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Marburg virus VP40 antagonizes interferon signaling in a species-specific manner.

ABSTRACT: Marburgviruses are zoonotic pathogens that cause lethal hemorrhagic fever in humans and nonhuman primates. However, they do not cause lethal disease in immunocompetent mice unless they are adapted to this species. The adaptation process can therefore provide insight into the specific virus-host interactions that determine virulence. In primate cells, the Lake Victoria marburgvirus Musoke strain (MARV) VP40 matrix protein antagonizes alpha/beta interferon (IFN-?/?) and IFN-? signaling by inhibiting the activation of the cellular tyrosine kinase Jak1. Here, VP40 from the Ravn strain (RAVV VP40)-from a distinct Marburg virus clade-is demonstrated to also inhibit IFN signaling in human cells. However, neither MARV nor RAVV VP40 effectively inhibited IFN-signaling in mouse cells, as assessed by assays of the antiviral effects of IFN-?/? and the IFN-?/?-induced phosphorylation of Jak1, STAT1, and STAT2. In contrast, the VP40 from a mouse-adapted RAVV (maRAVV) did inhibit IFN signaling. Effective Jak1 inhibition correlated with the species from which the cells were derived and did not depend upon whether Jak1 was of human or mouse origin. Of the seven amino acid changes that accumulated in VP40 during mouse adaptation, two (V57A and T165A) are sufficient to allow efficient IFN signaling antagonism by RAVV VP40 in mouse cells. The same two changes also confer efficient IFN antagonist function upon MARV VP40 in mouse cells. The mouse-adaptive changes did not affect the budding of RAVV VP40 in mouse cells, suggesting that this second major function of VP40 did not undergo adaptation. These data identify an apparent determinant of RAVV host range and virulence and define specific genetic determinants of this function.

SUBMITTER: Valmas C

PROVIDER: S-EPMC3126248 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Marburg virus VP40 antagonizes interferon signaling in a species-specific manner.

Valmas Charalampos C Basler Christopher F CF

Journal of virology 20110216 9

Marburgviruses are zoonotic pathogens that cause lethal hemorrhagic fever in humans and nonhuman primates. However, they do not cause lethal disease in immunocompetent mice unless they are adapted to this species. The adaptation process can therefore provide insight into the specific virus-host interactions that determine virulence. In primate cells, the Lake Victoria marburgvirus Musoke strain (MARV) VP40 matrix protein antagonizes alpha/beta interferon (IFN-α/β) and IFN-γ signaling by inhibiti ...[more]

PMID: 21325424

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Project description:Marburg virus (MARV) induces severe hemorrhagic fever in humans and nonhuman primates but only transient nonlethal disease in rodents. However, sequential passages of MARV in rodents boosts infection leading to lethal disease. Guinea pig-adapted MARV contains one mutation in the viral matrix protein VP40 at position 184 (VP40D184N). The contribution of the D184N mutation to the efficacy of replication in a new host is unknown. In the present study, we demonstrated that recombinant MARV containing the D184N mutation in VP40 [rMARVVP40(D184N)] grew to higher titers than wild-type recombinant MARV (rMARVWT) in guinea pig cells. Moreover, rMARVVP40(D184N) displayed higher infectivity in guinea pig cells. Comparative analysis of VP40 functions indicated that neither the interferon (IFN)-antagonistic function nor the membrane binding capabilities of VP40 were affected by the D184N mutation. However, the production of VP40-induced virus-like particles (VLPs) and the recruitment of other viral proteins to the budding site was improved by the D184N mutation in guinea pig cells, which resulted in the higher infectivity of VP40D184N-induced infectious VLPs (iVLPs) compared to that of VP40-induced iVLPs. In addition, the function of VP40 in suppressing viral RNA synthesis was influenced by the D184N mutation specifically in guinea pig cells, thus allowing greater rates of transcription and replication. Our results showed that the improved viral fitness of rMARVVP40(D184N) in guinea pig cells was due to the better viral assembly function of VP40D184N and its lower inhibitory effect on viral transcription and replication rather than modulation of the VP40-mediated suppression of IFN signaling.The increased virulence achieved by virus passaging in a new host was accompanied by mutations in the viral genome. Analyzing how these mutations affect the functions of viral proteins and the ability of the virus to grow within new host cells helps in the understanding of the molecular mechanisms increasing virulence. Using a reverse genetics approach, we demonstrated that a single mutation in MARV VP40 detected in a guinea pig-adapted MARV provided a replicative advantage of rMARVVP40(D184N) in guinea pig cells. Our studies show that this replicative advantage of rMARV VP40D184N was based on the improved functions of VP40 in iVLP assembly and in the regulation of transcription and replication rather than on the ability of VP40 to combat the host innate immunity.

Project description:Porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus from the Nidovirales order that causes reproductive failure and respiratory disease in pigs and poses a constant threat to the global pig industry. The PRRSV-encoded nonstructural protein 11 (nsp11) is a nidovirus-specific endoribonuclease (NendoU) that is conserved throughout the Arteriviridae and Coronaviridae families. Previously, our research and that of others demonstrated that PRRSV nsp11 inhibits type I interferon (IFN) production through NendoU activity-dependent mechanisms. Here, we found that PRRSV nsp11 also inhibited IFN-stimulated response element (ISRE) promoter activity and subsequent transcription of IFN-stimulated genes (ISGs). Detailed analysis showed that nsp11 targeted interferon regulatory factor 9 (IRF9), but not transducer and activator of transcription 1 (STAT1) or STAT2, key molecules in the type I IFN signaling pathway. Furthermore, the nsp11-IRF9 interaction impaired the formation and nuclear translocation of the transcription factor complex IFN-stimulated gene factor 3 (ISGF3) in both nsp11-overexpressed and PRRSV-infected cells. Importantly, nsp11 mutations (H129A, H144A, and K173A) that ablate NendoU activity or its cell cytotoxicity also interacted with IRF9 and retained the ability to block IFN signaling, indicating that the nsp11-IRF9 interaction is independent of NendoU activity or cell cytotoxicity of nsp11. Taking the results together, our study demonstrated that PRRSV nsp11 antagonizes type I IFN signaling by targeting IRF9 via a NendoU activity-independent mechanism, and this report describes a novel strategy evolved by PRRSV to counteract host innate antiviral responses, revealing a potential new function for PRRSV nsp11 in type I IFN signaling.IMPORTANCE The nidovirus-specific endoribonuclease (NendoU) encoded by PRRSV nonstructural protein 11 (nsp11) is a unique NendoU of nidoviruses that infect vertebrates; thus, it is an attractive target for the development of antinidovirus drugs. Previous studies have revealed that the NendoU of nidoviruses, including porcine reproductive and respiratory syndrome virus (PRRSV) and human coronavirus 229E (HCoV-229E), acts as a type I interferon (IFN) antagonist. Here, for the first time, we demonstrated that overexpression of PRRSV nsp11 also inhibits IFN signaling by targeting the C-terminal interferon regulatory factor (IRF) association domain of IRF9. This interaction impaired the ability of IRF9 to form the transcription factor complex IFN-stimulated gene factor 3 (ISGF3) and to act as a signaling protein of IFN signaling. Collectively, our data identify IRF9 as a natural target of PRRSV NendoU and reveal a novel mechanism evolved by an arterivirus to counteract innate immune signaling.

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Marburg virus VP40 antagonizes interferon signaling in a species-specific manner.

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Marburg virus VP40 antagonizes interferon signaling in a species-specific manner.

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