# Chemotaxis

 Gene Ontology Parent Taxi's response to chemical stimulus Subordinate positive / negative cellular chemotaxis axon steering QuickGO

Chemotaxis (Gr. Chêmeia = chemistry and ancient Greek τάξις, taxis = order, parade) describes the influencing of the direction of movement of living beings or cells by substance concentration gradients . If the movement is controlled in such a gradient in the direction of higher concentrations of the substance, so is referred to as the positive chemotaxis and identifies the substance attractant or Attractant . If the movement is directed in the opposite direction, it is called negative chemotaxis and the substance in question is called a deterrent or repellent . Positive chemotaxis can turn into negative at high concentrations of a substance.

## Phylogenesis and chemotactic signaling

Chemotaxis is one of the most basic cellular physiological responses. In the early stages of phylogenesis , the emergence of receptor systems for the detection of harmful and beneficial substances for unicellular organisms was of significant advantage. Extensive analyzes of the chemotactic processes of the eukaryotic protozoon Tetrahymena pyriformis and the consensus sequence of occurring amino acids in the primordial soup indicate a good correlation between chemotactic properties of these relatively simple organic molecules and the development of the earth. It was therefore assumed that molecules that appeared early (e.g. glycine , glutamine , proline ) are chemically very attractive and those that appear later (e.g. tyrosine , tryptophan , phenylalanine ) have a chemically repellent effect.

## Bacterial chemotaxis

In bacteria, the way in which chemotaxis is controlled differs depending on the type of locomotion: free swimming by means of flagella or by rotating helical bacteria ( spirochetes ), crawling on surfaces of solid or gel-like surfaces ( myxobacteria , some cyanobacteria ).

In the case of bacteria that use flagella to move freely in liquid medium, a distinction must be made between polar and peritrich flagella , i.e. between those that only have flagella at one or two ends (“poles”) and those that have multiple flagella Wear distributed over the entire cell surface.

Polar flagellated bacteria when moving by swimming
Peritrich flagellated bacteria when moving and staggering
• Monopolar flagellated bacteria let their flagella rotate around the helix axis according to their helix direction so that a feed is generated. If there are several flagella at the flagellated end of the cell, they combine to form a coiled bundle that rotates around the helix axis (also known as flagella). The bacterial body rotates with a lower rotational frequency in the opposite direction (preservation of the angular momentum).
• Bipolar flagellated bacteria rotate their flagella at one end of the cell like those of the monopolar flagellated bacteria, but the flagella at the other cell end are repulsed by the bacterial body and rotate (individually or as a flagella bundle) around the cell end.
• Bacteria flagellated by Peritrich let their flagella rotate in the same direction, so that they combine to form a rearwardly directed, helical bundle of flagella ("flagella") rotating around the helix axis, whereby a feed is generated. If the direction of rotation of the flagella is reversed, the flagella align themselves in different directions, the advancements of the individual flagella approximately cancel each other out and the bacterium staggers around one point.

The problem with the chemotaxis of bacteria is that in the size dimension of the usual bacteria (1 - 10 µm) the substance concentration gradient is covered by the Brownian molecular movement. As a result, a bacterium at a certain location in the substance concentration field cannot recognize the direction of the gradient.

With free-swimming, polar flagellated bacteria, the way out is for the bacterium to swim a distance in a randomly determined direction. If the substance concentration increases along this route, with positive chemotaxis, the more the concentration increases, the longer it will maintain this random swimming direction. But if the concentration drops, the bacterium very soon reverses the direction of movement by switching the direction of rotation of the flagella. The swimming direction is not exactly, but only roughly opposite. The length of this second locomotion phase depends in turn on whether the substance concentration rises more or less or falls. The distance covered is longer, the more the substance concentration increases. The result is that the overall bacterium moves in the direction of increasing concentration. In the case of negative chemotaxis, the bacterium behaves in the opposite way: When the concentration falls, it swims longer in the chosen direction than when the concentration increases. Overall, the bacterium moves in the direction of falling substance concentration.

Movement behavior of peritrich bacteria with positive chemotaxis

Free swimming, peritrich flagellated bacteria behave somewhat differently. They too swim a distance in a randomly determined direction. In the case of positive chemotaxis, they too maintain this random swimming direction the longer the higher the concentration increases, and only briefly when the concentration decreases. Then the bacterium starts to tumble by reversing the direction of rotation of the flagella distributed over the entire surface - unlike polar flagellated bacteria - and after a short tumbling phase it moves in a new, again random direction. The length of this second movement phase depends in turn on the change in the substance concentration. Movement and staggering alternate constantly and the distance covered when moving is longer, the more the substance concentration increases. The result is that the overall bacterium moves in the direction of increasing concentration. In the case of negative chemotaxis, the bacterium behaves in the opposite way: When the concentration falls, it swims longer in the chosen direction than when the concentration increases. Overall, the bacterium moves in the direction of falling substance concentration.

