Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus

Messaoudi, Ilhem; Amarasinghe, Gaya K.; Basler, Christopher F.

doi:10.1038/nrmicro3524

Cited by 212 publications

(227 citation statements)

References 165 publications

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Section: Immune Evasionmentioning

confidence: 99%

“…This unbridled replication is thought to stem from the multiple means by which filovirus proteins can subvert the host immune system. In addition to serving structural and replication roles, both Ebolavirus and Marburgvirus proteins exploit specific intracellular and/or extracellular immune-mediated antiviral pathways 8,102,103 .One of the best studied and likely most versatile of these proteins is VP35, which suppresses the cytosolic detection of viral products, thus blunting traditional intracellular antiviral responses. VP35 binds to double-stranded RNA, a by-product of viral replication, which serves two purposes: avoidance of RNAdependent antiviral sensing pathways -including retinoic acid-inducible gene I protein (RIG-I; also known as probable ATP-dependent RNA helicase DDX58), melanoma differentiation-associated protein 5 (MDA5; also known as interferon-induced helicase C domain-containing protein 1 (IFIH1)) and protein kinase R (PKR; also known as interferon-induced, doublestranded RNA-activated protein kinase (EIF2AK2)) -and protection against endogenous host RNAses 104-107 .…”

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confidence: 99%

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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: Immune Evasionmentioning

confidence: 99%

mentioning

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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“…1D). The root mean square deviation (RMSD) for all atoms between any two single chains falls between 0.5 and 2 Å, while the trimer from the I2 space group superimposed on the trimer from the P4 2 22 space group has an RMSD of 2.4 Å. The largest differences are observed in the N and C termini: before proline 78 and after proline 109 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…MARV does not produce sGP or ssGP protein and does not require VP30 for transcription. MARV and EBOV also exhibit differences in their immune evasion strategies (2).…”

mentioning

confidence: 99%

Crystal Structure of the Marburg Virus VP35 Oligomerization Domain

Bruhn

Kirchdoerfer

Urata

et al. 2017

J Virol

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Marburg virus (MARV) is a highly pathogenic filovirus that is classified in a genus distinct from that of Ebola virus (EBOV) (genera Marburgvirus and Ebolavirus, respectively). Both viruses produce a multifunctional protein termed VP35, which acts as a polymerase cofactor, a viral protein chaperone, and an antagonist of the innate immune response. VP35 contains a central oligomerization domain with a predicted coiled-coil motif. This domain has been shown to be essential for RNA polymerase function. Here we present crystal structures of the MARV VP35 oligomerization domain. These structures and accompanying biophysical characterization suggest that MARV VP35 is a trimer. In contrast, EBOV VP35 is likely a tetramer in solution. Differences in the oligomeric state of this protein may explain mechanistic differences in replication and immune evasion observed for MARV and EBOV.IMPORTANCE Marburg virus can cause severe disease, with up to 90% human lethality. Its genome is concise, only producing seven proteins. One of the proteins, VP35, is essential for replication of the viral genome and for evasion of host immune responses. VP35 oligomerizes (self-assembles) in order to function, yet the structure by which it assembles has not been visualized. Here we present two crystal structures of this oligomerization domain. In both structures, three copies of VP35 twist about each other to form a coiled coil. This trimeric assembly is in contrast to tetrameric predictions for VP35 of Ebola virus and to known structures of homologous proteins in the measles, mumps, and Nipah viruses. Distinct oligomeric states of the Marburg and Ebola virus VP35 proteins may explain differences between them in polymerase function and immune evasion. These findings may provide a more accurate understanding of the mechanisms governing VP35's functions and inform the design of therapeutics. KEYWORDS VP35, filovirus, RNA-dependent RNA polymerase, phosphoprotein, coiled coil, oligomerization, Marburg virus, Ebola virus, X-ray crystallography M arburg virus (MARV) can cause severe hemorrhagic fever in humans with high case fatality rates. Though less well known than its relative Ebola virus (EBOV), MARV was the first filovirus identified. MARV has caused sporadic outbreaks since its identification in 1968, including the 1998 to 2000 outbreak in the Democratic Republic of the Congo, which occurred with 83% lethality, and the 2004 to 2005 outbreak in Angola, which occurred with 90% lethality (1). Currently, there are no approved vaccines or therapeutics available to treat individuals infected with MARV. Despite sharing ϳ50% nucleotide sequence identity, MARV and EBOV have several striking functional differences. MARV does not produce sGP or ssGP protein and does not require VP30 for transcription. MARV and EBOV also exhibit differences in their immune evasion strategies (2).

