (2): 225–240.e5. doi:10.1016/j.stem.2017.06.013. PMID 28736216.

[42] Lohmann KL, Vandenplas ML, Barton MH, Bryant CE, Moore JN (2007). "The equine TLR4/MD-2 complex mediates recognition of lipopolysaccharide from Rhodobacter sphaeroides as an agonist". Journal of Endotoxin Research. 13 (4): 235–242. doi:10.1177/0968051907083193. PMID 17956942. S2CID 36784237.

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 {{Use dmy dates|date=October 2022}}[[File:LPS.svg|thumb|200px|Structure of a lipopolysaccharide (LPS)]]
-'''Lipopolysaccharides''' ('''LPS''') are large [[molecule]]s consisting of a [[lipid]] and a [[polysaccharide]] that are [[bacterial toxins]]. They are composed of an O-[[antigen]], an outer core, and an inner core all joined by [[covalent bond|covalent bonds]], and are found in the [[bacterial capsule]], the outermost membrane of [[cell envelope]] of Gram-negative bacteria, such as [[Escherichia coli|E. coli]] and [[Salmonella]].<ref name="pmid33746909" /> Today, the term '''''endotoxin''''' is often used synonymously with LPS,<ref name="lipopolysaccharide">{{Cite journal |vauthors=Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, Ulmer AJ, Zähringer U, Seydel U, Di Padova F |year=1994 |title=Bacterial endotoxin: molecular relationships of structure to activity and function |journal=FASEB J. |volume=8 |issue=2 |pages=217–25 |doi=10.1096/fasebj.8.2.8119492 |pmid=8119492 |s2cid=28156137}}</ref> although there are a few endotoxins (in the original sense of [[toxin]]s that are inside the bacterial cell that are released when the cell disintegrates) that are not related to LPS, such as the so-called [[delta endotoxin]] [[protein]]s produced by ''[[Bacillus thuringiensis]]''.<ref>{{Cite journal |last1=Höfte |first1=H. |last2=de Greve |first2=H. |last3=Seurinck |first3=J. |last4=Jansens |first4=S. |last5=Mahillon |first5=J. |last6=Ampe |first6=C. |last7=Vandekerckhove |first7=J. |last8=Vanderbruggen |first8=H. |last9=van Montagu |first9=M. |last10=Zabeau |first10=M. |date=1 December 1986 |title=Structural and functional analysis of a cloned delta endotoxin of Bacillus thuringiensis berliner 1715 |journal=European Journal of Biochemistry |volume=161 |issue=2 |pages=273–280 |doi=10.1111/j.1432-1033.1986.tb10443.x |issn=0014-2956 |pmid=3023091|doi-access=free }}</ref>
+'''Lipopolysaccharides''' ('''LPS''') are large [[molecule]]s consisting of a [[lipid]] and a [[polysaccharide]] that are [[bacterial toxins]]. They are composed of an O-[[antigen]], an outer core, and an inner core all joined by [[covalent bond|covalent bonds]], and are found in the [[bacterial capsule]], the outermost membrane of [[cell envelope]] of Gram-negative bacteria, such as [[Escherichia coli|E. coli]] and [[Salmonella]].<ref name="Avila-Calderón_2021" /> Today, the term '''''endotoxin''''' is often used synonymously with LPS,<ref name="Rietschel_1994">{{cite journal | vauthors = Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, Ulmer AJ, Zähringer U, Seydel U, Di Padova F | display-authors = 6 | title = Bacterial endotoxin: molecular relationships of structure to activity and function | journal = FASEB Journal | volume = 8 | issue = 2 | pages = 217–225 | date = February 1994 | pmid = 8119492 | doi = 10.1096/fasebj.8.2.8119492 | doi-access = free | s2cid = 28156137 }}</ref> although there are a few endotoxins (in the original sense of [[toxin]]s that are inside the bacterial cell that are released when the cell disintegrates) that are not related to LPS, such as the so-called [[delta endotoxin]] [[protein]]s produced by ''[[Bacillus thuringiensis]]''.<ref>{{cite journal | vauthors = Höfte H, de Greve H, Seurinck J, Jansens S, Mahillon J, Ampe C, Vandekerckhove J, Vanderbruggen H, van Montagu M, Zabeau M | display-authors = 6 | title = Structural and functional analysis of a cloned delta endotoxin of Bacillus thuringiensis berliner 1715 | journal = European Journal of Biochemistry | volume = 161 | issue = 2 | pages = 273–280 | date = December 1986 | pmid = 3023091 | doi = 10.1111/j.1432-1033.1986.tb10443.x | doi-access = free }}</ref>
-Lipopolysaccharides can have substantial impacts on human health, primarily through interactions with the immune system. LPS is a potent activator of the immune system and [[Pyrogen (fever)|pyrogen]] (agent that causes fever).<ref name=":2">{{Cite journal |last1=Roth |first1=Joachim |last2=Blatteis |first2=Clark M. |date=October 2014 |title=Mechanisms of fever production and lysis: lessons from experimental LPS fever |url=https://pubmed.ncbi.nlm.nih.gov/25428854 |journal=Comprehensive Physiology |volume=4 |issue=4 |pages=1563–1604 |doi=10.1002/cphy.c130033 |issn=2040-4603 |pmid=25428854}}</ref> In severe cases, LPS can play a role in causing [[septic shock]].<ref>{{Cite journal |last1=Dellinger |first1=R. Phillip |last2=Levy |first2=Mitchell M. |last3=Rhodes |first3=Andrew |last4=Annane |first4=Djillali |last5=Gerlach |first5=Herwig |last6=Opal |first6=Steven M. |last7=Sevransky |first7=Jonathan E. |last8=Sprung |first8=Charles L. |last9=Douglas |first9=Ivor S. |last10=Jaeschke |first10=Roman |last11=Osborn |first11=Tiffany M. |date=February 2013 |title=Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 |journal=Critical Care Medicine |volume=41 |issue=2 |pages=580–637 |doi=10.1097/CCM.0b013e31827e83af |issn=1530-0293 |pmid=23353941 |s2cid=34855187|doi-access=free }}</ref> In lower levels and over a longer time period, there is evidence LPS may play an important and harmful role in [[autoimmunity]], [[obesity]], [[Depression (mood)|depression]], and [[cellular senescence]].<ref name="Moran_et_al" /><ref name="epidemiology_1" /><ref name=":1" /><ref name="pmid30078211" />
+Lipopolysaccharides can have substantial impacts on human health, primarily through interactions with the immune system. LPS is a potent activator of the immune system and [[Pyrogen (fever)|pyrogen]] (agent that causes fever).<ref name="Roth_2014">{{cite journal | vauthors = Roth J, Blatteis CM | title = Mechanisms of fever production and lysis: lessons from experimental LPS fever | journal = Comprehensive Physiology | volume = 4 | issue = 4 | pages = 1563–1604 | date = October 2014 | pmid = 25428854 | doi = 10.1002/cphy.c130033 | isbn = 978-0-470-65071-4 }}</ref> In severe cases, LPS can play a role in causing [[septic shock]].<ref>{{cite journal | vauthors = Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R | display-authors = 6 | title = Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 | journal = Critical Care Medicine | volume = 41 | issue = 2 | pages = 580–637 | date = February 2013 | pmid = 23353941 | doi = 10.1097/CCM.0b013e31827e83af | s2cid = 34855187 | doi-access = free }}</ref> In lower levels and over a longer time period, there is evidence LPS may play an important and harmful role in [[autoimmunity]], [[obesity]], [[Depression (mood)|depression]], and [[cellular senescence]].<ref name="Moran_1996" /><ref name="Moreno-Navarrete_2012" /><ref name="Lasselin_2020" /><ref name="Wei_2018" />
 ==Discovery==
-The toxic activity of LPS was first discovered and termed ''endotoxin'' by [[Richard Friedrich Johannes Pfeiffer]]. He distinguished between [[exotoxins]], toxins that are released by bacteria into the surrounding environment, and endotoxins, which are toxins "within" the bacterial cell and released only after destruction of the bacterial outer membrane.<ref>{{Cite book |last=Parija SC |url=https://books.google.com/books?id=HcgGLfxDJSQC |title=Textbook of Microbiology & Immunology |date=1 January 2009 |publisher=Elsevier |isbn=978-8131221631 |location=India}}</ref> Subsequent work showed that release of LPS from [[gram negative]] microbes does not necessarily require the destruction of the bacterial cell wall, but rather, LPS is secreted as part of the normal physiological activity of [[membrane vesicle trafficking]] in the form of [[Bacterial outer membrane vesicles |bacterial outer membrane vesicles (OMVs)]], which may also contain other [[virulence factor]]s and proteins.<ref name="pmid20825345">{{Cite journal |vauthors=Kulp A, Kuehn MJ |year=2010 |title=Biological functions and biogenesis of secreted bacterial outer membrane vesicles |journal=Annu. Rev. Microbiol. |volume=64 |pages=163–84 |doi=10.1146/annurev.micro.091208.073413 |pmc=3525469 |pmid=20825345}}</ref><ref name="pmid33746909" />
+The toxic activity of LPS was first discovered and termed ''endotoxin'' by [[Richard Friedrich Johannes Pfeiffer]]. He distinguished between [[exotoxins]], toxins that are released by bacteria into the surrounding environment, and endotoxins, which are toxins "within" the bacterial cell and released only after destruction of the bacterial outer membrane.<ref>{{Cite book | vauthors = Parija SC |url=https://books.google.com/books?id=HcgGLfxDJSQC |title=Textbook of Microbiology & Immunology |date=1 January 2009 |publisher=Elsevier |isbn=978-8131221631 |location=India}}</ref> Subsequent work showed that release of LPS from [[gram negative]] microbes does not necessarily require the destruction of the bacterial cell wall, but rather, LPS is secreted as part of the normal physiological activity of [[membrane vesicle trafficking]] in the form of [[Bacterial outer membrane vesicles |bacterial outer membrane vesicles (OMVs)]], which may also contain other [[virulence factor]]s and proteins.<ref name="Kulp_2010">{{cite journal | vauthors = Kulp A, Kuehn MJ | title = Biological functions and biogenesis of secreted bacterial outer membrane vesicles | journal = Annual Review of Microbiology | volume = 64 | pages = 163–184 | year = 2010 | pmid = 20825345 | pmc = 3525469 | doi = 10.1146/annurev.micro.091208.073413 }}</ref><ref name="Avila-Calderón_2021" />
 == Functions in bacteria ==
-LPS is a major component of the outer membrane of [[Gram-negative bacteria]], contributing greatly to the structural integrity of the bacteria and protecting the membrane from certain kinds of chemical attack. LPS is the most abundant [[antigen]] on the cell surface of most Gram-negative bacteria, contributing up to 80% of the outer membrane of ''E. coli'' and ''Salmonella''.<ref name="pmid33746909">{{Cite journal |vauthors=Avila-Calderón ED, Ruiz-Palma MD, Contreras-Rodríguez A |year=2021 |title=Outer Membrane Vesicles of Gram-Negative Bacteria: An Outlook on Biogenesis |journal=[[Frontiers in Microbiology]] |volume=12 |pages=557902 |doi=10.3389/fmicb.2021.557902 |pmc=7969528 |pmid=33746909 |doi-access=free}}</ref>  LPS increases the negative charge of the [[cell membrane]] and helps stabilize the overall membrane structure. It is of crucial importance to many Gram-negative bacteria, which die if the genes coding for it are mutated or removed. However, it appears that LPS is nonessential in at least some Gram-negative bacteria, such as ''Neisseria meningitidis'', ''Moraxella catarrhalis'', and ''Acinetobacter baumannii''.<ref>{{Cite journal |vauthors=Zhang G, Meredith TC, Kahne D |year=2013 |title=On the essentiality of lipopolysaccharide to Gram-negative bacteria |journal=Curr. Opin. Microbiol. |volume=16 |issue=6 |pages=779–785 |doi=10.1016/j.mib.2013.09.007 |pmc=3974409 |pmid=24148302}}</ref> It has also been implicated in non-pathogenic aspects of bacterial ecology, including surface adhesion, [[bacteriophage]] sensitivity, and interactions with predators such as [[amoebae]]. LPS is also required for the functioning of [[omptin]]s, a class of bacterial protease.<ref>{{Cite journal |last1=Kukkonen |first1=Maini |last2=Korhonen |first2=Timo K. |date=July 2004 |title=The omptin family of enterobacterial surface proteases/adhesins: from housekeeping in Escherichia coli to systemic spread of Yersinia pestis |url=https://pubmed.ncbi.nlm.nih.gov/15293449 |journal=International Journal of Medical Microbiology |volume=294 |issue=1 |pages=7–14 |doi=10.1016/j.ijmm.2004.01.003 |issn=1438-4221 |pmid=15293449}}</ref>
+LPS is a major component of the outer membrane of [[Gram-negative bacteria]], contributing greatly to the structural integrity of the bacteria and protecting the membrane from certain kinds of chemical attack. LPS is the most abundant [[antigen]] on the cell surface of most Gram-negative bacteria, contributing up to 80% of the outer membrane of ''E. coli'' and ''Salmonella''.<ref name="Avila-Calderón_2021">{{cite journal | vauthors = Avila-Calderón ED, Ruiz-Palma MD, Aguilera-Arreola MG, Velázquez-Guadarrama N, Ruiz EA, Gomez-Lunar Z, Witonsky S, Contreras-Rodríguez A | display-authors = 6 | title = Outer Membrane Vesicles of Gram-Negative Bacteria: An Outlook on Biogenesis | journal = Frontiers in Microbiology | volume = 12 | pages = 557902 | year = 2021 | pmid = 33746909 | pmc = 7969528 | doi = 10.3389/fmicb.2021.557902 | doi-access = free }}</ref>  LPS increases the negative charge of the [[cell membrane]] and helps stabilize the overall membrane structure. It is of crucial importance to many Gram-negative bacteria, which die if the genes coding for it are mutated or removed. However, it appears that LPS is nonessential in at least some Gram-negative bacteria, such as ''Neisseria meningitidis'', ''Moraxella catarrhalis'', and ''Acinetobacter baumannii''.<ref>{{cite journal | vauthors = Zhang G, Meredith TC, Kahne D | title = On the essentiality of lipopolysaccharide to Gram-negative bacteria | journal = Current Opinion in Microbiology | volume = 16 | issue = 6 | pages = 779–785 | date = December 2013 | pmid = 24148302 | pmc = 3974409 | doi = 10.1016/j.mib.2013.09.007 }}</ref> It has also been implicated in non-pathogenic aspects of bacterial ecology, including surface adhesion, [[bacteriophage]] sensitivity, and interactions with predators such as [[amoebae]]. LPS is also required for the functioning of [[omptin]]s, a class of bacterial protease.<ref>{{cite journal | vauthors = Kukkonen M, Korhonen TK | title = The omptin family of enterobacterial surface proteases/adhesins: from housekeeping in Escherichia coli to systemic spread of Yersinia pestis | journal = International Journal of Medical Microbiology | volume = 294 | issue = 1 | pages = 7–14 | date = July 2004 | pmid = 15293449 | doi = 10.1016/j.ijmm.2004.01.003 }}</ref>
 ==Composition==
 [[File:Kdo2-lipidA.png|thumb|right|300px|The saccharolipid Kdo<sub>2</sub>-Lipid A. [[3-Deoxy-D-manno-oct-2-ulosonic acid|Kdo]] residues in {{red|red}} (core), glucosamine residues in {{blue|blue}}, acyl chains in {{black|black}} and phosphate groups in {{green|green}}.]]