### Chemotaxis in peritrichal bacteria

The flagella distributed on the surface of a perithric bacterium rotate as follows:

1. Counterclockwise rotating flagella, seen from the tip of the flagella to the bacterial body, nestle against each other to form a helical, rotating bundle; so the bacteria swim in a straight line with the flagella bundle pointing backwards. The flagella bundle acts as a thrust propeller.
2. When flagella rotate clockwise, no bundle is formed and each flagellum points in a different direction. As a result, the bacterium stumbles in place.

The direction of rotation of the flagella can be reversed. When the direction of rotation changes from counterclockwise to clockwise, the bundle of flagella loosens and the flagella align itself in all directions.

#### behavior

The general dynamics of a bacterium result from alternating tumbling and swimming movements. If you observe a bacterium in a uniform environment, it looks like a sequence of random movements: relatively straight movements are interrupted by seemingly arbitrary tumbling movements. It is generally not possible for bacteria to choose the direction of movement or to always move in a straight line. This means that the bacteria “forget” in which direction they are moving. Given these limitations, it's noteworthy that bacteria can follow certain chemical attractants and evade pollutants.

In the presence of a substance concentration gradient , bacteria adapt to this environment. If a bacterium “notices” that it is moving in the right direction (towards the attractant / away from the pollutant), it swims longer in a straight line before tumbling. If it moves in the wrong direction, tumbling occurs more quickly and the bacterium randomly takes a different direction. In this way, bacteria reach the higher concentration of the attractant very effectively. Even in an environment with extremely high concentrations, they can respond to minimal deviations.

It is noteworthy that this expedient, seemingly arbitrary mode of movement results from the choice between two arbitrary modes of movement; namely the straight swimming and the tumbling. The chemotactic reactions of the bacteria appear like in higher living beings, which have a brain, the forgetting, the choosing of movements and the quorum.

#### Signal transduction

Substance concentration gradients are perceived by multiple transmembrane receptors called methyl-accepting chemotaxis proteins (MCPs), which differ in terms of their ligands. Attractants or deterrents can be bound either directly or indirectly through interaction with proteins of the periplasm. Signals from these receptors are transmitted through the cell membrane into the cytoplasm and activate Che proteins, which in turn modify the tumbling frequency of the cell or the receptors themselves.

##### Flagella regulation

The proteins CheW and CheA bind the receptor. External stimuli cause autophosphorylation in the histidine kinase, CheA, on a single highly conserved histidine residue. CheA, in turn, transfers the phosphoryl group to aspartate residues in response coordinators CheB and CheY. This signal transduction mechanism is called the “two-component system” and is often found in bacteria. CheY induces rotation of the bacterium through interaction with the flagellar switch protein FliM and thus changes the direction of rotation of the flagella from left-handed to right-handed. Changing the direction of rotation of a single flagellum can stop its entire function and cause confusion.

##### Receptor regulation

CheB, activated by CheA, acts as a methylesterase and thus separates methyl groups from glutamate residues on the cytosolic side of the receptor. It is an antagonist to CheR - a methyl transferase - that adds methyl groups to the same glutamate side chains. The more methyl esters are bound to the receptor, the more sensitive it is to frightful substances. Since the signal from the receptor triggers its demethylation through a feedback loop, the system is constantly adapted to chemical conditions in the environment and therefore remains sensitive to small changes even at extreme concentrations. This regulation enables the bacterium to “remember” chemical conditions of the recent past and to compare them with the current ones. In this respect, it “knows” whether it is moving with or against a concentration gradient. Further regulatory mechanisms such as receptor clustering and receptor-receptor interactions must be mentioned, as these are also important elements of signal transmission and influence the sensitivity of the bacterium.

## Eukaryotic chemotaxis

The mechanism used in eukaryotes is different from the prokaryotic. Nevertheless, the perception of the substance concentration gradient forms the basis here too. Because of their size, prokaryotes cannot sense effective concentration gradients; thus they scan and assess their surroundings by constantly swimming (alternating straight ahead or rotating). Eukaryotes, in turn, are able to detect gradients, which is reflected in a dynamic and polarized distribution of receptors in the plasma membrane. Induction of these receptors by attractants or chemorepellents triggers migration to or away from the chemical substance. Receptor levels, intracellular signal pathways, and effector mechanisms all represent diverse components of eukaryotic chemotaxis. Here amoeboid movement as well as cilia or flagella are characteristic effectors of unicellular organisms (e.g. amoeba, Tetrahymena). Some representatives of higher vertebral origin, such as B. immune cells, also move to where they are needed. Apart from a few immunocompetent cells (granulocyte, monocyte, lymphocyte), an astonishingly large group of cells - formerly classified as tissue-bound - are in fact under certain physiological (e.g. mast cell, fibroblast, endothelial cell) or pathological conditions (e.g. Metastasis) capable of migration. Chemotaxis is also of great importance in the early phases of embryogenesis , since the development of the cotyledons is controlled by concentration gradients of messenger substances.

