Marburg virus

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Marburg virus
Marburg virus.jpg

Marburg virus

Systematics
Classification : Viruses
Area : Riboviria
Empire : Orthornavirae
Phylum : Negarnaviricota
Subphylum : Haploviricotina
Class : Monjiviricetes
Order : Mononegavirals
Family : Filoviridae
Genre : Marburg virus
Type : Marburg-Marburg virus
Subspecies : Marburg virus
Taxonomic characteristics
Genome : (-) ssRNA
Baltimore : Group 5
Symmetry : helical
Cover : available
Scientific name
Marburg marburg virus
Short name
MARV
Left
NCBI  Taxonomy: 11269
NCBI  Reference: DQ217792
ViralZone ( ExPASy , SIB): 224
ICTV Taxon History: 201851571
ICTVdB Virus Code : 01.025.0.01.001

The Marburg virus is an enveloped single (-) - strand RNA virus (ss (-) RNA) of the Filoviridae family and genus Marburg virus and the causative agent of Marburg fever .

features

Fig. 2: Representation of part of the nucleocapsid of the Marburg virus in cryoelectron tomography (CryoEM), inserted scale = 50  Å = 5  nm .

Size and shape

This virus has a thread-like ( Latin filum , "thread") shape, this basic structure can be elongated or curved or bent. This results in structures that are U-shaped, circular, like the number 6 or bent like a fish hook . The virus has a length of about 800  nm (range from 130 to 2600 nanometers), while the diameter is relatively constant at 80-100 nm. In electron microscopic image is cross-shaped grooves can be recognized. Investigations from 2011 with the help of cryoelectron tomography show an average length of 892 nm, the average diameter is 91 nm. Together with the Ebola viruses from the same family, the Marburg virus is one of the largest known RNA viruses.

Structure of the virion

The virion consists of a virus envelope that surrounds the helical capsid in which the virus genome is located. A total of seven structural proteins are involved in the construction of the virion . In infected host cells , replication takes place within intracellular inclusions in which precursors of the nucleocapsid are formed. These tubular structures with an outer diameter of 45-50 nm are formed by the nucleoproteins (NP). Together with the viral proteins VP30, VP35 and L, this creates the nucleocapsid. The viral genome is bound to the NP, which is why one speaks of a nucleocapsid. The NP is necessary for transcription and replication and is also important in so-called budding , the strangulation of virus particles from the host cell. The complex of proteins VP35 and L serves as an RNA-dependent RNA polymerase , VP35 being the cofactor of the polymerase. In addition to NP, VP35 and L, VP30 is also involved in transcription and replication, but the exact mode of action of this protein has not yet been clarified.

The two matrix proteins VP40 (main component) and VP24 represent the connection of the virus envelope with the nucleocapsid, whereby in the cross-section of the virion VP24 is more present in the inside and VP40 in the outer part. VP40 can easily be cleaved from the nucleocapsid. After protein synthesis in the host cell, VP40 associates with the cell membrane and is thus involved in budding , as parts of the cell membrane form the virus envelope. Although VP24 is more likely to be located inside the virion, this viral protein can be detached from the nucleocapsid by salt solutions with increasing concentrations. In the release of virus particles, VP24 is involved after replication and before budding . In addition to the lipids of the cell membrane, which come from the host cell, the virus envelope also contains viral glycoproteins (GP). The GP is a transmembrane protein that is anchored in the viral envelope and thorn-like to the outside bulges ( English spikes forms). In the host cell, it is glycosylated during transport from the endoplasmic reticulum to the cell membrane ; H. There are carbohydrate chains to the protein attached. The functions of GP lie in the attachment to the host cell at special receptors and in the fusion of the virus envelope.

Figure 2 shows a cross section of the virion. Inside, the RNA (red) can be seen, connected to the nucleoproteins (yellow) and other viral proteins that together form the nucleocapsid. This is surrounded by the virus envelope (green to blue), the glycoproteins of which can be seen as protrusions about 10 nm long (dark blue).

Genome

The viral genome is in the form of a single-stranded RNA molecule ( ribonucleic acid ) with (-) polarity ( antisense ) . The RNA comprises 19 kb ( kilobase pairs ), with a single strand not having base pairs but unpaired bases in the nucleotides . Genetic analyzes show that the RNA is composed of 19,111 to 19,114 nucleotides. The genome comprises seven genes , which are considered to be cistrons and which are linearly behind one another. Each gene consists of a highly conserved start and stop signal , an unusually long gene segment at the 3 'and 5' end which is not for the translation is used, and the intermediate open reading frame (engl. Open reading frame , ORF). The genes can be separated from one another by short sections of non-coding ribonucleic acid ( intergenic regions , IR), as is the case, for example, with the genes for GP and VP30. The IR segments range from 4 to 97 nucleotides. Alternatively, the stop signal and the start signal of the next gene can overlap; this applies, for example, to the genes for VP30 and VP24. This overlap can only be found in members of the Filoviridae family . At the 3 'and 5' ends there are sections that serve as promoters for transcription and replication.