-Lipopolysaccharides are composed of three parts: The O antigen (or O polysaccharide), the [[Core oligosaccharide]], and [[Lipid A]].
+Lipopolysaccharides are composed of three parts: the O antigen (or O polysaccharide), the [[core oligosaccharide]], and [[Lipid A]].
 === O-antigen ===
-The repetitive [[glycan]] [[polymer]] contained within an LPS is referred to as the O [[antigen]], O [[polysaccharide]], or O side-chain of the bacteria. The O antigen is attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. The composition of the O chain varies from strain to strain; there are over 160 different O antigen structures produced by different ''[[Escherichia coli|E. coli]]'' strains.<ref name="pmid12045108">{{Cite journal |vauthors=Raetz CR, Whitfield C |year=2002 |title=Lipopolysaccharide endotoxins |journal=Annu. Rev. Biochem. |volume=71 |pages=635–700 |doi=10.1146/annurev.biochem.71.110601.135414 |pmc=2569852 |pmid=12045108}}</ref> The presence or absence of O chains determines whether the LPS is considered "rough" or "smooth". Full-length O-chains would render the LPS smooth, whereas the absence or reduction of O-chains would make the LPS rough.<ref>{{Cite journal |vauthors=Rittig MG, Kaufmann A, Robins A, Shaw B, Sprenger H, Gemsa D, Foulongne V, Rouot B, Dornand J |year=2003 |title=Smooth and rough lipopolysaccharide phenotypes of Brucella induce different intracellular trafficking and cytokine/chemokine release in human monocytes |journal=J. Leukoc. Biol. |volume=74 |issue=6 |pages=1045–55 |doi=10.1189/jlb.0103015 |pmid=12960272 |doi-access=free}}</ref> Bacteria with rough LPS usually have more penetrable cell membranes to hydrophobic antibiotics, since a rough LPS is more [[hydrophobic]].<ref>{{Cite journal |vauthors=Tsujimoto H, Gotoh N, Nishino T |year=1999 |title=Diffusion of macrolide antibiotics through the outer membrane of Moraxella catarrhalis |journal=J. Infect. Chemother. |volume=5 |issue=4 |pages=196–200 |doi=10.1007/s101560050034 |pmid=11810516 |s2cid=2742306}}</ref> O antigen is exposed on the very outer surface of the bacterial cell, and, as a consequence, is a target for recognition by host [[antibody|antibodies]].
+The repetitive [[glycan]] [[polymer]] contained within an LPS is referred to as the O [[antigen]], O [[polysaccharide]], or O side-chain of the bacteria. The O antigen is attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. The composition of the O chain varies from strain to strain; there are over 160 different O antigen structures produced by different ''[[Escherichia coli|E. coli]]'' strains.<ref name="Raetz_2002">{{cite journal | vauthors = Raetz CR, Whitfield C | title = Lipopolysaccharide endotoxins | journal = Annual Review of Biochemistry | volume = 71 | pages = 635–700 | year = 2002 | pmid = 12045108 | pmc = 2569852 | doi = 10.1146/annurev.biochem.71.110601.135414 }}</ref> The presence or absence of O chains determines whether the LPS is considered "rough" or "smooth". Full-length O-chains would render the LPS smooth, whereas the absence or reduction of O-chains would make the LPS rough.<ref>{{cite journal | vauthors = Rittig MG, Kaufmann A, Robins A, Shaw B, Sprenger H, Gemsa D, Foulongne V, Rouot B, Dornand J | display-authors = 6 | title = Smooth and rough lipopolysaccharide phenotypes of Brucella induce different intracellular trafficking and cytokine/chemokine release in human monocytes | journal = Journal of Leukocyte Biology | volume = 74 | issue = 6 | pages = 1045–1055 | date = December 2003 | pmid = 12960272 | doi = 10.1189/jlb.0103015 | doi-access = free }}</ref> Bacteria with rough LPS usually have more penetrable cell membranes to hydrophobic antibiotics, since a rough LPS is more [[hydrophobic]].<ref>{{cite journal | vauthors = Tsujimoto H, Gotoh N, Nishino T | title = Diffusion of macrolide antibiotics through the outer membrane of Moraxella catarrhalis | journal = Journal of Infection and Chemotherapy | volume = 5 | issue = 4 | pages = 196–200 | date = December 1999 | pmid = 11810516 | doi = 10.1007/s101560050034 | s2cid = 2742306 }}</ref> O antigen is exposed on the very outer surface of the bacterial cell, and, as a consequence, is a target for recognition by host [[antibody|antibodies]].
 ===Core===
 {{main|Core oligosaccharide}}
-The core domain always contains an oligosaccharide component that attaches directly to [[lipid A]] and commonly contains [[sugar]]s such as [[heptose]] and [[3-Deoxy-D-manno-oct-2-ulosonic acid]] (also known as KDO, keto-deoxyoctulosonate).<ref>{{Cite journal |vauthors=Hershberger C, Binkley SB |year=1968 |title=Chemistry and metabolism of 3-deoxy-D-mannooctulosonic acid. I. Stereochemical determination |url=http://www.jbc.org/cgi/reprint/243/7/1578?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=3-Deoxy-D-mannooctulosonic+Acid+&searchid=1&FIRSTINDEX=0&volume=243&issue=7&resourcetype=HWCIT |journal=J. Biol. Chem. |volume=243 |issue=7 |pages=1578–84 |doi=10.1016/S0021-9258(18)93581-7 |pmid=4296687 |doi-access=free}}</ref>  The LPS cores of many bacteria also contain non-carbohydrate components, such as phosphate, amino acids, and ethanolamine substituents.
+The core domain always contains an oligosaccharide component that attaches directly to [[lipid A]] and commonly contains [[sugar]]s such as [[heptose]] and [[3-Deoxy-D-manno-oct-2-ulosonic acid]] (also known as KDO, keto-deoxyoctulosonate).<ref>{{cite journal | vauthors = Hershberger C, Binkley SB | title = Chemistry and metabolism of 3-deoxy-D-mannooctulosonic acid. I. Stereochemical determination | journal = The Journal of Biological Chemistry | volume = 243 | issue = 7 | pages = 1578–1584 | date = April 1968 | pmid = 4296687 | doi = 10.1016/S0021-9258(18)93581-7 | doi-access = free }}</ref>  The LPS cores of many bacteria also contain non-carbohydrate components, such as phosphate, amino acids, and ethanolamine substituents.
 ===Lipid A===
 {{main|Lipid A}}
-Lipid A is, in normal circumstances, a [[phosphorylated]] [[glucosamine]] [[disaccharide]] decorated with multiple [[fatty acids]]. These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane, and the rest of the LPS projects from the cell surface. The lipid A domain is responsible for much of the toxicity of [[Gram-negative bacteria]]. When bacterial cells are [[lysis|lysed]] by the [[immune system]], fragments of membrane containing lipid A are released into the circulation, causing fever, diarrhea, and possible fatal endotoxic shock (also called [[septic shock]]). The Lipid A moiety is a very conserved component of the LPS.<ref name="pmid11948150">{{Cite journal |vauthors=Tzeng YL, Datta A, Kolli VK, Carlson RW, Stephens DS |date=May 2002 |title=Endotoxin of Neisseria meningitidis composed only of intact lipid A: inactivation of the meningococcal 3-deoxy-D-manno-octulosonic acid transferase |journal=J. Bacteriol. |volume=184 |issue=9 |pages=2379–88 |doi=10.1128/JB.184.9.2379-2388.2002 |pmc=134985 |pmid=11948150}}</ref> However Lipid A structure varies among bacterial species. Lipid A structure largely defines the degree and nature of the overall host immune activation.<ref>{{Cite journal |last1=Khan |first1=Mohd M. |last2=Ernst |first2=Orna |last3=Sun |first3=Jing |last4=Fraser |first4=Iain D. C. |last5=Ernst |first5=Robert K. |last6=Goodlett |first6=David R. |last7=Nita-Lazar |first7=Aleksandra |date=24 June 2018 |title=Mass Spectrometry-based Structural Analysis and Systems Immunoproteomics Strategies for Deciphering the Host Response to Endotoxin |journal=Journal of Molecular Biology |volume=430 |issue=17 |pages=2641–2660 |doi=10.1016/j.jmb.2018.06.032 |issn=1089-8638 |pmid=29949751 |s2cid=49481716}}</ref>
+Lipid A is, in normal circumstances, a [[phosphorylated]] [[glucosamine]] [[disaccharide]] decorated with multiple [[fatty acids]]. These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane, and the rest of the LPS projects from the cell surface. The lipid A domain is responsible for much of the toxicity of [[Gram-negative bacteria]]. When bacterial cells are [[lysis|lysed]] by the [[immune system]], fragments of membrane containing lipid A are released into the circulation, causing fever, diarrhea, and possible fatal endotoxic shock (also called [[septic shock]]). The Lipid A moiety is a very conserved component of the LPS.<ref name="Tzeng_2002">{{cite journal | vauthors = Tzeng YL, Datta A, Kolli VK, Carlson RW, Stephens DS | title = Endotoxin of Neisseria meningitidis composed only of intact lipid A: inactivation of the meningococcal 3-deoxy-D-manno-octulosonic acid transferase | journal = Journal of Bacteriology | volume = 184 | issue = 9 | pages = 2379–2388 | date = May 2002 | pmid = 11948150 | pmc = 134985 | doi = 10.1128/JB.184.9.2379-2388.2002 }}</ref> However Lipid A structure varies among bacterial species. Lipid A structure largely defines the degree and nature of the overall host immune activation.<ref>{{cite journal | vauthors = Khan MM, Ernst O, Sun J, Fraser ID, Ernst RK, Goodlett DR, Nita-Lazar A | title = Mass Spectrometry-based Structural Analysis and Systems Immunoproteomics Strategies for Deciphering the Host Response to Endotoxin | journal = Journal of Molecular Biology | volume = 430 | issue = 17 | pages = 2641–2660 | date = August 2018 | pmid = 29949751 | doi = 10.1016/j.jmb.2018.06.032 | s2cid = 49481716 }}</ref>
 ==Lipooligosaccharides==
-The "rough form" of LPS has a lower molecular weight due to the absence of the O polysaccharide. In its place is   a short oligosaccharide: this form is known as Lipooligosaccharide (LOS), and is a glycolipid found in the outer membrane of some types of [[Gram-negative bacteria]], such as ''[[Neisseria]]'' spp. and ''[[Haemophilus]]'' spp.<ref name="Moran_et_al">{{Cite journal |vauthors=Moran AP, Prendergast MM, Appelmelk BJ |year=1996 |title=Molecular mimicry of host structures by bacterial lipopolysaccharides and its contribution to disease |journal=FEMS Immunol. Med. Microbiol. |volume=16 |issue=2 |pages=105–15 |doi=10.1016/s0928-8244(96)00072-7 |pmid=8988391 |doi-access=free}}</ref><ref name="Kilar_et_al">{{Cite journal |vauthors=Kilár A, Dörnyei Á, Kocsis B |year=2013 |title=Structural characterization of bacterial lipopolysaccharides with mass spectrometry and on- and off-line separation techniques |journal=Mass Spectrom Rev |volume=32 |issue=2 |pages=90–117 |bibcode=2013MSRv...32...90K |doi=10.1002/mas.21352 |pmid=23165926}}</ref>  LOS plays a central role in maintaining the integrity and functionality of the outer membrane of the [[Gram negative]] cell envelope. LOS play an important role in the pathogenesis of certain bacterial infections because they are capable of acting as [[immunostimulant|immunostimulators]] and immunomodulators.<ref name="Moran_et_al" /> Furthermore, LOS molecules are responsible for the ability of some bacterial strains to display molecular [[mimicry]] and [[antigenic variation|antigenic diversity]], aiding in the evasion of host immune defenses and thus contributing to the [[virulence]] of these bacterial [[strain (biology)|strains]]. In the case of ''[[Neisseria meningitidis]]'', the [[lipid A]] portion of the molecule has a symmetrical structure and the inner core is composed of [[3-Deoxy-D-manno-oct-2-ulosonic acid|3-deoxy-D-manno-2-octulosonic acid]] (KDO) and [[heptose]] (Hep) moieties. The outer core oligosaccharide chain varies depending on the bacterial [[strain (biology)|strain]].<ref name="Moran_et_al" /><ref name="Kilar_et_al" />
+The "rough form" of LPS has a lower molecular weight due to the absence of the O polysaccharide. In its place is   a short oligosaccharide: this form is known as Lipooligosaccharide (LOS), and is a glycolipid found in the outer membrane of some types of [[Gram-negative bacteria]], such as ''[[Neisseria]]'' spp. and ''[[Haemophilus]]'' spp.<ref name="Moran_1996">{{cite journal | vauthors = Moran AP, Prendergast MM, Appelmelk BJ | title = Molecular mimicry of host structures by bacterial lipopolysaccharides and its contribution to disease | journal = FEMS Immunology and Medical Microbiology | volume = 16 | issue = 2 | pages = 105–115 | date = December 1996 | pmid = 8988391 | doi = 10.1016/s0928-8244(96)00072-7 | doi-access = free }}</ref><ref name="Kilar_2013">{{cite journal | vauthors = Kilár A, Dörnyei Á, Kocsis B | title = Structural characterization of bacterial lipopolysaccharides with mass spectrometry and on- and off-line separation techniques | journal = Mass Spectrometry Reviews | volume = 32 | issue = 2 | pages = 90–117 | year = 2013 | pmid = 23165926 | doi = 10.1002/mas.21352 | bibcode = 2013MSRv...32...90K }}</ref>  LOS plays a central role in maintaining the integrity and functionality of the outer membrane of the [[Gram negative]] cell envelope. LOS play an important role in the pathogenesis of certain bacterial infections because they are capable of acting as [[immunostimulant|immunostimulators]] and immunomodulators.<ref name="Moran_1996" /> Furthermore, LOS molecules are responsible for the ability of some bacterial strains to display molecular [[mimicry]] and [[antigenic variation|antigenic diversity]], aiding in the evasion of host immune defenses and thus contributing to the [[virulence]] of these bacterial [[strain (biology)|strains]]. In the case of ''[[Neisseria meningitidis]]'', the [[lipid A]] portion of the molecule has a symmetrical structure and the inner core is composed of [[3-Deoxy-D-manno-oct-2-ulosonic acid|3-deoxy-D-manno-2-octulosonic acid]] (KDO) and [[heptose]] (Hep) moieties. The outer core oligosaccharide chain varies depending on the bacterial [[strain (biology)|strain]].<ref name="Moran_1996" /><ref name="Kilar_2013" />
 ==LPS detoxification ==
-A highly conserved host enzyme called [[acyloxyacyl hydrolase]] (AOAH) may detoxify LPS when it enters, or is produced in, animal tissues. It may also convert LPS in the intestine into an LPS inhibitor. Neutrophils, macrophages and dendritic cells produce this lipase, which inactivates LPS by removing the two secondary acyl chains from lipid A to produce tetraacyl LPS.  If mice are given LPS parenterally, those that lack AOAH develop high titers of non-specific antibodies, develop prolonged hepatomegaly, and experience prolonged endotoxin tolerance. LPS inactivation may be required for animals to restore homeostasis after parenteral LPS exposure.<ref>{{Cite book |title=Kill the Bacteria...and Also Their Messengers? |vauthors=Munford R, Lu M, Varley AW |date=2009 |series=Advances in Immunology |isbn=9780123748324 |volume=103 |pages=29–48 |doi=10.1016/S0065-2776(09)03002-8 |pmc=2812913 |pmid=19755182}}</ref>  Although mice have many other mechanisms for inhibiting LPS signaling, none is able to prevent these changes in animals that lack AOAH.