### Motility

In contrast to bacterial chemotaxis, the mechanisms by which eukaryotes move are relatively unclear. In some cases, external chemotactic gradients seem to be perceived, which are reflected in an intracellular PIP3 gradient that influences a signal cascade that culminates in the polymerization of actin filaments. Their growing distal end forms connections with the internal surface of the plasma membrane via various peptides and pseudopodia are formed. A eukaryotic cilium can also be involved in eukaryotic chemotaxis. The movement can be explained by a Ca 2+ based modification of the microtubular system of the basal body and the axoneme (9 * 2 + 2). The coordinated rowing of hundreds of cilia is synchronized by a submembranous system between the basal bodies. The details of the signal cascades responsible are still not clear.

Chemotaxis of granulocytes, explanations in the picture description

#### Migratory resonance associated with chemotaxis

Although chemotaxis is the most widely studied method of cell migration, other forms of locomotion at the cellular level should be mentioned.

• Chemokinesis is also triggered by soluble molecules in the environment. However, this is a non-vector, random taxis. It can be described as a scanning of the environment rather than a movement between two clear points. No directional components can be specified for occurrence or extent.
• In haptotaxis , the attractant gradient is expressed on the cell surface, while in the classic model it was more likely to be detected in free space. The extracellular matrix (ECM) plays a key role here. Fascinating examples of the haptotaxis model are transendothelial migration and angiogenesis, in which the presence of bound ligands is considered to be the trigger.
• Necrotaxis embodies a special kind of chemotaxis in which messenger substances are released from necrotic or apoptotic cells. The character of these substances determines whether cells are attracted or rejected, which underlines the pathophysiological importance of this phenomenon.

### Receptors

Eukaryotes sense the presence of chemotactic stimuli mainly through 7-transmembrane (tortuous) heterotrimeric G-protein coupled receptors, the vast class of which makes up a significant part of the genome. Some members of this gene superfamily are used in the visual process (rhodopsin) or the sense of smell. The main classes of specialized chemotactic receptors are controlled by formyl peptides (FPR), chemokines (CCR or CXCR) and leukotrienes (BLT). By the way, cell migration can also be initiated via an abundance of membrane receptors by amino acids, insulin or vasoactive peptides.

#### Chemotactic selection

Due to their genetic basis, some receptors are integrated into the cell membrane for a long time; others show short-term dynamics in which they assemble ad hoc in the presence of a ligand. Its various facets and the versatility of the ligands allow the selection of a responder through a simple test. Chemotactic selection can be used to demonstrate whether an as yet uncharacterized molecule functions via the long or short-term path. The term chemotactic selection also designates a technique that sorts eukaryotes or prokaryotes based on their sensitivity to selector ligands.

### Chemotactic ligands

The list of molecules that elicit chemotactic phenomena is relatively long - a distinction is made between primary and secondary. The most important representatives of primary ligands are:

• Formyl peptides are di-, tri- and tetrapeptides of bacterial origin (formyl group at the N-terminus of the peptide). They are released in vivo or after the bacterium has decomposed. A typical representative of this group is N-formylmethionyl-leucyl-phenylalanine (fMLF or fMLP in references). It plays in inflammatory processes a key component in Beckoning neutrophilic granulocytes and monocytes .
• C3a and C5a are intermediates in the complement cascade . Their synthesis is coupled with three alternative ways of complement activation (classic, lectin and alternative way). The main targets of these derivatives are also neutrophils and monocytes.
• Chemokines represent a class of their own as cytokines . Their grouping (C, CC, CXC, CX³C) speaks not only for their structure (special alignment of disulfide bridges), but also for their accuracy: CC chemokines act on monocytes (e.g. RANTES ), CXC in turn are neutrophil-specific ( e.g. IL-8 ).

Investigations of the 3D structure of chemokines allow us to conclude that a characteristic linkage of β-sheets and alpha-helixes enables sequence expression that is essential for interaction with the receptor. Dimerization and increased biological activity have been shown by crystallography for several chemokines such as B. IL-8 demonstrated.

• Leukotrienes belong to the group of eicosanoids : They are important lipid mediators of the arachidonic acid cascade, converted by 5-dipoxygenase. Leukotriene B4 (LTB4), which triggers adhesion , chemotaxis and leukocyte aggregation, should be emphasized . Its characteristic effect is induced via G-protein-coupled heptahelical leukotriene receptors and is particularly evident during inflammatory and allergic processes.

