A Single Amino Acid Change in the Marburg Virus Matrix Protein VP40 Provides a Replicative Advantage in a Species-Specific Manner

Koehler, Alexander; Kolesnikova, Larissa; Welzel, Ulla; Schudt, Gordian; Herwig, Astrid; Becker, Stephan

doi:10.1128/jvi.02670-15

Cited by 16 publications

(16 citation statements)

References 43 publications

(61 reference statements)

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“…The generation of recombinant viruses from cDNA plasmids has been developed for several filoviruses as full-length genome or life imaging systems [287][288][289][290] . The full-length genome systems expressing reporter genes reduce the time and effort needed to detect virus growth but still require biosafety level 4 (BSL-4) biocontainment and have the potential to be attenuated.…”

Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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“…This mutation, which occurs in the flexible linker region between the VP40 N- and C-terminal domains [90], has no effect on the ability of VP40 to inhibit the IFN response in guinea pig or human cells. Instead, D184N contributes to VP40’s role as the viral matrix protein [116]. In guinea pig but not human cells, the D184N mutation improves the ability of VP40 to attract nucleocapsids to the site of virion budding, and it improves budding, itself.…”

Section: Rodent-adapted Filoviruses and Their Mutationsmentioning

confidence: 99%

“…The mutation also reduces the suppressive effect that VP40 has on viral RNA synthesis in guinea pig cells, thereby improving replication and transcription. Accordingly, recombinant MARV containing only the D184N mutation in VP40 outgrows WT-MARV in guinea pig cells, although whether the mutation is solely responsible for the increase in GPA-MARV/Mus virulence remains to be determined [116]. Two other guinea pig-adapted marburgviruses have been generated, GPA-MARV variant Angola (GPA-MARV/Ang) and GPA-RAVV; however, neither of these viruses possesses the D184N mutation (Fig.…”

Section: Rodent-adapted Filoviruses and Their Mutationsmentioning

confidence: 99%

“…This necessarily implies the existence of some host-specific factor or condition that is required for proper structural assembly of virions; however, the identity of this host factor is unknown. Likewise, mouse- and guinea pig-adaptation of marburgviruses produces in most, but not all, cases the D184N mutation in VP40 that affects virion assembly and budding [68, 82, 83, 90, 116]. The question of why this step in the viral life-cycle should be a restricting factor remains unanswered, but it presumably depends on elements or conditions in rodent cells that differ from human cells.…”

Section: Conlcusions and Perspectivesmentioning

confidence: 99%

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Rodent-Adapted Filoviruses and the Molecular Basis of Pathogenesis

Banadyga

Dolan

Ebihara

2016

Journal of Molecular Biology

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Ebola, Marburg, and Ravn virus, all filoviruses, are the causative agents of severe hemorrhagic fever. Much of what we understand about the pathogenesis of filovirus disease is derived from work with animal models, including non-human primates (NHPs), which are considered the “gold standard” filovirus model since they faithfully recapitulate the clinical hallmarks of filovirus disease. However, rodent models, including the mouse, guinea pig, and hamster, also exist for Ebola, Marburg, and Ravn viruses, and although they may not reproduce all the clinical signs of filovirus disease, thanks to their relative ease-of-use and low cost they are often the first choice for initial descriptions of virus pathogenesis and evaluation of anti-viral prophylactics and therapeutics. Since filoviruses do not cause significant disease in adult, immunocompetent rodents, these models rely on “rodent-adapted” viruses that have been passaged several times through their host until virulence and lethality are achieved. In the process of adaptation, the viruses acquire numerous nucleotide/amino acid mutations that contribute to virulence in their rodent host. Interestingly, virus protein 24 (VP24) and nucleoprotein (NP) appear to be major virulence factors for ebolaviruses in rodents, whereas VP40 appears to be the major virulence factor for marburgviruses. By characterizing these mutations and understanding the molecular mechanisms that lead to the acquisition of virulence, we can gain better insight into the pathogenic processes that underlie filovirus disease in humans. These processes, and the viral and/or cellular proteins that contribute to them, will make attractive targets for the development of novel therapeutics and countermeasures.

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“…Our previous study showed that the D184N mutation in VP40 negated its suppressive function on MARV polymerase activity specifically in guinea pig cells, and thus conveys a species-specific improved viral fitness (Koehler et al, 2015). We therefore presumed a functional co-selection of the mutations in VP40 and in L, and tested the function of L mutants in the presence of VP40 and VP40 D184N .…”

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confidence: 99%

An active site mutation increases the polymerase activity of the guinea pig-lethal Marburg virus

Koehler

Kolesnikova

Becker

2016

Journal of General Virology

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Marburg virus (MARV) causes severe, often fatal, disease in humans and transient illness in rodents. Sequential passaging of MARV in guinea pigs resulted in selection of a lethal virus containing 4 aa changes. A D184N mutation in VP40 (VP40 D184N ), which leads to a speciesspecific gain of viral fitness, and three mutations in the active site of viral RNA-dependent RNA polymerase L, which were investigated in the present study for functional significance in human and guinea pig cells. The transcription/replication activity of L mutants was strongly enhanced by a substitution at position 741 (S741C), and inhibited by other substitutions (D758A and A759D) in both species. The polymerase activity of L carrying the S741C substitution was eightfold higher in guinea pig cells than in human cells upon co-expression with VP40 D184N , suggesting that the additive effect of the two mutations provides MARV a replicative advantage in the new host.

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A Single Amino Acid Change in the Marburg Virus Matrix Protein VP40 Provides a Replicative Advantage in a Species-Specific Manner

Cited by 16 publications

References 43 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

Rodent-Adapted Filoviruses and the Molecular Basis of Pathogenesis

An active site mutation increases the polymerase activity of the guinea pig-lethal Marburg virus

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