+A highly conserved host enzyme called [[acyloxyacyl hydrolase]] (AOAH) may detoxify LPS when it enters, or is produced in, animal tissues. It may also convert LPS in the intestine into an LPS inhibitor. Neutrophils, macrophages and dendritic cells produce this lipase, which inactivates LPS by removing the two secondary acyl chains from lipid A to produce tetraacyl LPS.  If mice are given LPS parenterally, those that lack AOAH develop high titers of non-specific antibodies, develop prolonged hepatomegaly, and experience prolonged endotoxin tolerance. LPS inactivation may be required for animals to restore homeostasis after parenteral LPS exposure.<ref>{{Cite book |title=Chapter 2 Kill the Bacteria…and Also Their Messengers? |vauthors=Munford R, Lu M, Varley AW |date=2009 |series=Advances in Immunology |isbn=9780123748324 |volume=103 |pages=29–48 |doi=10.1016/S0065-2776(09)03002-8 |pmc=2812913 |pmid=19755182}}</ref>  Although mice have many other mechanisms for inhibiting LPS signaling, none is able to prevent these changes in animals that lack AOAH.
-Dephosphorylation of LPS by [[Alkaline phosphatase#Intestinal alkaline phosphatase|intestinal alkaline phosphatase]] can reduce the severity of ''[[Salmonella tryphimurium]]'' and ''[[Clostridioides difficile]]'' [[Clostridioides difficile infection|infection]] restoring normal gut microbiota.<ref name="pmid28316376">{{Cite journal |vauthors=Bilski J, Mazur-Bialy A, Wojcik D, Zahradnik-Bilska J, Brzozowski B, Magierowski M, Mach T, Magierowska K, Brzozowski T |date=2017 |title=The Role of Intestinal Alkaline Phosphatase in Inflammatory Disorders of Gastrointestinal Tract |journal=[[List of Hindawi academic journals#M|Mediators of Inflammation]] |volume=2017 |pages=9074601 |doi=10.1155/2017/9074601 |pmc=5339520 |pmid=28316376 |doi-access=free}}</ref> [[Alkaline phosphatase]] prevents intestinal inflammation (and
+Dephosphorylation of LPS by [[Alkaline phosphatase#Intestinal alkaline phosphatase|intestinal alkaline phosphatase]] can reduce the severity of ''[[Salmonella tryphimurium]]'' and ''[[Clostridioides difficile]]'' [[Clostridioides difficile infection|infection]] restoring normal gut microbiota.<ref name="Bilski_2017">{{cite journal | vauthors = Bilski J, Mazur-Bialy A, Wojcik D, Zahradnik-Bilska J, Brzozowski B, Magierowski M, Mach T, Magierowska K, Brzozowski T | display-authors = 6 | title = The Role of Intestinal Alkaline Phosphatase in Inflammatory Disorders of Gastrointestinal Tract | journal = Mediators of Inflammation | volume = 2017 | pages = 9074601 | date = 2017 | pmid = 28316376 | pmc = 5339520 | doi = 10.1155/2017/9074601 | doi-access = free }}</ref> [[Alkaline phosphatase]] prevents intestinal inflammation (and
-"[[Intestinal permeability|leaky gut]]") from bacteria by dephosphorylating the Lipid&nbsp;A portion of LPS.<ref name="pmid18078689">{{Cite journal |vauthors=Bates JM, Akerlund J, Mittge E, Guillemin K |year=2007 |title=Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota |journal=[[Cell Host & Microbe]] |volume=2 |issue=6 |pages=371–382 |doi=10.1016/j.chom.2007.10.010 |pmc=2730374 |pmid=18078689}}</ref><ref>{{Cite journal |vauthors=Alam SN, Yammine H, Moaven O, Ahmed R, Moss AK, Biswas B, Muhammad N, Biswas R, Raychowdhury A, Kaliannan K, Ghosh S, Ray M, Hamarneh SR, Barua S, Malo NS, Bhan AK, Malo MS, Hodin RA |date=April 2014 |title=Intestinal alkaline phosphatase prevents antibiotic-induced susceptibility to enteric pathogens |journal=Annals of Surgery |volume=259 |issue=4 |pages=715–22 |doi=10.1097/sla.0b013e31828fae14 |pmc=3855644 |pmid=23598380}}</ref><ref>{{Cite journal |vauthors=Lallès JP |date=February 2014 |title=Intestinal alkaline phosphatase: novel functions and protective effects |journal=Nutrition Reviews |volume=72 |issue=2 |pages=82–94 |doi=10.1111/nure.12082 |pmid=24506153}}</ref>
+"[[Intestinal permeability|leaky gut]]") from bacteria by dephosphorylating the Lipid&nbsp;A portion of LPS.<ref name="Bates_2007">{{cite journal | vauthors = Bates JM, Akerlund J, Mittge E, Guillemin K | title = Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota | journal = Cell Host & Microbe | volume = 2 | issue = 6 | pages = 371–382 | date = December 2007 | pmid = 18078689 | pmc = 2730374 | doi = 10.1016/j.chom.2007.10.010 }}</ref><ref>{{cite journal | vauthors = Alam SN, Yammine H, Moaven O, Ahmed R, Moss AK, Biswas B, Muhammad N, Biswas R, Raychowdhury A, Kaliannan K, Ghosh S, Ray M, Hamarneh SR, Barua S, Malo NS, Bhan AK, Malo MS, Hodin RA | display-authors = 6 | title = Intestinal alkaline phosphatase prevents antibiotic-induced susceptibility to enteric pathogens | journal = Annals of Surgery | volume = 259 | issue = 4 | pages = 715–722 | date = April 2014 | pmid = 23598380 | pmc = 3855644 | doi = 10.1097/sla.0b013e31828fae14 }}</ref><ref>{{cite journal | vauthors = Lallès JP | title = Intestinal alkaline phosphatase: novel functions and protective effects | journal = Nutrition Reviews | volume = 72 | issue = 2 | pages = 82–94 | date = February 2014 | pmid = 24506153 | doi = 10.1111/nure.12082 | doi-access = free }}</ref>
 ==Biosynthesis and transport==
-{{Clear}}[[File:LPS-Assembly.svg|thumb|left|380px|'''LPS final assembly:''' [[O antigen|O-antigen]] subunits are translocated across the inner membrane (by Wzx) where they are polymerized (by Wzy, chain length determined by Wzz) and ligated (by WaaL) on to complete Core-[[Lipid A]] molecules (which were translocated by MsbA).<ref name="Wang">{{Cite journal |vauthors=Wang X, Quinn PJ |year=2010 |title=Lipopolysaccharide: Biosynthetic pathway and structure modification |journal=Prog. Lipid Res. |volume=49 |issue=2 |pages=97–107 |doi=10.1016/j.plipres.2009.06.002 |pmid=19815028}}</ref>]] [[File:LPS-Transport.svg|thumb|left|380px|'''LPS transport:''' Completed LPS molecules are transported across the periplasm and outer membrane by the proteins [[LptA]], B, C, D, E, F, and G<ref name="ruiz">{{Cite journal |vauthors=Ruiz N, Kahne D, Silhavy TJ |year=2009 |title=Transport of lipopolysaccharide across the cell envelope: the long road of discovery |journal=Nat. Rev. Microbiol. |volume=7 |issue=9 |pages=677–83 |doi=10.1038/nrmicro2184 |pmc=2790178 |pmid=19633680}}</ref>]]
 {{clear}}
+[[File:LPS-Assembly.svg|thumb|left|380px|'''LPS final assembly:''' [[O antigen|O-antigen]] subunits are translocated across the inner membrane (by Wzx) where they are polymerized (by Wzy, chain length determined by Wzz) and ligated (by WaaL) on to complete Core-[[Lipid A]] molecules (which were translocated by MsbA).<ref name="Wang_2010">{{cite journal | vauthors = Wang X, Quinn PJ | title = Lipopolysaccharide: Biosynthetic pathway and structure modification | journal = Progress in Lipid Research | volume = 49 | issue = 2 | pages = 97–107 | date = April 2010 | pmid = 19815028 | doi = 10.1016/j.plipres.2009.06.002 }}</ref>]] [[File:LPS-Transport.svg|thumb|left|380px|'''LPS transport:''' Completed LPS molecules are transported across the [[periplasm]] and outer membrane by the lipopolysaccharide transport (Lpt) proteins A, B, C, D, E, F, and G.<ref name="Ruiz_2009">{{cite journal | vauthors = Ruiz N, Kahne D, Silhavy TJ | title = Transport of lipopolysaccharide across the cell envelope: the long road of discovery | journal = Nature Reviews. Microbiology | volume = 7 | issue = 9 | pages = 677–683 | date = September 2009 | pmid = 19633680 | pmc = 2790178 | doi = 10.1038/nrmicro2184 }}</ref>]]
-<ref>{{Cite journal |last=Romano |first=K.P. |last2=Hung |first2=D.T. |date=2023-03 |title=Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance |url=https://linkinghub.elsevier.com/retrieve/pii/S0167488922001999 |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |language=en |volume=1870 |issue=3 |pages=119407 |doi=10.1016/j.bbamcr.2022.119407 |pmc=PMC9922520 |pmid=36543281}}</ref>The entire process of making LPS starts with a molecule called lipid A-Kdo2, which is first created on the surface of a cell's inner membrane. Then, additional sugars are added to this molecule on the inner membrane before it's moved to the space between the inner and outer membranes with the help of a protein called MsbA. The O-antigen, another part of LPS, is made by special enzyme complexes on the inner membrane. It's then moved to the outer membrane through three different systems: one is Wzy-dependent, another relies on ABC transporters, and the third involves a synthase-dependent process.