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“…The coiled-coil domain promotes VP35 oligomerization and is important for different functions, including polymerase activity (10)(11)(12)(13)(14). In addition to VP35's critical role in virus replication as a cofactor of the viral polymerase, it has also been extensively studied for its function in inhibition of innate signaling pathways and expression of antiviral type I interferons (IFN-I) (10,11,(14)(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

The Host E3-Ubiquitin Ligase TRIM6 Ubiquitinates the Ebola Virus VP35 Protein and Promotes Virus Replication

Bharaj

Atkins

Luthra

et al. 2017

J Virol

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Ebola virus (EBOV), a member of the Filoviridae family, is a highly pathogenic virus that causes severe hemorrhagic fever in humans and is responsible for epidemics throughout sub-Saharan, central, and West Africa. The EBOV genome encodes VP35, an important viral protein involved in virus replication by acting as an essential cofactor of the viral polymerase as well as a potent antagonist of the host antiviral type I interferon (IFN-I) system. By using mass spectrometry analysis and coimmunoprecipitation assays, we show here that VP35 is ubiquitinated on lysine 309 (K309), a residue located on its IFN antagonist domain. We also found that VP35 interacts with TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family. We recently reported that TRIM6 promotes the synthesis of unanchored K48-linked polyubiquitin chains, which are not covalently attached to any protein, to induce efficient antiviral IFN-I-mediated responses. Consistent with this notion, VP35 also associated noncovalently with polyubiquitin chains and inhibited TRIM6-mediated IFN-I induction. Intriguingly, we also found that TRIM6 enhances EBOV polymerase activity in a minigenome assay and TRIM6 knockout cells have reduced replication of infectious EBOV, suggesting that VP35 hijacks TRIM6 to promote EBOV replication through ubiquitination. Our work provides evidence that TRIM6 is an important host cellular factor that promotes EBOV replication, and future studies will focus on whether TRIM6 could be targeted for therapeutic intervention against EBOV infection.IMPORTANCE EBOV belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans and other mammals with high mortality rates (40 to 90%). Because of its high pathogenicity and lack of licensed antivirals and vaccines, EBOV is listed as a tier 1 select-agent risk group 4 pathogen. An important mechanism for the severity of EBOV infection is its suppression of innate immune responses. The EBOV VP35 protein contributes to pathogenesis, because it serves as an essential cofactor of the viral polymerase as well as a potent antagonist of innate immunity. However, how VP35 function is regulated by host cellular factors is poorly understood. Here, we report that the host E3-ubiquitin ligase TRIM6 promotes VP35 ubiquitination and is important for efficient virus replication. Therefore, our study identifies a new host factor, TRIM6, as a potential target in the development of antiviral drugs against EBOV.KEYWORDS TRIM6, tripartite motif (TRIM) protein, VP35, viral RNA polymerase, Ebola virus, innate immunity, ubiquitination, unanchored ubiquitin, virus-host interactions

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Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus

Cited by 212 publications

References 165 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

Crystal Structure of the Marburg Virus VP35 Oligomerization Domain

The Host E3-Ubiquitin Ligase TRIM6 Ubiquitinates the Ebola Virus VP35 Protein and Promotes Virus Replication

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