Fig. 3: Structure of the Marburg virus genome

Figure 3 shows the basic structure of the genome of the Marburg virus. The genes which code for the seven viral proteins NP, VP35, VP40, GP, VP30, VP24 and L are arranged linearly from the 3 'to the 5' end . Their ORF are colored differently. Sections that belong to a gene but are not used for translation are shown as light gray boxes, the IR are shown as dark gray connectors and the starting and ending sequences at the 3 'and 5' ends appear black. Green triangles symbolize the start signals for transcription, while red stripes represent the stop signals.

Reservoir and diffusion

The reservoir from which the virus originates, or its reservoir host, is still not exactly known. It is believed to be the carrier of the Egyptian bat , a species of flying fox found in Europe and Africa . The virus and virus-specific antibodies could be detected in their blood, even in regions where no cases of the disease have so far been registered. As the fruit bat roosts in caves, outbreaks among miners can be associated with it.

The Marburg virus originates primarily from Africa and occurs in Uganda , Kenya (West Kenya) and probably Zimbabwe . Scientists believe that a further expansion is likely. The first cases of the disease were documented in Europe in 1967. In 2018 and 2020, the virus was also detected in flying foxes in Sierra Leone in West Africa .

virulence

This virus is a highly pathogenic agent that causes Marburg fever, a hemorrhagic fever , in humans. The mortality in this disease is, according to the Centers for Disease Control and Prevention (CDC) at least 23 to 25 percent. However , it was much higher in outbreaks in the Congo and Angola (see cases of illness ). As with the Ebola viruses, this high mortality indicates that neither the virus is adapted to humans nor humans to the Marburg virus, since it primarily infects other hosts . The rapid damage to its host up to its death is also not an advantageous effect for a virus, since it depends on a living host for its own reproduction and spread.

transmission

The Marburg virus is transmitted through the exchange of body fluids and through smear infection or contact infection . Virus particles remain infectious within clotted blood for a period of 4-5 days. In convalescents , the virus can  remain in pathogenic form in individual parts of the body - especially the sperm - for a few months after the acute infection has ended .

Systematics

Fig. 4: Phylogenetic tree of the genera Ebolavirus and Marburg virus (as of November 2008)

The genera Ebolavirus and Marburgvirus in the Filoviridae family are closely related, which is evident in the structure of the virions, among other things. The virus particles of the Marburg viruses are, however, significantly smaller than those of the Ebola virus, whereby the genome of the Marburg virus (MARV) is somewhat larger than that of the Ebola virus (EBOV).

The genus Marburg virus only contains one species that was formerly known as Lake Victoria Marburg virus . In 2010 the ICTV Filoviridae Study Group proposed an updated systematics and nomenclature for the representatives of the Filoviridae , which was implemented in the 9th ICTV Report of 2011. Accordingly, the following nomenclature should be used, in which the genus is referred to as Marburg virus and the species as Marburg-Marburg virus ( English Marburg marburg virus ).

  • Genus Marburg virus
    • Species Marburg-Marburgvirus (en. Marburg marburgvirus , obsolete Lake Victoria Marburg virus )
      • Virus 1: Marburg virus (en. Marburg virus, MARV)
      • Virus 2: Ravn virus (en. Ravn virus, RAVV)

history

Fig. 5: Electron microscopic representation of the Marburg virus

The virus was first found in 1967 in laboratory workers in Marburg (Hesse), later in Frankfurt am Main and Belgrade . When several people died in Marburg on August 25, 1967, the city was put into a kind of state of emergency. All infected people, including those who died later, previously had a very high fever , followed by nausea , vomiting and diarrhea . These symptoms indicated an infection with Salmonella or Shigella , but these bacteria could not be detected. In the second week after the onset of the disease, there were hemorrhagic symptoms, the patients were bleeding from body orifices and after needle punctures, and the internal organs , e.g. B. affects the liver . This resulted in death in about 25% of the patients. The yellow fever virus was initially considered as a possible pathogen , but was later ruled out. Bacteria of the genus Leptospira or Rickettsia were also excluded in the course of the investigations.

To clarify the aetiology of the previously unknown disease, specialists in tropical diseases traveled on behalf of the World Health Organization (WHO), including Werner Mohr from Hamburg and the virologist George B. Dick from London. A total of eight laboratories worldwide examined blood and tissue samples. In animal experiments were guinea pigs infected with these samples. They developed similar symptoms including a. Fever up to 40.3 ° C. Attempts to grow the unknown virus in cell culture turned out to be less effective. On November 20, 1967, less than three months after the outbreak began, the new virus could be viewed under an electron microscope. Blood samples of the infected guinea pigs were treated with formalin inactivated and using a then-new technique of negative staining (Engl. Negative stain examined). Werner Slenczka , Rudolf Siegert and their Chinese colleague Hsin Lu Shu at the Institute for Virology in Marburg and Dietrich Peters and Gerhard Müller at the Bernhard Nocht Institute for Tropical Medicine were involved in the study and the following publication .