+{{clear}}
+The entire process of making LPS starts with a molecule called lipid A-Kdo2, which is first created on the surface of the bacterial cell's inner membrane. Then, additional sugars are added to this molecule on the inner membrane before it's moved to the space between the inner and outer membranes ([[periplasmic space]]) with the help of a protein called MsbA. The O-antigen, another part of LPS, is made by special enzyme complexes on the inner membrane. It is then moved to the outer membrane through three different systems: one is Wzy-dependent, another relies on ABC transporters, and the third involves a synthase-dependent process.<ref name="Romano_2003">{{cite journal | vauthors = Romano KP, Hung DT | title = Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance | journal = Biochimica et Biophysica Acta. Molecular Cell Research | volume = 1870 | issue = 3 | pages = 119407 | date = March 2023 | pmid = 36543281 | pmc = 9922520 | doi = 10.1016/j.bbamcr.2022.119407 }}</ref>
+Ultimately, LPS is transported to the outer membrane by a membrane-to-membrane bridge of lipolysaccharide transport (Lpt) proteins.<ref name="Ruiz_2009" /><ref>{{cite journal | vauthors = Sherman DJ, Xie R, Taylor RJ, George AH, Okuda S, Foster PJ, Needleman DJ, Kahne D | display-authors = 6 | title = Lipopolysaccharide is transported to the cell surface by a membrane-to-membrane protein bridge | journal = Science | volume = 359 | issue = 6377 | pages = 798–801 | date = February 2018 | pmid = 29449493 | pmc = 5858563 | doi = 10.1126/science.aar1886 }}</ref> This transporter is a potential antibiotic target.<ref>{{cite journal | vauthors = Pahil KS, Gilman MS, Baidin V, Clairfeuille T, Mattei P, Bieniossek C, Dey F, Muri D, Baettig R, Lobritz M, Bradley K, Kruse AC, Kahne D | display-authors = 6 | title = A new antibiotic traps lipopolysaccharide in its intermembrane transporter | journal = Nature | pages = 572–577 | date = January 2024 | volume = 625 | issue = 7995 | doi = 10.1038/s41586-023-06799-7 | doi-access = free | pmid = 38172635 | pmc = 10794137 }}</ref><ref>{{cite journal | vauthors = Zampaloni C, Mattei P, Bleicher K, Winther L, Thäte C, Bucher C, Adam JM, Alanine A, Amrein KE, Baidin V, Bieniossek C, Bissantz C, Boess F, Cantrill C, Clairfeuille T, Dey F, Di Giorgio P, du Castel P, Dylus D, Dzygiel P, Felici A, García-Alcalde F, Haldimann A, Leipner M, Leyn S, Louvel S, Misson P, Osterman A, Pahil K, Rigo S, Schäublin A, Scharf S, Schmitz P, Stoll T, Trauner A, Zoffmann S, Kahne D, Young JA, Lobritz MA, Bradley KA | display-authors = 6 | title = A novel antibiotic class targeting the lipopolysaccharide transporter | journal = Nature | pages = 566–571 | date = January 2024 | volume = 625 | issue = 7995 | pmid = 38172634 | doi = 10.1038/s41586-023-06873-0 | doi-access = free | pmc = 10794144 }}</ref>
 ==Biological effects on hosts infected with Gram-negative bacteria==
 ===Immune response===
-LPS acts as the prototypical endotoxin because it binds the [[CD14]]/[[TLR 4|TLR4]]/[[Lymphocyte antigen 96|MD2]] [[receptor (biochemistry)|receptor]] complex in many cell types, but especially in [[monocytes]], [[dendritic cells]], [[macrophage]]s and [[B cell]]s, which promotes the secretion of pro-[[inflammation|inflammatory]] [[cytokine]]s, [[nitric oxide]], and [[eicosanoids]].<ref>{{Cite book |last=Abbas |first=Abul |title=Basic Immunology |publisher=Elsevier |year=2006 |isbn=978-1-4160-2974-8}}</ref> [[Bruce Beutler]] was awarded a portion of the 2011 Nobel Prize in Physiology or Medicine for his work demonstrating that [[TLR4]] is the LPS receptor.<ref>{{Cite journal |vauthors=Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B |year=1998 |title=Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene |journal=Science |volume=282 |issue=5396 |pages=2085–8 |bibcode=1998Sci...282.2085P |doi=10.1126/science.282.5396.2085 |pmid=9851930}}</ref><ref>{{Cite web |title=The 2011 Nobel Prize in Physiology or Medicine - Press Release |url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/press.html |url-status=live |archive-url=https://web.archive.org/web/20180323183552/https://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/press.html |archive-date=23 March 2018 |access-date=28 April 2018 |website=www.nobelprize.org}}</ref>
+LPS acts as the prototypical endotoxin because it binds the [[CD14]]/[[TLR 4|TLR4]]/[[Lymphocyte antigen 96|MD2]] [[receptor (biochemistry)|receptor]] complex in many cell types, but especially in [[monocytes]], [[dendritic cells]], [[macrophage]]s and [[B cell]]s, which promotes the secretion of pro-[[inflammation|inflammatory]] [[cytokine]]s, [[nitric oxide]], and [[eicosanoids]].<ref>{{Cite book | vauthors = Abbas A |title=Basic Immunology |publisher=Elsevier |year=2006 |isbn=978-1-4160-2974-8}}</ref> [[Bruce Beutler]] was awarded a portion of the 2011 Nobel Prize in Physiology or Medicine for his work demonstrating that [[TLR4]] is the LPS receptor.<ref>{{cite journal | vauthors = Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B | display-authors = 6 | title = Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene | journal = Science | volume = 282 | issue = 5396 | pages = 2085–2088 | date = December 1998 | pmid = 9851930 | doi = 10.1126/science.282.5396.2085 | bibcode = 1998Sci...282.2085P }}</ref><ref>{{Cite web |title=The 2011 Nobel Prize in Physiology or Medicine - Press Release |url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/press.html |url-status=live |archive-url=https://web.archive.org/web/20180323183552/https://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/press.html |archive-date=23 March 2018 |access-date=28 April 2018 |website=www.nobelprize.org}}</ref>
-As part of the cellular [[stress response]], [[superoxide]] is one of the major [[reactive oxygen species]] induced by LPS in various cell types that express TLR ([[toll-like receptor]]).<ref>{{Cite journal |last1=Li |first1=Yao |last2=Deng |first2=Shou-Long |last3=Lian |first3=Zheng-Xing |last4=Yu |first4=Kun |date=12 June 2019 |title=Roles of Toll-Like Receptors in Nitroxidative Stress in Mammals |journal=Cells |volume=8 |issue=6 |page=576 |doi=10.3390/cells8060576 |issn=2073-4409 |pmc=6627996 |pmid=31212769 |doi-access=free}}</ref> LPS is also an exogenous [[Pyrogen (fever)|pyrogen]] (fever-inducing substance).<ref name=":2" />
+As part of the cellular [[stress response]], [[superoxide]] is one of the major [[reactive oxygen species]] induced by LPS in various cell types that express TLR ([[toll-like receptor]]).<ref>{{cite journal | vauthors = Li Y, Deng SL, Lian ZX, Yu K | title = Roles of Toll-Like Receptors in Nitroxidative Stress in Mammals | journal = Cells | volume = 8 | issue = 6 | page = 576 | date = June 2019 | pmid = 31212769 | pmc = 6627996 | doi = 10.3390/cells8060576 | doi-access = free }}</ref> LPS is also an exogenous [[Pyrogen (fever)|pyrogen]] (fever-inducing substance).<ref name="Roth_2014" />
-LPS function has been under experimental research for several years due to its role in activating many [[transcription factor]]s. LPS also produces many types of mediators involved in [[septic shock]]. Humans are much more sensitive to LPS than other animals (e.g., mice). A dose of 1&nbsp;µg/kg induces shock in humans, but mice will tolerate a dose up to a thousand times higher.<ref>{{Cite journal |vauthors=Warren HS, Fitting C, Hoff E, Adib-Conquy M, Beasley-Topliffe L, Tesini B, Liang X, Valentine C, Hellman J, Hayden D, Cavaillon JM |year=2010 |title=Resilience to bacterial infection: difference between species could be due to proteins in serum |journal=J. Infect. Dis. |volume=201 |issue=2 |pages=223–32 |doi=10.1086/649557 |pmc=2798011 |pmid=20001600}}</ref> This may relate to differences in the level of circulating natural antibodies between the two species.<ref>{{Cite journal |vauthors=Reid RR, Prodeus AP, Khan W, Hsu T, Rosen FS, Carroll MC |year=1997 |title=Endotoxin shock in antibody-deficient mice: unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide |journal=J. Immunol. |volume=159 |issue=2 |pages=970–5 |doi=10.4049/jimmunol.159.2.970 |pmid=9218618|doi-access=free }}</ref><ref>{{Cite journal |vauthors=Boes M, Prodeus AP, Schmidt T, Carroll MC, Chen J |year=1998 |title=A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection |journal=J. Exp. Med. |volume=188 |issue=12 |pages=2381–6 |doi=10.1084/jem.188.12.2381 |pmc=2212438 |pmid=9858525}}</ref>
+LPS function has been under experimental research for several years due to its role in activating many [[transcription factor]]s. LPS also produces many types of mediators involved in [[septic shock]]. Humans are much more sensitive to LPS than other animals (e.g., mice). A dose of 1&nbsp;μg/kg induces shock in humans, but mice will tolerate a dose up to a thousand times higher.<ref>{{cite journal | vauthors = Warren HS, Fitting C, Hoff E, Adib-Conquy M, Beasley-Topliffe L, Tesini B, Liang X, Valentine C, Hellman J, Hayden D, Cavaillon JM | display-authors = 6 | title = Resilience to bacterial infection: difference between species could be due to proteins in serum | journal = The Journal of Infectious Diseases | volume = 201 | issue = 2 | pages = 223–232 | date = January 2010 | pmid = 20001600 | pmc = 2798011 | doi = 10.1086/649557 }}</ref> This may relate to differences in the level of circulating natural antibodies between the two species.<ref>{{cite journal | vauthors = Reid RR, Prodeus AP, Khan W, Hsu T, Rosen FS, Carroll MC | title = Endotoxin shock in antibody-deficient mice: unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide | journal = Journal of Immunology | volume = 159 | issue = 2 | pages = 970–975 | date = July 1997 | pmid = 9218618 | doi = 10.4049/jimmunol.159.2.970 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Boes M, Prodeus AP, Schmidt T, Carroll MC, Chen J | title = A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection | journal = The Journal of Experimental Medicine | volume = 188 | issue = 12 | pages = 2381–2386 | date = December 1998 | pmid = 9858525 | pmc = 2212438 | doi = 10.1084/jem.188.12.2381 }}</ref>
-Said et al. showed that LPS causes an [[Interleukin 10|IL-10]]-dependent inhibition of [[CD4 T-cell]] expansion and function by up-regulating [[PD-1]] levels on [[monocytes]] which leads to IL-10 production by monocytes after binding of PD-1 by [[PD-L1]].<ref>{{Cite journal |vauthors=Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP |year=2010 |title=Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection |journal=Nat. Med. |volume=16 |issue=4 |pages=452–9 |doi=10.1038/nm.2106 |pmc=4229134 |pmid=20208540}}</ref>
+Said et al. showed that LPS causes an [[Interleukin 10|IL-10]]-dependent inhibition of [[CD4 T-cell]] expansion and function by up-regulating [[PD-1]] levels on [[monocytes]] which leads to IL-10 production by monocytes after binding of PD-1 by [[PD-L1]].<ref>{{cite journal | vauthors = Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP | display-authors = 6 | title = Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection | journal = Nature Medicine | volume = 16 | issue = 4 | pages = 452–459 | date = April 2010 | pmid = 20208540 | pmc = 4229134 | doi = 10.1038/nm.2106 }}</ref>
 Endotoxins are in large part responsible for the dramatic clinical manifestations of infections with pathogenic Gram-negative bacteria, such as ''[[Neisseria meningitidis]]'', the pathogens that causes [[meningococcal disease]], including [[meningococcemia]], [[Waterhouse–Friderichsen syndrome]], and [[meningitis]].
-Portions of the LPS from several bacterial strains have been shown to be chemically similar to human host cell surface molecules; the ability of some bacteria to present molecules on their surface which are chemically identical or similar to the surface molecules of some types of host cells is termed molecular [[mimicry]].<ref name="Chastain_and_Miller">{{Cite journal |vauthors=Chastain EM, Miller SD |year=2012 |title=Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease |journal=Immunol. Rev. |volume=245 |issue=1 |pages=227–38 |doi=10.1111/j.1600-065X.2011.01076.x |pmc=3586283 |pmid=22168423}}</ref>  For example, in ''[[Neisseria meningitidis]]'' L2,3,5,7,9, the terminal tetrasaccharide portion of the oligosaccharide (lacto-N-neotetraose) is the same tetrasaccharide as that found in [[paragloboside]], a precursor for [[ABO blood group system|ABH]] [[glycolipid]] antigens found on human [[erythrocyte]]s.<ref name="Moran_et_al" /> In another example, the terminal trisaccharide portion (lactotriaose) of the oligosaccharide from pathogenic ''[[Neisseria]]'' spp. LOS is also found in lactoneoseries [[glycosphingolipid]]s from human cells.<ref name="Moran_et_al" />  Most meningococci from groups B and C, as well as [[Neisseria gonorrhoeae|gonococci]], have been shown to have this trisaccharide as part of their LOS structure.<ref name="Moran_et_al" />  The presence of these human cell surface 'mimics' may, in addition to acting as a 'camouflage' from the immune system, play a role in the abolishment of [[immune tolerance]] when infecting hosts with certain [[human leukocyte antigen]] (HLA) genotypes, such as [[HLA-B35]].<ref name="Moran_et_al" />
+Portions of the LPS from several bacterial strains have been shown to be chemically similar to human host cell surface molecules; the ability of some bacteria to present molecules on their surface which are chemically identical or similar to the surface molecules of some types of host cells is termed molecular [[mimicry]].<ref name="Chastain_2012">{{cite journal | vauthors = Chastain EM, Miller SD | title = Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease | journal = Immunological Reviews | volume = 245 | issue = 1 | pages = 227–238 | date = January 2012 | pmid = 22168423 | pmc = 3586283 | doi = 10.1111/j.1600-065X.2011.01076.x }}</ref>  For example, in ''[[Neisseria meningitidis]]'' L2,3,5,7,9, the terminal tetrasaccharide portion of the oligosaccharide (lacto-N-neotetraose) is the same tetrasaccharide as that found in [[paragloboside]], a precursor for [[ABO blood group system|ABH]] [[glycolipid]] antigens found on human [[erythrocyte]]s.<ref name="Moran_1996" /> In another example, the terminal trisaccharide portion (lactotriaose) of the oligosaccharide from pathogenic ''[[Neisseria]]'' spp. LOS is also found in lactoneoseries [[glycosphingolipid]]s from human cells.<ref name="Moran_1996" />  Most meningococci from groups B and C, as well as [[Neisseria gonorrhoeae|gonococci]], have been shown to have this trisaccharide as part of their LOS structure.<ref name="Moran_1996" />  The presence of these human cell surface 'mimics' may, in addition to acting as a 'camouflage' from the immune system, play a role in the abolishment of [[immune tolerance]] when infecting hosts with certain [[human leukocyte antigen]] (HLA) genotypes, such as [[HLA-B35]].<ref name="Moran_1996" />
-LPS can be sensed directly by [[hematopoietic stem cell]]s (HSCs) through the bonding with TLR4, causing them to proliferate in reaction to a systemic infection.  This response activate the TLR4-TRIF-ROS-p38 signaling within the HSCs and through a sustained TLR4 activation can cause a proliferative stress, leading to impair their competitive repopulating ability.<ref>{{Cite journal |last1=Takizawa |first1=Hitoshi |last2=Fritsch |first2=Kristin |last3=Kovtonyuk |first3=Larisa V. |last4=Saito |first4=Yasuyuki |last5=Yakkala |first5=Chakradhar |last6=Jacobs |first6=Kurt |last7=Ahuja |first7=Akshay K. |last8=Lopes |first8=Massimo |last9=Hausmann |first9=Annika |date=3 August 2017 |title=Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness |journal=Cell Stem Cell |volume=21 |issue=2 |pages=225–240.e5 |doi=10.1016/j.stem.2017.06.013 |issn=1875-9777 |pmid=28736216 |doi-access=free}}</ref>  Infection in mice using ''[[S. typhimurium]]'' showed similar results, validating the experimental model also ''in vivo''.
+LPS can be sensed directly by [[hematopoietic stem cell]]s (HSCs) through the bonding with TLR4, causing them to proliferate in reaction to a systemic infection.  This response activate the TLR4-TRIF-ROS-p38 signaling within the HSCs and through a sustained TLR4 activation can cause a proliferative stress, leading to impair their competitive repopulating ability.<ref>{{cite journal | vauthors = Takizawa H, Fritsch K, Kovtonyuk LV, Saito Y, Yakkala C, Jacobs K, Ahuja AK, Lopes M, Hausmann A, Hardt WD, Gomariz Á, Nombela-Arrieta C, Manz MG | display-authors = 6 | title = Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness | journal = Cell Stem Cell | volume = 21 | issue = 2 | pages = 225–240.e5 | date = August 2017 | pmid = 28736216 | doi = 10.1016/j.stem.2017.06.013 | doi-access = free }}</ref>  Infection in mice using ''[[S. typhimurium]]'' showed similar results, validating the experimental model also ''in vivo''.
 ===Effect of variability on immune response===
 [[File:Toll-like receptor pathways revised.jpg|thumbnail|right|300px|[[Toll-like receptor]]s of the [[innate immune system]] recognize LPS and trigger an [[immune response]].]]