#### Chemotactic Range Fitting (CRF)

A differentiation is generally made on the basis of the optimal effective concentration of the ligand. Sometimes, however, correlation of the evoked effect and the ratio between responder cells and the total number are also considered. Studies on ligand families (e.g. amino acids or oligopeptides) have shown that there is an interaction between range (deflection, number of responders) and chemotactic activity: The lock function can also be observed over great distances; repulsive character, on the other hand, acts at a short distance.

## Clinical significance

An altered migratory potential of the cells is of relatively great importance in the development of several clinical symptoms and syndromes. Modified chemotactic activity of extracellular (e.g. Escherichia coli) or intracellular (e.g. Listeria monocytogenes) pathogens is of tremendous clinical interest. Changing the endogenous chemotactic competence of these microorganisms can reduce or even erase the incidence of infections or the spread of many contagious diseases. Aside from infectious diseases, there are several other conditions in which impaired chemotaxis is the primary aetiological factor, such as Chediak-Higashi syndrome , where gigantic intracellular vesicles inhibit normal cell migration.

Chemotaxis (Chtx.) In diseases
Disease type increased Chtx. decreased Chtx.
Infections Inflammation AIDS , brucellosis
Chtx. leads to disease - Chediak-Higashi syndrome, Kartagener syndrome
Chtx. is impaired Atherosclerosis , arthritis , periodontal disease , psoriasis , reperfusion injury , metastatic tumors Multiple sclerosis , Hodgkin's disease , male infertility
Intoxication, intoxication Asbestosis , benzopyrene Hg and Cr salts, ozone (O 3 )

## Measurement of chemotaxis

A variety of techniques are available to evaluate the chemotactic activity of the cell or the attractive or repulsive character of the ligand. The basic requirements for the measurement are as follows:

• Substance concentration gradients can develop very quickly within the system and are maintained for a long time
• Chemotactic and chemokinetic activities are profiled
• Cell migration is possible towards and away from the axis of the concentration gradient
• Recorded reactions are actually the result of active cell migration

Aside from the fact that there is still no ideal chemotactic exam, some protocols and pieces of equipment are consistent with the conditions described above. Most commonly used are:

• Agar sample, e.g. B. PP chamber
• Two-chamber techniques, e.g. B. Boyden chambers , Zigmond chambers, Dunn chambers, multi-well chambers, capillary techniques
• Others: T-Maze method, opalescence technique, orientation samples

In order for a cell to move, it needs some cellular components (such as cellular motors, various enzymes, etc.). Furthermore, it must be able to change its shape. In general, one speaks of two types of cell locomotion:

• Hapoptatic (movement based on physical and mechanical stimuli)
• Chemotactic (migration in response to a chemical gradient)

## Theoretical description

The question of the temporal development of the concentration of chemotactically excitable cells or living beings in a volume leads to the partial differential equation using the Gaussian integral theorem. In addition to the chemotactically induced movement along the gradient , the flow usually also has a diffusion component. The equation thus takes the form . It denotes a diffusion constant. In addition to this simplest case, there are mathematical descriptions of more complex situations in theoretical biology in which, for example, the chemotactically active substance can be produced by the cells themselves. ${\ displaystyle {\ frac {\ partial {u}} {\ partial {t}}} + \ nabla J = 0.}$${\ displaystyle J}$${\ displaystyle {\ frac {\ partial {u}} {\ partial {t}}} + \ nabla J _ {\ rm {chemo}} - \ nabla D \ nabla u = 0}$${\ displaystyle D}$

## History of chemotaxis research

Movement of living beings and cells was first discovered during the development of microscopes ( Leeuwenhoek ). More detailed investigations, including chemotaxis, were carried out by Theodor Wilhelm Engelmann (1881) and Wilhelm Pfeffer (1884) in the field of bacteria and by HS Jennings (1906) in the field of ciliates .

The Nobel laureate Ilya Ilyich Metschnikow has contributed to further advances with his studies of phagocytosis . The importance of chemotaxis in biology and clinical pathology was largely recognized in the 1930s. During this time, basic definitions were drawn up on the subject. H. Harris described the most important quality control methods for chemotaxis tests during the 1950s.

In the 1960s and 1970s, the breakthrough in modern cell biology and biochemistry laid the foundation for new methods that enabled the study of migratory responder cells and subcell fractions that are responsible for the chemotaxis of cells. J. Adler's pioneering studies marked a major turning point in our understanding of the entire process of intracellular signaling in bacteria. On November 3, 2006, Dennis Bray, University of Cambridge, received the Microsoft European Science Award for his studies of the chemotaxis of Escherichia coli .

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