A consensus of doctors Rudolf Siegert, Walter Hennessen and Gustav Adolf Martini submitted a daily report on research into the virus. By the end of August 1967, two zookeepers and two laboratory workers had died. 24 sufferers were in the University Hospital Frankfurt and the University Hospital of the University of Marburg on the isolation ward . A total of five people later died in Marburg and two in Frankfurt from the new virus.

In addition to the search for the new virus, an epidemiological investigation began at the same time to clarify its origin. The virus is most likely infected monkey trial - is the kind grivet ( Chlorocebus aethiops from -) Uganda in the laboratories of the pharmaceutical company Behringwerke been introduced in Marburg. That is why it was named Marburg virus. The pharmaceutical company used the animals to obtain measles and poliomyelitis vaccines. At the Paul Ehrlich Institute near Frankfurt, these vaccines were tested on Torlak Institute in Belgrade vaccines were also prepared. In retrospect, it was clarified that all those primarily infected had contact with blood, organs or cell cultures of the Ethiopian green monkeys. However, it was not possible to obtain sufficient information about the monkeys' health. Because of the Six Day War in June 1967, the animals could not be transported directly from Uganda to Frankfurt, but had to be housed in an enclosure at a London airport for some time . They had contact with finches from South Africa and langurs from Ceylon (today Sri Lanka ). A transmission of the virus from one animal species to another would have been theoretically possible, but could neither be proven nor ruled out. The monkeys of the species Chlorocebus aethiops were distributed to the institutes in several deliveries. In Marburg and Frankfurt no abnormalities regarding their state of health were noted, but the experimental animals were killed according to plan after a short time. The animals were kept in Belgrade for six weeks, with an above-average mortality rate of 33%. In retrospect, however, it was no longer possible to clarify whether the virus infection was responsible. In Germany, the monkeys of the species Chlorocebus aethiops , which were suspected to be carriers of the virus, were killed. This also affected animals from previous deliveries; the total number of test animals killed with hydrogen cyanide was over 600.

Socialist propaganda used the initially inexplicable infection as an occasion for anti-Western propaganda: For example, the then GDR state newspaper Neues Deutschland claimed that African monkeys were just a scapegoat to cover up secret attempts to develop chemical weapons.

Risk group, official classification

According to the Biological Agents Ordinance in conjunction with the TRBA ( Technical Rules for Biological Agents) 462, the virus species Marburg Marburg virus with the representative Marburg virus (MARV) is classified in the highest risk group  4.

The Biological Agents Ordinance defines four risk groups for biological agents . The work must be carried out taking appropriate protective measures into account, which are divided into four biological protection levels ( BSL) by the Biological Agents Ordinance . As a result, work with the Marburg virus must be carried out under the strict requirements of protection level 4. Filoviruses are researched in 20 laboratories worldwide (as of 2013). These must therefore comply with protection level 4 and are also referred to as BSL-4 laboratories . For Germany, this applies to the Bernhard Nocht Institute for Tropical Medicine in Hamburg , the Robert Koch Institute in Berlin , the Friedrich Loeffler Institute on the island of Riems , which is part of the Greifswald city, and the Institute for Virology at the University of Marburg .

Use as a biological weapon

The Marburg virus has been classified by the US CDC as a potential biological warfare agent of the highest hazard class. In military terms, the possibilities as a biological warfare agent were researched by the Soviet warfare agent program Biopreparat , which obtained samples of the virus during the initial outbreak in 1967. As far as is known, the distribution of the Marburg virus as an aerosol and the stability of freeze-dried virus particles have been researched.

With a simulated Bioterrorismusangriff was determined in 1998 that a variola -Marburg- chimera an economic would cause damage of about 26 billion US dollars per 100,000 people infected.