-O-antigens (the outer carbohydrates) are the most variable portion of the LPS molecule, imparting antigenic specificity. In contrast, lipid A is the most conserved part. However, lipid A composition also may vary (e.g., in number and nature of [[acyl]] chains even within or between genera). Some of these variations may impart antagonistic properties to these LPS. For example, diphosphoryl lipid A of ''[[Rhodobacter sphaeroides]]'' (RsDPLA) is a potent antagonist of LPS in human cells, but is an agonist in hamster and equine cells.<ref>{{cite journal|vauthors=Lohmann KL, Vandenplas ML, Barton MH, Bryant CE, Moore JN|title=The equine TLR4/MD-2 complex mediates recognition of lipopolysaccharide from ''Rhodobacter sphaeroides'' as an agonist|journal=Journal of Endotoxin Research|volume=13|issue=4|pages=235–242|year=2007|doi=10.1177/0968051907083193|pmid=17956942|s2cid=36784237 |doi-access=}}</ref>
+O-antigens (the outer carbohydrates) are the most variable portion of the LPS molecule, imparting antigenic specificity. In contrast, lipid A is the most conserved part. However, lipid A composition also may vary (e.g., in number and nature of [[acyl]] chains even within or between genera). Some of these variations may impart antagonistic properties to these LPS. For example, diphosphoryl lipid A of ''[[Rhodobacter sphaeroides]]'' (RsDPLA) is a potent antagonist of LPS in human cells, but is an agonist in hamster and equine cells.<ref>{{cite journal | vauthors = Lohmann KL, Vandenplas ML, Barton MH, Bryant CE, Moore JN | title = The equine TLR4/MD-2 complex mediates recognition of lipopolysaccharide from Rhodobacter sphaeroides as an agonist | journal = Journal of Endotoxin Research | volume = 13 | issue = 4 | pages = 235–242 | year = 2007 | pmid = 17956942 | doi = 10.1177/0968051907083193 | s2cid = 36784237 | doi-access =  }}</ref>
-It has been speculated that conical lipid A (e.g., from ''[[Escherichia coli|E. coli]]'') is more agonistic, while less conical lipid A like that of ''Porphyromonas gingivalis'' may activate a different signal ([[TLR2]] instead of TLR4), and completely cylindrical lipid A like that of ''Rhodobacter sphaeroides'' is antagonistic to TLRs.<ref>{{Cite journal |vauthors=Netea MG, van Deuren M, Kullberg BJ, Cavaillon JM, Van der Meer JW |year=2002 |title=Does the shape of lipid A determine the interaction of LPS with Toll-like receptors? |journal=Trends Immunol. |volume=23 |issue=3 |pages=135–9 |doi=10.1016/S1471-4906(01)02169-X |pmid=11864841}}</ref><ref>{{Cite journal |vauthors=Seydel U, Oikawa M, Fukase K, Kusumoto S, Brandenburg K |year=2000 |title=Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity |journal=Eur. J. Biochem. |volume=267 |issue=10 |pages=3032–9 |doi=10.1046/j.1432-1033.2000.01326.x |pmid=10806403}}</ref> In general, LPS gene clusters are highly variable between different strains, subspecies, species of bacterial pathogens of plants and animals.<ref>{{Cite book |title=Pathogenicity Islands and the Evolution of Pathogenic Microbes |vauthors=Reeves PP, Wang L |chapter=Genomic Organization of LPS-Specific Loci |editor-last1=Hacker|editor-first1=J.|editor-last2=Kaper|editor-first2=J.B.|year=2002 |isbn=978-3-540-42682-0 |series=Current Topics in Microbiology and Immunology |volume=2|id=264 |pages=109–35 |doi=10.1007/978-3-642-56031-6_7 |pmid=12014174 |issue=1}}</ref><ref>{{Cite journal |vauthors=Patil PB, Sonti RV |year=2004 |title=Variation suggestive of horizontal gene transfer at a lipopolysaccharide (lps) biosynthetic locus in Xanthomonas oryzae pv. oryzae, the bacterial leaf blight pathogen of rice |journal=BMC Microbiol. |volume=4 |pages=40 |doi=10.1186/1471-2180-4-40 |pmc=524487 |pmid=15473911 |doi-access=free }}</ref>
+It has been speculated that conical lipid A (e.g., from ''[[Escherichia coli|E. coli]]'') is more agonistic, while less conical lipid A like that of ''Porphyromonas gingivalis'' may activate a different signal ([[TLR2]] instead of TLR4), and completely cylindrical lipid A like that of ''Rhodobacter sphaeroides'' is antagonistic to TLRs.<ref>{{cite journal | vauthors = Netea MG, van Deuren M, Kullberg BJ, Cavaillon JM, Van der Meer JW | title = Does the shape of lipid A determine the interaction of LPS with Toll-like receptors? | journal = Trends in Immunology | volume = 23 | issue = 3 | pages = 135–139 | date = March 2002 | pmid = 11864841 | doi = 10.1016/S1471-4906(01)02169-X }}</ref><ref>{{cite journal | vauthors = Seydel U, Oikawa M, Fukase K, Kusumoto S, Brandenburg K | title = Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity | journal = European Journal of Biochemistry | volume = 267 | issue = 10 | pages = 3032–3039 | date = May 2000 | pmid = 10806403 | doi = 10.1046/j.1432-1033.2000.01326.x }}</ref> In general, LPS gene clusters are highly variable between different strains, subspecies, species of bacterial pathogens of plants and animals.<ref>{{Cite book | vauthors = Reeves PP, Wang L | chapter= Genomic Organization of LPS-Specific Loci | veditors = Hacker J, Kaper JB |title=Pathogenicity Islands and the Evolution of Pathogenic Microbes |year=2002 |isbn=978-3-540-42682-0 |series=Current Topics in Microbiology and Immunology |volume=2|id=264 |pages=109–35 |doi=10.1007/978-3-642-56031-6_7 |pmid=12014174 |issue=1}}</ref><ref>{{cite journal | vauthors = Patil PB, Sonti RV | title = Variation suggestive of horizontal gene transfer at a lipopolysaccharide (lps) biosynthetic locus in Xanthomonas oryzae pv. oryzae, the bacterial leaf blight pathogen of rice | journal = BMC Microbiology | volume = 4 | pages = 40 | date = October 2004 | pmid = 15473911 | pmc = 524487 | doi = 10.1186/1471-2180-4-40 | doi-access = free }}</ref>
-Normal human blood [[serum (blood)|serum]] contains anti-LOS antibodies that are bactericidal and patients that have infections caused by serotypically distinct strains possess anti-LOS antibodies that differ in their specificity compared with normal serum.<ref name="Yamasaki_et_al">{{Cite journal |vauthors=Yamasaki R, Kerwood DE, Schneider H, Quinn KP, Griffiss JM, Mandrell RE |year=1994 |title=The structure of lipooligosaccharide produced by Neisseria gonorrhoeae, strain 15253, isolated from a patient with disseminated infection. Evidence for a new glycosylation pathway of the gonococcal lipooligosaccharide |journal=J. Biol. Chem. |volume=269 |issue=48 |pages=30345–51 |doi=10.1016/S0021-9258(18)43819-7 |pmid=7982947 |doi-access=free}}</ref> These differences in humoral immune response to different LOS types can be attributed to the structure of the LOS molecule, primarily within the structure of the oligosaccharide portion of the LOS molecule.<ref name="Yamasaki_et_al" />
+Normal human blood [[serum (blood)|serum]] contains anti-LOS antibodies that are bactericidal and patients that have infections caused by serotypically distinct strains possess anti-LOS antibodies that differ in their specificity compared with normal serum.<ref name="Yamasaki_1994">{{cite journal | vauthors = Yamasaki R, Kerwood DE, Schneider H, Quinn KP, Griffiss JM, Mandrell RE | title = The structure of lipooligosaccharide produced by Neisseria gonorrhoeae, strain 15253, isolated from a patient with disseminated infection. Evidence for a new glycosylation pathway of the gonococcal lipooligosaccharide | journal = The Journal of Biological Chemistry | volume = 269 | issue = 48 | pages = 30345–30351 | date = December 1994 | pmid = 7982947 | doi = 10.1016/S0021-9258(18)43819-7 | doi-access = free }}</ref> These differences in humoral immune response to different LOS types can be attributed to the structure of the LOS molecule, primarily within the structure of the oligosaccharide portion of the LOS molecule.<ref name="Yamasaki_1994" />
-In ''[[Neisseria gonorrhoeae]]'' it has been demonstrated that the antigenicity of LOS molecules can change during an infection due to the ability of these bacteria to synthesize more than one type of LOS,<ref name="Yamasaki_et_al" /> a characteristic known as [[phase variation]]. Additionally, ''[[Neisseria gonorrhoeae]]'', as well as ''[[Neisseria meningitidis]]'' and ''[[Haemophilus influenzae]]'',<ref name="Moran_et_al" /> are capable of further modifying their LOS ''in vitro'', for example through [[sialic acid|sialylation]] (modification with sialic acid residues), and as a result are able to increase their resistance to [[complement system|complement]]-mediated killing <ref name="Yamasaki_et_al" /> or even down-regulate complement activation<ref name="Moran_et_al" /> or evade the effects of [[bactericide|bactericidal]] antibodies.<ref name="Moran_et_al" /> Sialylation may also contribute to hindered [[neutrophil]] attachment and [[phagocytosis]] by immune system cells as well as a reduced oxidative burst.<ref name="Moran_et_al" /> ''[[Haemophilus somnus]]'', a pathogen of cattle, has also been shown to display LOS phase variation, a characteristic which may help in the evasion of [[bovine]] host immune defenses.<ref name="Howard_et_al">{{Cite journal |vauthors=Howard MD, Cox AD, Weiser JN, Schurig GG, Inzana TJ |year=2000 |title=Antigenic diversity of Haemophilus somnus lipooligosaccharide: phase-variable accessibility of the phosphorylcholine epitope |journal=J. Clin. Microbiol. |volume=38 |issue=12 |pages=4412–9 |doi=10.1128/JCM.38.12.4412-4419.2000 |pmc=87614 |pmid=11101573}}</ref>
+In ''[[Neisseria gonorrhoeae]]'' it has been demonstrated that the antigenicity of LOS molecules can change during an infection due to the ability of these bacteria to synthesize more than one type of LOS,<ref name="Yamasaki_1994" /> a characteristic known as [[phase variation]]. Additionally, ''[[Neisseria gonorrhoeae]]'', as well as ''[[Neisseria meningitidis]]'' and ''[[Haemophilus influenzae]]'',<ref name="Moran_1996" /> are capable of further modifying their LOS ''in vitro'', for example through [[sialic acid|sialylation]] (modification with sialic acid residues), and as a result are able to increase their resistance to [[complement system|complement]]-mediated killing <ref name="Yamasaki_1994" /> or even down-regulate complement activation<ref name="Moran_1996" /> or evade the effects of [[bactericide|bactericidal]] antibodies.<ref name="Moran_1996" /> Sialylation may also contribute to hindered [[neutrophil]] attachment and [[phagocytosis]] by immune system cells as well as a reduced oxidative burst.<ref name="Moran_1996" /> ''[[Haemophilus somnus]]'', a pathogen of cattle, has also been shown to display LOS phase variation, a characteristic which may help in the evasion of [[bovine]] host immune defenses.<ref name="Howard_et_al">{{cite journal | vauthors = Howard MD, Cox AD, Weiser JN, Schurig GG, Inzana TJ | title = Antigenic diversity of Haemophilus somnus lipooligosaccharide: phase-variable accessibility of the phosphorylcholine epitope | journal = Journal of Clinical Microbiology | volume = 38 | issue = 12 | pages = 4412–4419 | date = December 2000 | pmid = 11101573 | pmc = 87614 | doi = 10.1128/JCM.38.12.4412-4419.2000 }}</ref>
 Taken together, these observations suggest that variations in bacterial surface molecules such as LOS can help the pathogen evade both the [[humoral immunity|humoral]] (antibody and complement-mediated) and the [[cell-mediated immunity|cell-mediated]] (killing by neutrophils, for example) host immune defenses.
 ===Non-canonical pathways of LPS recognition===
-Recently, it was shown that in addition to [[TLR4]] mediated pathways, certain members of the family of the [[Transient receptor potential channel|transient receptor potential ion channels]] recognize LPS.<ref>{{Cite journal |last1=Boonen |first1=Brett |last2=Alpizar |first2=Yeranddy |last3=Meseguer |first3=Victor |last4=Talavera |first4=Karel |last5=Boonen |first5=Brett |last6=Alpizar |first6=Yeranddy A. |last7=Meseguer |first7=Victor M. |last8=Talavera |first8=Karel |date=11 August 2018 |title=TRP Channels as Sensors of Bacterial Endotoxins |journal=Toxins |language=en |volume=10 |issue=8 |pages=326 |doi=10.3390/toxins10080326 |pmc=6115757 |pmid=30103489 |doi-access=free}}</ref> LPS-mediated activation of [[TRPA1]] was shown in mice<ref>{{Cite journal |last1=Meseguer |first1=Victor |last2=Alpizar |first2=Yeranddy A. |last3=Luis |first3=Enoch |last4=Tajada |first4=Sendoa |last5=Denlinger |first5=Bristol |last6=Fajardo |first6=Otto |last7=Manenschijn |first7=Jan-Albert |last8=Fernández-Peña |first8=Carlos |last9=Talavera |first9=Arturo |last10=Kichko |first10=Tatiana |last11=Navia |first11=Belén |date=20 January 2014 |title=TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins |journal=Nature Communications |volume=5 |pages=3125 |bibcode=2014NatCo...5.3125M |doi=10.1038/ncomms4125 |pmc=3905718 |pmid=24445575 |last12=Sánchez |first12=Alicia |last13=Señarís |first13=Rosa |last14=Reeh |first14=Peter |last15=Pérez-García |first15=María Teresa |last16=López-López |first16=José Ramón |last17=Voets |first17=Thomas |last18=Belmonte |first18=Carlos |last19=Talavera |first19=Karel |last20=Viana |first20=Félix}}</ref> and ''[[Drosophila melanogaster]]'' flies.<ref>{{Cite journal |last1=Soldano |first1=Alessia |last2=Alpizar |first2=Yeranddy A |last3=Boonen |first3=Brett |last4=Franco |first4=Luis |last5=López-Requena |first5=Alejandro |last6=Liu |first6=Guangda |last7=Mora |first7=Natalia |last8=Yaksi |first8=Emre |last9=Voets |first9=Thomas |last10=Vennekens |first10=Rudi |last11=Hassan |first11=Bassem A |date=14 June 2016 |title=Gustatory-mediated avoidance of bacterial lipopolysaccharides via TRPA1 activation in Drosophila |journal=eLife |volume=5 |doi=10.7554/eLife.13133 |pmc=4907694 |pmid=27296646 |last12=Talavera |first12=Karel |doi-access=free }}</ref> At higher concentrations, LPS activates other members of the sensory [[Transient receptor potential channel|TRP channel]] family as well, such as [[TRPV1]], [[TRPM3]] and to some extent [[TRPM8]].<ref>{{Cite journal |last1=Boonen |first1=Brett |last2=Alpizar |first2=Yeranddy A. |last3=Sanchez |first3=Alicia |last4=López-Requena |first4=Alejandro |last5=Voets |first5=Thomas |last6=Talavera |first6=Karel |date=July 2018 |title=Differential effects of lipopolysaccharide on mouse sensory TRP channels |url=https://lirias.kuleuven.be/handle/123456789/623401 |journal=Cell Calcium |volume=73 |pages=72–81 |doi=10.1016/j.ceca.2018.04.004 |pmid=29689522 |s2cid=13681499}}</ref>
+Recently, it was shown that in addition to [[TLR4]] mediated pathways, certain members of the family of the [[Transient receptor potential channel|transient receptor potential ion channels]] recognize LPS.<ref>{{cite journal | vauthors = Boonen B, Alpizar YA, Meseguer VM, Talavera K | title = TRP Channels as Sensors of Bacterial Endotoxins | journal = Toxins | volume = 10 | issue = 8 | pages = 326 | date = August 2018 | pmid = 30103489 | pmc = 6115757 | doi = 10.3390/toxins10080326 | doi-access = free }}</ref> LPS-mediated activation of [[TRPA1]] was shown in mice<ref>{{cite journal | vauthors = Meseguer V, Alpizar YA, Luis E, Tajada S, Denlinger B, Fajardo O, Manenschijn JA, Fernández-Peña C, Talavera A, Kichko T, Navia B, Sánchez A, Señarís R, Reeh P, Pérez-García MT, López-López JR, Voets T, Belmonte C, Talavera K, Viana F | display-authors = 6 | title = TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins | journal = Nature Communications | volume = 5 | pages = 3125 | date = 20 January 2014 | pmid = 24445575 | pmc = 3905718 | doi = 10.1038/ncomms4125 | bibcode = 2014NatCo...5.3125M }}</ref> and ''[[Drosophila melanogaster]]'' flies.<ref>{{cite journal | vauthors = Soldano A, Alpizar YA, Boonen B, Franco L, López-Requena A, Liu G, Mora N, Yaksi E, Voets T, Vennekens R, Hassan BA, Talavera K | display-authors = 6 | title = Gustatory-mediated avoidance of bacterial lipopolysaccharides via TRPA1 activation in Drosophila | journal = eLife | volume = 5 | date = June 2016 | pmid = 27296646 | pmc = 4907694 | doi = 10.7554/eLife.13133 | doi-access = free }}</ref> At higher concentrations, LPS activates other members of the sensory [[Transient receptor potential channel|TRP channel]] family as well, such as [[TRPV1]], [[TRPM3]] and to some extent [[TRPM8]].<ref>{{cite journal | vauthors = Boonen B, Alpizar YA, Sanchez A, López-Requena A, Voets T, Talavera K | title = Differential effects of lipopolysaccharide on mouse sensory TRP channels | journal = Cell Calcium | volume = 73 | pages = 72–81 | date = July 2018 | pmid = 29689522 | doi = 10.1016/j.ceca.2018.04.004 | s2cid = 13681499 }}</ref>
-LPS is recognized by [[TRPV4]] on epithelial cells. TRPV4 activation by LPS was necessary and sufficient to induce nitric oxide production with a bactericidal effect.<ref>{{Cite journal |last1=Alpizar |first1=Yeranddy A. |last2=Boonen |first2=Brett |last3=Sanchez |first3=Alicia |last4=Jung |first4=Carole |last5=López-Requena |first5=Alejandro |last6=Naert |first6=Robbe |last7=Steelant |first7=Brecht |last8=Luyts |first8=Katrien |last9=Plata |first9=Cristina |last10=De Vooght |first10=Vanessa |last11=Vanoirbeek |first11=Jeroen A. J. |date=20 October 2017 |title=TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells |journal=Nature Communications |volume=8 |issue=1 |pages=1059 |bibcode=2017NatCo...8.1059A |doi=10.1038/s41467-017-01201-3 |pmc=5651912 |pmid=29057902 |last12=Meseguer |first12=Victor M. |last13=Voets |first13=Thomas |last14=Alvarez |first14=Julio L. |last15=Hellings |first15=Peter W. |last16=Hoet |first16=Peter H. M. |last17=Nemery |first17=Benoit |last18=Valverde |first18=Miguel A. |last19=Talavera |first19=Karel}}</ref>
+LPS is recognized by [[TRPV4]] on epithelial cells. TRPV4 activation by LPS was necessary and sufficient to induce nitric oxide production with a bactericidal effect.<ref>{{cite journal | vauthors = Alpizar YA, Boonen B, Sanchez A, Jung C, López-Requena A, Naert R, Steelant B, Luyts K, Plata C, De Vooght V, Vanoirbeek JA, Meseguer VM, Voets T, Alvarez JL, Hellings PW, Hoet PH, Nemery B, Valverde MA, Talavera K | display-authors = 6 | title = TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells | journal = Nature Communications | volume = 8 | issue = 1 | pages = 1059 | date = October 2017 | pmid = 29057902 | pmc = 5651912 | doi = 10.1038/s41467-017-01201-3 | bibcode = 2017NatCo...8.1059A }}</ref>
-'''Testing'''
+===Testing===
-<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>Lipopolysaccharide, is a significant factor that makes bacteria harmful, and it helps categorize them into different groups based on their structure and function. This makes LPS a useful marker for telling apart various Gram-negative bacteria. Swiftly identifying and understanding the types of pathogens involved is crucial for promptly managing and treating infections. Since LPS is the main trigger for the immune response in our cells, it acts as an early signal of an acute infection. Therefore, LPS testing is more specific and meaningful than many other serological tests.'''
+Lipopolysaccharide is a significant factor that makes bacteria harmful, and it helps categorize them into different groups based on their structure and function. This makes LPS a useful marker for telling apart various Gram-negative bacteria. Swiftly identifying and understanding the types of pathogens involved is crucial for promptly managing and treating infections. Since LPS is the main trigger for the immune response in our cells, it acts as an early signal of an acute infection. Therefore, LPS testing is more specific and meaningful than many other serological tests.<ref name="Page_2022">{{cite journal | vauthors = Page MJ, Kell DB, Pretorius E | title = The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation | journal = Chronic Stress | volume = 6 | issue =  | pages = 24705470221076390 | date = 2022 | pmid = 35155966 | pmc = 8829728 | doi = 10.1177/24705470221076390 }}</ref>
-''<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>'The current methods for testing LPS are quite sensitive, but many of them struggle to differentiate between different LPS groups. Additionally, the nature of LPS, which has both water-attracting and water-repelling properties (amphiphilic), makes it challenging to develop sensitive and user-friendly tests.'''
+The current methods for testing LPS are quite sensitive, but many of them struggle to differentiate between different LPS groups. Additionally, the nature of LPS, which has both water-attracting and water-repelling properties (amphiphilic), makes it challenging to develop sensitive and user-friendly tests.<ref name="Page_2022" />
-'''<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>The typical detection methods rely on identifying the lipid A part of LPS. However, this method has limitations because Lipid A is very similar among different bacterial species and serotypes. LPS testing techniques fall into six categories, and they often overlap: in vivo tests, in vitro tests, modified immunoassays, biological assays, and chemical assays.'''
+The typical detection methods rely on identifying the lipid A part of LPS. However, this method has limitations because Lipid A is very similar among different bacterial species and serotypes. LPS testing techniques fall into six categories, and they often overlap: in vivo tests, in vitro tests, modified immunoassays, biological assays, and chemical assays.<ref name="Page_2022" />
-'''Pathophysiology'''
+===Pathophysiology===
-<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>LPS is a powerful toxin that, when in the body, triggers inflammation by binding to cell receptors. Excessive LPS in the blood can lead to endotoxemia, potentially causing a harmful condition called septic shock. This condition includes symptoms like rapid heart rate, quick breathing, temperature changes, and blood clotting issues, resulting in blood vessels widening and reduced blood volume, leading to cellular dysfunction.'''
+LPS is a powerful toxin that, when in the body, triggers inflammation by binding to cell receptors. Excessive LPS in the blood can lead to endotoxemia, potentially causing a harmful condition called septic shock. This condition includes symptoms like rapid heart rate, quick breathing, temperature changes, and blood clotting issues, resulting in blood vessels widening and reduced blood volume, leading to cellular dysfunction.<ref name="Page_2022" />
-'<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>''Recent research indicates that even small LPS exposure is associated with autoimmune diseases and allergies. High levels of LPS in the blood can lead to metabolic syndrome, increasing the risk of conditions like diabetes, heart disease, and liver problems.'''
+Recent research indicates that even small LPS exposure is associated with autoimmune diseases and allergies. High levels of LPS in the blood can lead to metabolic syndrome, increasing the risk of conditions like diabetes, heart disease, and liver problems.<ref name="Page_2022" />
-'<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>''LPS also plays a crucial role in symptoms caused by infections from harmful bacteria, including severe conditions like Waterhouse-Friderichsen syndrome, meningococcemia, and meningitis. Certain bacteria can adapt their LPS to cause long-lasting infections in the respiratory and digestive systems.'''
+LPS also plays a crucial role in symptoms caused by infections from harmful bacteria, including severe conditions like Waterhouse-Friderichsen syndrome, meningococcemia, and meningitis. Certain bacteria can adapt their LPS to cause long-lasting infections in the respiratory and digestive systems.<ref name="Page_2022" />
-''<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>'Recent studies have shown that LPS disrupts cell membrane lipids, affecting cholesterol and metabolism, potentially leading to high cholesterol, abnormal blood lipid levels, and non-alcoholic fatty liver disease. In some cases, LPS can interfere with toxin clearance, which may be linked to neurological issues.'''
+Recent studies have shown that LPS disrupts cell membrane lipids, affecting cholesterol and metabolism, potentially leading to high cholesterol, abnormal blood lipid levels, and non-alcoholic fatty liver disease. In some cases, LPS can interfere with toxin clearance, which may be linked to neurological issues.<ref name="Page_2022" />
 ==Health effects==
@@ Line 98: / Line 102: @@
 ===Endotoxemia===
-The presence of endotoxins in the blood is called endotoxemia. High level of endotoxemia can lead to [[septic shock]],<ref name="pmid20519895">{{Cite book |title=Endotoxemia and Endotoxin Shock |vauthors=Opal SM |year=2010 |isbn=978-3-8055-9484-4 |series=Contributions to Nephrology |volume=167 |pages=14–24 |chapter=Endotoxins and other sepsis triggers |doi=10.1159/000315915 |pmid=20519895}}</ref> while lower concentration of endotoxins in the bloodstream is called metabolic endotoxemia.<ref name=":0">{{Cite journal |last1=Gomes |first1=Júnia Maria Geraldo |last2=Costa |first2=Jorge de Assis |last3=Alfenas |first3=Rita de Cássia Gonçalves |date=March 2017 |title=Metabolic endotoxemia and diabetes mellitus: A systematic review |url=https://linkinghub.elsevier.com/retrieve/pii/S0026049516301871 |journal=Metabolism |language=en |volume=68 |pages=133–144 |doi=10.1016/j.metabol.2016.12.009 |pmid=28183445}}</ref> Endotoxemia is associated with obesity, diet,<ref name="Kallio 395–404">{{Cite journal |last1=Kallio |first1=K. A. Elisa |last2=Hätönen |first2=Katja A. |last3=Lehto |first3=Markku |last4=Salomaa |first4=Veikko |last5=Männistö |first5=Satu |last6=Pussinen |first6=Pirkko J. |date=April 2015 |title=Endotoxemia, nutrition, and cardiometabolic disorders |url=http://link.springer.com/10.1007/s00592-014-0662-3 |journal=Acta Diabetologica |language=en |volume=52 |issue=2 |pages=395–404 |doi=10.1007/s00592-014-0662-3 |issn=0940-5429 |pmid=25326898 |s2cid=24020127}}</ref> cardiovascular diseases,<ref name="Kallio 395–404" /> and diabetes,<ref name=":0" /> while also host genetics might have an effect.<ref>{{Cite journal |last1=Leskelä |first1=Jaakko |last2=Toppila |first2=Iiro |last3=Härma |first3=Mari‐Anne |last4=Palviainen |first4=Teemu |last5=Salminen |first5=Aino |last6=Sandholm |first6=Niina |last7=Pietiäinen |first7=Milla |last8=Kopra |first8=Elisa |last9=Pais de Barros |first9=Jean‐Paul |last10=FinnGen |last11=Lassenius |first11=Mariann I. |date=20 October 2021 |title=Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke |journal=Journal of the American Heart Association |language=en |volume=10 |issue=21 |pages=e022482 |doi=10.1161/JAHA.121.022482 |issn=2047-9980 |pmc=8751832 |pmid=34668383}}</ref>
+The presence of endotoxins in the blood is called endotoxemia. High level of endotoxemia can lead to [[septic shock]],<ref name="Opal_2010">{{Cite book |title=Endotoxemia and Endotoxin Shock |vauthors=Opal SM |year=2010 |isbn=978-3-8055-9484-4 |series=Contributions to Nephrology |volume=167 |pages=14–24 |chapter=Endotoxins and other sepsis triggers |doi=10.1159/000315915 |pmid=20519895}}</ref> while lower concentration of endotoxins in the bloodstream is called metabolic endotoxemia.<ref name="Gomes_2017">{{cite journal | vauthors = Gomes JM, Costa JA, Alfenas RC | title = Metabolic endotoxemia and diabetes mellitus: A systematic review | journal = Metabolism | volume = 68 | pages = 133–144 | date = March 2017 | pmid = 28183445 | doi = 10.1016/j.metabol.2016.12.009 }}</ref> Endotoxemia is associated with obesity, diet,<ref name="Kallio_2015">{{cite journal | vauthors = Kallio KA, Hätönen KA, Lehto M, Salomaa V, Männistö S, Pussinen PJ | title = Endotoxemia, nutrition, and cardiometabolic disorders | journal = Acta Diabetologica | volume = 52 | issue = 2 | pages = 395–404 | date = April 2015 | pmid = 25326898 | doi = 10.1007/s00592-014-0662-3 | s2cid = 24020127 }}</ref> cardiovascular diseases,<ref name="Kallio_2015" /> and diabetes,<ref name="Gomes_2017" /> while also host genetics might have an effect.<ref>{{cite journal | vauthors = Leskelä J, Toppila I, Härma MA, Palviainen T, Salminen A, Sandholm N, Pietiäinen M, Kopra E, Pais de Barros JP, Lassenius MI, Kumar A, Harjutsalo V, Roslund K, Forsblom C, Loukola A, Havulinna AS, Lagrost L, Salomaa V, Groop PH, Perola M, Kaprio J, Lehto M, Pussinen PJ | display-authors = 6 | title = Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke | journal = Journal of the American Heart Association | volume = 10 | issue = 21 | pages = e022482 | date = November 2021 | pmid = 34668383 | pmc = 8751832 | doi = 10.1161/JAHA.121.022482 | first11 = Mariann I. }}</ref>
-Moreover, endotoxemia of intestinal origin, especially, at the [[host-pathogen interface]], is considered to be an important factor in the development of alcoholic hepatitis,<ref>{{Cite journal |vauthors=Ceccanti M, Attili A, Balducci G, Attilia F, Giacomelli S, Rotondo C, Sasso GF, Xirouchakis E, Attilia ML |year=2006 |title=Acute alcoholic hepatitis |journal=J. Clin. Gastroenterol. |volume=40 |issue=9 |pages=833–41 |doi=10.1097/01.mcg.0000225570.04773.5d |pmid=17016141}}</ref>  which is likely to develop on the basis of the [[small bowel bacterial overgrowth syndrome]] and an increased [[intestinal permeability]].<ref>{{Cite journal |vauthors=Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C |year=2000 |title=Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease |journal=J. Hepatol. |volume=32 |issue=5 |pages=742–7 |doi=10.1016/S0168-8278(00)80242-1 |pmid=10845660}}</ref>
+Moreover, endotoxemia of intestinal origin, especially, at the [[host-pathogen interface]], is considered to be an important factor in the development of alcoholic hepatitis,<ref>{{cite journal | vauthors = Ceccanti M, Attili A, Balducci G, Attilia F, Giacomelli S, Rotondo C, Sasso GF, Xirouchakis E, Attilia ML | display-authors = 6 | title = Acute alcoholic hepatitis | journal = Journal of Clinical Gastroenterology | volume = 40 | issue = 9 | pages = 833–841 | date = October 2006 | pmid = 17016141 | doi = 10.1097/01.mcg.0000225570.04773.5d }}</ref>  which is likely to develop on the basis of the [[small bowel bacterial overgrowth syndrome]] and an increased [[intestinal permeability]].<ref>{{cite journal | vauthors = Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C | title = Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease | journal = Journal of Hepatology | volume = 32 | issue = 5 | pages = 742–747 | date = May 2000 | pmid = 10845660 | doi = 10.1016/S0168-8278(00)80242-1 }}</ref>
-[[Lipid A]] may cause uncontrolled activation of mammalian immune systems with production of [[inflammation|inflammatory]] mediators that may lead to [[septic shock]].<ref name="Kilar_et_al" /> This [[inflammation|inflammatory]] reaction is mediated by [[TLR 4|Toll-like receptor 4]] which is responsible for immune system cell activation.<ref name="Kilar_et_al" /> Damage to the [[endothelial]] layer of blood vessels caused by these [[inflammation|inflammatory]] mediators can lead to [[capillary leak syndrome]], dilation of blood vessels and a decrease in cardiac function and can lead to [[septic shock]].<ref name="Stephens_et_al">{{Cite journal |vauthors=Stephens DS, Greenwood B, Brandtzaeg P |year=2007 |title=Epidemic meningitis, meningococcaemia, and Neisseria meningitidis |journal=Lancet |volume=369 |issue=9580 |pages=2196–210 |doi=10.1016/S0140-6736(07)61016-2 |pmid=17604802 |s2cid=16951072}}</ref> Pronounced complement activation can also be observed later in the course as the bacteria multiply in the blood.<ref name="Stephens_et_al" /> High bacterial proliferation triggering destructive endothelial damage can also lead to [[disseminated intravascular coagulation]] (DIC) with loss of function of certain internal organs such as the kidneys, [[adrenal gland]]s and lungs due to compromised blood supply. The skin can show the effects of vascular damage often coupled with depletion of coagulation factors in the form of [[petechiae]], [[purpura]] and [[ecchymosis|ecchymoses]]. The limbs can also be affected, sometimes with devastating consequences such as the development of [[gangrene]], requiring subsequent [[amputation]].<ref name="Stephens_et_al" /> Loss of function of the adrenal glands can cause [[adrenal insufficiency]] and additional [[bleeding|hemorrhage]] into the adrenals causes [[Waterhouse-Friderichsen syndrome]], both of which can be life-threatening.