Cases of illness

Fig. 6: The Marburg virus spread in Angola (red) in 2005
On March 21, 2005, the Marburg virus was discovered in several blood samples from fatalities in Angola . In April the disease broke out in seven provinces. By then, over 215 Angolans had died of the Marburg virus. Most of the victims were younger than five years. The refusal of the population to isolate the infected was particularly problematic. In addition, the funeral of the deceased traditionally includes a personal farewell in the form of an embrace of the dead and then further direct, personal contact between the mourners. That is why it was extremely difficult to ensure the immediately necessary, immediate burial without any contact with the corpse. The risk of infection was thus increased considerably.
  • August 2007: Uganda , Kitaka, Kamwenge Province, 2 infected, 1 dead
  • July 10, 2008: The Bernhard Nocht Institute for Tropical Medicine in Hamburg announces the first case of the Marburg virus being introduced into Europe from Africa by a Dutch tourist in Bakel , the Netherlands. The 40-year-old woman died on July 11, 2008 in Leiden .
  • 2012: An outbreak in Uganda, in the Kabale district , in Ibanda in the Mbarara district and in the Kampala district , continues for three weeks, 15 infected, 4 dead
  • 2014: Uganda - one dead

Vaccinations

In April 2006, research results from researchers from the USA and Canada who succeeded in developing a vaccine against the Marburg virus were published. In animal experiments with rhesus monkeys , the vaccine was also found to be effective in post-exposure prophylaxis . The monkeys, which normally died after about 12 days of infection, survived the study period of 80 days after vaccination.

therapy

With AVI-7288, an American working group presented a drug for post -exposure prophylaxis for the first time in 2015 , which proved to be effective in primates . It is a 23 amino acids long Phosphorodiamidate- morpholino - oligomer (PMO) which is additionally loaded by the positive use of piperazines residuals (PMO plus). This oligomer selectively binds the mRNA - sequence of the nucleoprotein , thereby preventing its translation . In macaques showed in the placebo -controlled dose escalation study , a dose-dependent effect in use to four days after exposure with a survival up to 100% at 30 mg per kilogram of body weight (at 0% with placebo). So far there is no experience with the use on humans.

Reporting requirement

In Germany, direct or indirect evidence of the Marburg virus must be reported by name in accordance with Section 7 of the Infection Protection Act , provided the evidence indicates an acute infection. The obligation to notify primarily concerns the management of laboratories ( § 8 IfSG).

In Switzerland, the positive and negative laboratory analytical finding is a Marburg virus laboratory reportable namely after the Epidemics Act (EpG) in connection with the epidemic Regulation and Annex 3 of the Regulation of EDI on the reporting of observations of communicable diseases of man .

literature

  • Icon Health Publications: Marburg Virus - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet Referen. Icon Health, San Diego 2004, ISBN 0-497-00706-1 .
  • Kristina Brauburger, Adam J. Hume, Elke Mühlberger, Judith Olejnik: Forty-five years of Marburg virus research. In: Viruses. Volume 4, Number 10, October 2012, pp. 1878-1927, ISSN  1999-4915 . doi: 10.3390 / v4101878 . PMID 23202446 . PMC 3497034 (free full text). (Review).
  • Beate Lötfering: The nucleoprotein of the Marburg virus. Studies on the phosphorylation status. Tectum, Marburg 1998, ISBN 3-8288-0413-6 .
  • Christian Sänger: Studies on the transport and maturation of the Marburg virus surface protein GP as well as the release of progeny viruses. Tectum, Marburg 2000, ISBN 3-8288-1045-4 .
  • DIH Simpson: Marburg and Ebola Virus Infections: A Guide for their Diagnosis, Management, and Control. WHO Offset Publication, No. 36, Geneva 1977, full text (PDF)
  • Richard Preston : Hot zone: deadly viruses from the rainforest; a factual thriller. Droemer Knaur, Munich 1997, ISBN 3-426-77257-4 .
  • Ken Alibek, Stephen Handelman: Bioterror, Death From The Laboratory. Econ, Munich 2001, ISBN 3-548-75089-3 .

Web links

Commons : Marburg virus  - collection of pictures, videos and audio files

Individual evidence

  1. ↑ ICTV Master Species List 2018b.v2 . MSL # 34, March 2019
  2. ↑ a b ICTV: ICTV Taxonomy history: Akabane orthobunyavirus , EC 51, Berlin, Germany, July 2019; Email ratification March 2020 (MSL # 35)
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  26. ↑ IFRC : DREF Bulletin no. MDRUG005 of August 20, 2007: Uganda: Marburg Fever Ooutbreak. (PDF; 61 kB)
  27. ^ Bernhard Nocht Institute for Tropical Medicine , Hamburg: Dutch tourist falls ill with Marburg virus. Press release from July 10, 2008.
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  31. ↑ Alison E. Heald, Jay S. Charleston, Patrick L. Iversen, Travis K. Warren, Jay B. Saoud, Mohamed Al-Ibrahim, Jay Wells, Kelly L. Warfield, Dana L. Swenson, Lisa S. Welch, Peter Sazani, Michael Wong, Diane Berry, Edward M. Kaye, Sina Bavari: AVI-7288 for Marburg Virus in Nonhuman Primates and Humans. In: New England Journal of Medicine . Volume 373, No. 4, July 23, 2015, pp. 339-348, doi: 10.1056 / NEJMoa1410345 .