+[[Lipid A]] may cause uncontrolled activation of mammalian immune systems with production of [[inflammation|inflammatory]] mediators that may lead to [[septic shock]].<ref name="Kilar_2013" /> This [[inflammation|inflammatory]] reaction is mediated by [[TLR 4|Toll-like receptor 4]] which is responsible for immune system cell activation.<ref name="Kilar_2013" /> Damage to the [[endothelial]] layer of blood vessels caused by these [[inflammation|inflammatory]] mediators can lead to [[capillary leak syndrome]], dilation of blood vessels and a decrease in cardiac function and can lead to [[septic shock]].<ref name="Stephens_2007">{{cite journal | vauthors = Stephens DS, Greenwood B, Brandtzaeg P | title = Epidemic meningitis, meningococcaemia, and Neisseria meningitidis | journal = Lancet | volume = 369 | issue = 9580 | pages = 2196–2210 | date = June 2007 | pmid = 17604802 | doi = 10.1016/S0140-6736(07)61016-2 | s2cid = 16951072 }}</ref> Pronounced complement activation can also be observed later in the course as the bacteria multiply in the blood.<ref name="Stephens_2007" /> High bacterial proliferation triggering destructive endothelial damage can also lead to [[disseminated intravascular coagulation]] (DIC) with loss of function of certain internal organs such as the kidneys, [[adrenal gland]]s and lungs due to compromised blood supply. The skin can show the effects of vascular damage often coupled with depletion of coagulation factors in the form of [[petechiae]], [[purpura]] and [[ecchymosis|ecchymoses]]. The limbs can also be affected, sometimes with devastating consequences such as the development of [[gangrene]], requiring subsequent [[amputation]].<ref name="Stephens_2007" /> Loss of function of the adrenal glands can cause [[adrenal insufficiency]] and additional [[bleeding|hemorrhage]] into the adrenals causes [[Waterhouse-Friderichsen syndrome]], both of which can be life-threatening.
-It has also been reported that [[Neisseria gonorrhoeae|gonococcal]] LOS can cause damage to human [[fallopian tube]]s.<ref name="Yamasaki_et_al" />
+It has also been reported that [[Neisseria gonorrhoeae|gonococcal]] LOS can cause damage to human [[fallopian tube]]s.<ref name="Yamasaki_1994" />
 ===Auto-immune disease===
-The [[molecular mimicry]] of some LOS molecules is thought to cause autoimmune-based host responses, such as flareups of [[multiple sclerosis]].<ref name="Moran_et_al" /><ref name="Chastain_and_Miller" />  Other examples of bacterial mimicry of host structures via LOS are found with the bacteria ''[[Helicobacter pylori]]'' and ''[[Campylobacter jejuni]]'', organisms which cause gastrointestinal disease in humans, and ''[[Haemophilus ducreyi]]'' which causes [[chancroid]]. Certain ''C. jejuni'' LPS serotypes (attributed to certain tetra- and pentasaccharide moieties of the core oligosaccharide) have also been implicated with [[Guillain–Barré syndrome]] and a variant of Guillain–Barré called [[Guillain–Barré syndrome#Classification|Miller-Fisher syndrome]].<ref name="Moran_et_al" />
+The [[molecular mimicry]] of some LOS molecules is thought to cause autoimmune-based host responses, such as flareups of [[multiple sclerosis]].<ref name="Moran_1996" /><ref name="Chastain_2012" />  Other examples of bacterial mimicry of host structures via LOS are found with the bacteria ''[[Helicobacter pylori]]'' and ''[[Campylobacter jejuni]]'', organisms which cause gastrointestinal disease in humans, and ''[[Haemophilus ducreyi]]'' which causes [[chancroid]]. Certain ''C. jejuni'' LPS serotypes (attributed to certain tetra- and pentasaccharide moieties of the core oligosaccharide) have also been implicated with [[Guillain–Barré syndrome]] and a variant of Guillain–Barré called [[Guillain–Barré syndrome#Classification|Miller-Fisher syndrome]].<ref name="Moran_1996" />
 ===Link to obesity===
-Epidemiological studies have shown that increased endotoxin load, which can be a result of increased populations of endotoxin-producing bacteria in the intestinal tract, is associated with certain obesity-related patient groups.<ref name="epidemiology_1">{{Cite journal |vauthors=Moreno-Navarrete JM, Ortega F, Serino M, Luche E, Waget A, Pardo G, Salvador J, Ricart W, Frühbeck G, Burcelin R, Fernández-Real JM |year=2012 |title=Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance |journal=Int J Obes (Lond) |volume=36 |issue=11 |pages=1442–9 |doi=10.1038/ijo.2011.256 |pmid=22184060 |doi-access=free}}</ref><ref name="epidemiology_2">{{Cite journal |vauthors=Lepper PM, Schumann C, Triantafilou K, Rasche FM, Schuster T, Frank H, Schneider EM, Triantafilou M, von Eynatten M |year=2007 |title=Association of lipopolysaccharide-binding protein and coronary artery disease in men |journal=J. Am. Coll. Cardiol. |volume=50 |issue=1 |pages=25–31 |doi=10.1016/j.jacc.2007.02.070 |pmid=17601541 |s2cid=12136094 |doi-access=}}</ref><ref name="epidemiology_3">{{Cite journal |vauthors=Ruiz AG, Casafont F, Crespo J, Cayón A, Mayorga M, Estebanez A, Fernadez-Escalante JC, Pons-Romero F |year=2007 |title=Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis |journal=Obes Surg |volume=17 |issue=10 |pages=1374–80 |doi=10.1007/s11695-007-9243-7 |pmid=18000721 |s2cid=44494003}}</ref> Other studies have shown that purified endotoxin from ''[[Escherichia coli]]'' can induce obesity and insulin-resistance when injected into germ-free [[mouse model]]s.<ref name="endotoxin_effects_1">{{Cite journal |vauthors=Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R |year=2007 |title=Metabolic endotoxemia initiates obesity and insulin resistance |journal=Diabetes |volume=56 |issue=7 |pages=1761–72 |doi=10.2337/db06-1491 |pmid=17456850 |doi-access=free}}</ref> A more recent study has uncovered a potentially contributing role for ''[[Enterobacter cloacae]]'' B29 toward obesity and insulin resistance in a human patient.<ref name="endotoxin_effects_2">{{Cite journal |vauthors=Fei N, Zhao L |date=December 2012 |title=An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice |journal=ISME J |volume=7 |issue=4 |pages=880–4 |doi=10.1038/ismej.2012.153 |pmc=3603399 |pmid=23235292}}</ref> The presumed mechanism for the association of endotoxin with obesity is that endotoxin induces an inflammation-mediated pathway accounting for the observed obesity and insulin resistance.<ref name="endotoxin_effects_1" /> Bacterial genera associated with endotoxin-related obesity effects include ''[[Escherichia]]'' and ''[[Enterobacter]].''
+Epidemiological studies have shown that increased endotoxin load, which can be a result of increased populations of endotoxin-producing bacteria in the intestinal tract, is associated with certain obesity-related patient groups.<ref name="Moreno-Navarrete_2012">{{cite journal | vauthors = Moreno-Navarrete JM, Ortega F, Serino M, Luche E, Waget A, Pardo G, Salvador J, Ricart W, Frühbeck G, Burcelin R, Fernández-Real JM | display-authors = 6 | title = Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance | journal = International Journal of Obesity | volume = 36 | issue = 11 | pages = 1442–1449 | date = November 2012 | pmid = 22184060 | doi = 10.1038/ijo.2011.256 | doi-access = free }}</ref><ref name="Lepper_2007">{{cite journal | vauthors = Lepper PM, Schumann C, Triantafilou K, Rasche FM, Schuster T, Frank H, Schneider EM, Triantafilou M, von Eynatten M | display-authors = 6 | title = Association of lipopolysaccharide-binding protein and coronary artery disease in men | journal = Journal of the American College of Cardiology | volume = 50 | issue = 1 | pages = 25–31 | date = July 2007 | pmid = 17601541 | doi = 10.1016/j.jacc.2007.02.070 | s2cid = 12136094 | doi-access =  }}</ref><ref name="Ruiz_2007">{{cite journal | vauthors = Ruiz AG, Casafont F, Crespo J, Cayón A, Mayorga M, Estebanez A, Fernadez-Escalante JC, Pons-Romero F | display-authors = 6 | title = Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis | journal = Obesity Surgery | volume = 17 | issue = 10 | pages = 1374–1380 | date = October 2007 | pmid = 18000721 | doi = 10.1007/s11695-007-9243-7 | s2cid = 44494003 }}</ref> Other studies have shown that purified endotoxin from ''[[Escherichia coli]]'' can induce obesity and insulin-resistance when injected into germ-free [[mouse model]]s.<ref name="Cani_2007">{{cite journal | vauthors = Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R | display-authors = 6 | title = Metabolic endotoxemia initiates obesity and insulin resistance | journal = Diabetes | volume = 56 | issue = 7 | pages = 1761–1772 | date = July 2007 | pmid = 17456850 | doi = 10.2337/db06-1491 | doi-access = free }}</ref> A more recent study has uncovered a potentially contributing role for ''[[Enterobacter cloacae]]'' B29 toward obesity and insulin resistance in a human patient.<ref name="Fei_2013">{{cite journal | vauthors = Fei N, Zhao L | title = An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice | journal = The ISME Journal | volume = 7 | issue = 4 | pages = 880–884 | date = April 2013 | pmid = 23235292 | pmc = 3603399 | doi = 10.1038/ismej.2012.153 | bibcode = 2013ISMEJ...7..880F }}</ref> The presumed mechanism for the association of endotoxin with obesity is that endotoxin induces an inflammation-mediated pathway accounting for the observed obesity and insulin resistance.<ref name="Cani_2007" /> Bacterial genera associated with endotoxin-related obesity effects include ''[[Escherichia]]'' and ''[[Enterobacter]].''
 === Depression ===
-There is experimental and observational evidence that LPS might play a role in depression. Administration of LPS in mice can lead to depressive symptoms, and there seem to be elevated levels of LPS in some people with depression. Inflammation may sometimes play a role in the development of depression, and LPS is pro-inflammatory.<ref name=":1">{{Cite journal |last1=Lasselin |first1=Julie |last2=Schedlowski |first2=Manfred |last3=Karshikoff |first3=Bianka |last4=Engler |first4=Harald |last5=Lekander |first5=Mats |last6=Konsman |first6=Jan Pieter |date=August 2020 |title=Comparison of bacterial lipopolysaccharide-induced sickness behavior in rodents and humans: Relevance for symptoms of anxiety and depression |journal=Neuroscience and Biobehavioral Reviews |volume=115 |pages=15–24 |doi=10.1016/j.neubiorev.2020.05.001 |issn=1873-7528 |pmid=32433924 |s2cid=218665128|doi-access=free }}</ref>
+There is experimental and observational evidence that LPS might play a role in depression. Administration of LPS in mice can lead to depressive symptoms, and there seem to be elevated levels of LPS in some people with depression. Inflammation may sometimes play a role in the development of depression, and LPS is pro-inflammatory.<ref name="Lasselin_2020">{{cite journal | vauthors = Lasselin J, Schedlowski M, Karshikoff B, Engler H, Lekander M, Konsman JP | title = Comparison of bacterial lipopolysaccharide-induced sickness behavior in rodents and humans: Relevance for symptoms of anxiety and depression | journal = Neuroscience and Biobehavioral Reviews | volume = 115 | pages = 15–24 | date = August 2020 | pmid = 32433924 | doi = 10.1016/j.neubiorev.2020.05.001 | s2cid = 218665128 | doi-access = free }}</ref>
 ===Cellular senescence===
-Inflammation induced by LPS can induce [[cellular senescence]], as has been shown for the lung [[Epithelium|epithelial cells]] and [[Microglia|microglial cells]] (the latter leading to [[neurodegeneration]]).<ref name="pmid30078211">{{Cite journal |vauthors=Wei W, Ji S |year=2018 |title=Cellular senescence: Molecular mechanisms and pathogenicity |journal=[[Journal of Cellular Physiology]] |volume=233 |issue=12 |pages=9121–9135 |doi=10.1002/jcp.26956 |pmid=30078211 |s2cid=51924586}}</ref>
+Inflammation induced by LPS can induce [[cellular senescence]], as has been shown for the lung [[Epithelium|epithelial cells]] and [[Microglia|microglial cells]] (the latter leading to [[neurodegeneration]]).<ref name="Wei_2018">{{cite journal | vauthors = Wei W, Ji S | title = Cellular senescence: Molecular mechanisms and pathogenicity | journal = Journal of Cellular Physiology | volume = 233 | issue = 12 | pages = 9121–9135 | date = December 2018 | pmid = 30078211 | doi = 10.1002/jcp.26956 | s2cid = 51924586 }}</ref>
 ==Role as contaminant in biotechnology and research ==
-Lipopolysaccharides are frequent contaminants in [[plasmid]] [[DNA]] prepared from bacteria or proteins expressed from bacteria, and ''must'' be removed from the DNA or protein to avoid contaminating experiments and to avoid toxicity of products manufactured using [[industrial fermentation]].<ref>{{Cite journal |last1=Wicks |first1=Ian P. |last2=Howell |first2=Meredith L. |last3=Hancock |first3=Tuesday |last4=Kohsaka |first4=Hitoshi |last5=Olee |first5=Tsaiwei |last6=Carson |first6=Dennis A. |date=March 1995 |title=Bacterial Lipopolysaccharide Copurifies with Plasmid DNA: Implications for Animal Models and Human Gene Therapy |journal=Human Gene Therapy |volume=6 |issue=3 |pages=317–323 |doi=10.1089/hum.1995.6.3-317 |pmid=7779915}}</ref>
+Lipopolysaccharides are frequent contaminants in [[plasmid]] [[DNA]] prepared from bacteria or proteins expressed from bacteria, and ''must'' be removed from the DNA or protein to avoid contaminating experiments and to avoid toxicity of products manufactured using [[industrial fermentation]].<ref>{{cite journal | vauthors = Wicks IP, Howell ML, Hancock T, Kohsaka H, Olee T, Carson DA | title = Bacterial lipopolysaccharide copurifies with plasmid DNA: implications for animal models and human gene therapy | journal = Human Gene Therapy | volume = 6 | issue = 3 | pages = 317–323 | date = March 1995 | pmid = 7779915 | doi = 10.1089/hum.1995.6.3-317 }}</ref>
-[[Ovalbumin]] is frequently contaminated with endotoxins. Ovalbumin is one of the extensively studied proteins in animal models and also an established model allergen for airway hyper-responsiveness (AHR). Commercially available ovalbumin that is contaminated with LPS can falsify research results, as it does not accurately reflect the effect of the protein antigen on animal physiology.<ref>{{Cite journal |last1=Watanabe |first1=Junji |last2=Miyazaki |first2=Yasunari |last3=Zimmerman |first3=Guy A. |last4=Albertine |first4=Kurt H. |last5=McIntyre |first5=Thomas M. |date=24 October 2003 |title=Endotoxin contamination of ovalbumin suppresses murine immunologic responses and development of airway hyper-reactivity |journal=The Journal of Biological Chemistry |volume=278 |issue=43 |pages=42361–42368 |doi=10.1074/jbc.M307752200 |issn=0021-9258 |pmid=12909619 |doi-access=free}}</ref>
-In pharmaceutical production, it is necessary to remove all traces of endotoxin from drug product containers, as even small amounts of endotoxin will cause illness in humans.  A [[depyrogenation]] oven is used for this purpose.  Temperatures in excess of 300&nbsp;°C are required to fully break down LPS.<ref>{{Cite web |last=16 December 2014 |title=The Detection of Endotoxins Via the LAL Test, the Chromogenic Method |url=http://www.wakopyrostar.com/blog/post/the-detection-of-endotoxins-via-the-lal-test-the-chromogenic-method/ |url-status=dead |archive-url=https://web.archive.org/web/20150329083636/http://www.wakopyrostar.com/blog/post/the-detection-of-endotoxins-via-the-lal-test-the-chromogenic-method |archive-date=29 March 2015 |access-date=14 March 2015}}</ref>
-The standard [[assay]] for detecting presence of endotoxin is the [[Limulus Amebocyte Lysate]] (LAL) assay, utilizing blood from the [[Horseshoe crab]] (''Limulus polyphemus'').<ref name="pmid24019589">{{Cite journal |vauthors=Iwanaga S |year=2007 |title=Biochemical principle of Limulus test for detecting bacterial endotoxins |journal=Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. |volume=83 |issue=4 |pages=110–9 |bibcode=2007PJAB...83..110I |doi=10.2183/pjab.83.110 |pmc=3756735 |pmid=24019589}}</ref> Very low levels of LPS can cause coagulation of the limulus lysate due to a powerful amplification through an enzymatic cascade. However, due to the dwindling population of horseshoe crabs, and the fact that there are factors that interfere with the LAL assay, efforts have been made to develop alternative assays, with the most promising ones being [[ELISA]] tests using a [[recombinant protein|recombinant]] version of a protein in the LAL assay, Factor C.<ref name="pmid11451451">{{Cite journal |vauthors=Ding JL, Ho B |year=2001 |title=A new era in pyrogen testing |url=http://www.horseshoecrab.org/research/sites/default/files/TIBTECH-rFC.pdf |url-status=dead |journal=Trends Biotechnol. |volume=19 |issue=8 |pages=277–81 |doi=10.1016/s0167-7799(01)01694-8 |pmid=11451451 |archive-url=https://web.archive.org/web/20140102191953/http://www.horseshoecrab.org/research/sites/default/files/TIBTECH-rFC.pdf |archive-date=2 January 2014 |access-date=2 January 2014}}</ref>
+[[Ovalbumin]] is frequently contaminated with endotoxins. Ovalbumin is one of the extensively studied proteins in animal models and also an established model allergen for airway hyper-responsiveness (AHR). Commercially available ovalbumin that is contaminated with LPS can falsify research results, as it does not accurately reflect the effect of the protein antigen on animal physiology.<ref>{{cite journal | vauthors = Watanabe J, Miyazaki Y, Zimmerman GA, Albertine KH, McIntyre TM | title = Endotoxin contamination of ovalbumin suppresses murine immunologic responses and development of airway hyper-reactivity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 43 | pages = 42361–42368 | date = October 2003 | pmid = 12909619 | doi = 10.1074/jbc.M307752200 | doi-access = free }}</ref>
-'''1.    Testing'''
+In pharmaceutical production, it is necessary to remove all traces of endotoxin from drug product containers, as even small amounts of endotoxin will cause illness in humans.  A [[depyrogenation]] oven is used for this purpose.  Temperatures in excess of 300&nbsp;°C are required to fully break down LPS.<ref>{{Cite web | vauthors = Komski L |date = 16 December 2014 |title=The Detection of Endotoxins Via the LAL Test, the Chromogenic Method | publisher = Wako Chemicals USA, Inc. |url= http://www.wakopyrostar.com/blog/post/the-detection-of-endotoxins-via-the-lal-test-the-chromogenic-method/ |url-status=dead |archive-url= https://web.archive.org/web/20150329083636/http://www.wakopyrostar.com/blog/post/the-detection-of-endotoxins-via-the-lal-test-the-chromogenic-method |archive-date=29 March 2015 |access-date=14 March 2015}}</ref>
-Lipopolysaccharide, is a significant factor that makes bacteria harmful, and it helps categorize them into different groups based on their structure and function. This makes LPS a useful marker for telling apart various Gram-negative bacteria. Swiftly identifying and understanding the types of pathogens involved is crucial for promptly managing and treating infections. Since LPS is the main trigger for the immune response in our cells, it acts as an early signal of an acute infection. Therefore, LPS testing is more specific and meaningful than many other serological tests. The current methods for testing LPS are quite sensitive, but many of them struggle to differentiate between different LPS groups. Additionally, the nature of LPS, which has both water-attracting and water-repelling properties (amphiphilic), makes it challenging to develop sensitive and user-friendly tests. The typical detection methods rely on identifying the lipid A part of LPS. However, this method has limitations because Lipid A is very similar among different bacterial species and serotypes. LPS testing techniques fall into six categories, and they often overlap: in vivo tests, in vitro tests, modified immunoassays, biological assays, and chemical assays.'''
+The standard [[assay]] for detecting presence of endotoxin is the [[Limulus Amebocyte Lysate]] (LAL) assay, utilizing blood from the [[Horseshoe crab]] (''Limulus polyphemus'').<ref name="Iwanaga_2007">{{cite journal | vauthors = Iwanaga S | title = Biochemical principle of Limulus test for detecting bacterial endotoxins | journal = Proceedings of the Japan Academy. Series B, Physical and Biological Sciences | volume = 83 | issue = 4 | pages = 110–119 | date = May 2007 | pmid = 24019589 | pmc = 3756735 | doi = 10.2183/pjab.83.110 | bibcode = 2007PJAB...83..110I }}</ref> Very low levels of LPS can cause coagulation of the limulus lysate due to a powerful amplification through an enzymatic cascade. However, due to the dwindling population of horseshoe crabs, and the fact that there are factors that interfere with the LAL assay, efforts have been made to develop alternative assays, with the most promising ones being [[ELISA]] tests using a [[recombinant protein|recombinant]] version of a protein in the LAL assay, Factor C.<ref name="pmid11451451">{{cite journal | vauthors = Ding JL, Ho B | title = A new era in pyrogen testing | journal = Trends in Biotechnology | volume = 19 | issue = 8 | pages = 277–281 | date = August 2001 | pmid = 11451451 | doi = 10.1016/s0167-7799(01)01694-8 | url = http://www.horseshoecrab.org/research/sites/default/files/TIBTECH-rFC.pdf | url-status = dead | access-date = 2 January 2014 | archive-url = https://web.archive.org/web/20140102191953/http://www.horseshoecrab.org/research/sites/default/files/TIBTECH-rFC.pdf | archive-date = 2 January 2014 }}</ref>
-'''2.    Pathophysiology'''
+;Testing: Lipopolysaccharide, is a significant factor that makes bacteria harmful, and it helps categorize them into different groups based on their structure and function. This makes LPS a useful marker for telling apart various Gram-negative bacteria. Swiftly identifying and understanding the types of pathogens involved is crucial for promptly managing and treating infections. Since LPS is the main trigger for the immune response in our cells, it acts as an early signal of an acute infection. Therefore, LPS testing is more specific and meaningful than many other serological tests. The current methods for testing LPS are quite sensitive, but many of them struggle to differentiate between different LPS groups. Additionally, the nature of LPS, which has both water-attracting and water-repelling properties (amphiphilic), makes it challenging to develop sensitive and user-friendly tests. The typical detection methods rely on identifying the lipid A part of LPS. However, this method has limitations because Lipid A is very similar among different bacterial species and serotypes. LPS testing techniques fall into six categories, and they often overlap: in vivo tests, in vitro tests, modified immunoassays, biological assays, and chemical assays.''' <ref name="Page_2022" />
-LPS is a powerful toxin that, when in the body, triggers inflammation by binding to cell receptors. Excessive LPS in the blood can lead to endotoxemia, potentially causing a harmful condition called septic shock. This condition includes symptoms like rapid heart rate, quick breathing, temperature changes, and blood clotting issues, resulting in blood vessels widening and reduced blood volume, leading to cellular dysfunction. Recent research indicates that even small LPS exposure is associated with autoimmune diseases and allergies. High levels of LPS in the blood can lead to metabolic syndrome, increasing the risk of conditions like diabetes, heart disease, and liver problems. LPS also plays a crucial role in symptoms caused by infections from harmful bacteria, including severe conditions like Waterhouse-Friderichsen syndrome, meningococcemia, and meningitis. Certain bacteria can adapt their LPS to cause long-lasting infections in the respiratory and digestive systems. Recent studies have shown that LPS disrupts cell membrane lipids, affecting cholesterol and metabolism, potentially leading to high cholesterol, abnormal blood lipid levels, and non-alcoholic fatty liver disease. In some cases, LPS can interfere with toxin clearance, which may be linked to neurological issues.'''
+;Pathophysiology: LPS is a powerful toxin that, when in the body, triggers inflammation by binding to cell receptors. Excessive LPS in the blood can lead to endotoxemia, potentially causing a harmful condition called septic shock. This condition includes symptoms like rapid heart rate, quick breathing, temperature changes, and blood clotting issues, resulting in blood vessels widening and reduced blood volume, leading to cellular dysfunction. Recent research indicates that even small LPS exposure is associated with autoimmune diseases and allergies. High levels of LPS in the blood can lead to metabolic syndrome, increasing the risk of conditions like diabetes, heart disease, and liver problems. LPS also plays a crucial role in symptoms caused by infections from harmful bacteria, including severe conditions like Waterhouse-Friderichsen syndrome, meningococcemia, and meningitis. Certain bacteria can adapt their LPS to cause long-lasting infections in the respiratory and digestive systems. Recent studies have shown that LPS disrupts cell membrane lipids, affecting cholesterol and metabolism, potentially leading to high cholesterol, abnormal blood lipid levels, and non-alcoholic fatty liver disease. In some cases, LPS can interfere with toxin clearance, which may be linked to neurological issues.<ref name="Page_2022" />
 == See also ==