Marburg Virus Evades Interferon Responses by a Mechanism Distinct from Ebola Virus

Abstract

Previous studies have demonstrated that Marburg viruses (MARV) and Ebola viruses (EBOV) inhibit interferon (IFN)-α/β signaling but utilize different mechanisms. EBOV inhibits IFN signaling via its VP24 protein which blocks the nuclear accumulation of tyrosine phosphorylated STAT1. In contrast, MARV infection inhibits IFNα/β induced tyrosine phosphorylation of STAT1 and STAT2. MARV infection is now demonstrated to inhibit not only IFNα/β but also IFNγ-induced STAT phosphorylation and to inhibit the IFNα/β and IFNγ-induced tyrosine phosphorylation of upstream Janus (Jak) family kinases. Surprisingly, the MARV matrix protein VP40, not the MARV VP24 protein, has been identified to antagonize Jak and STAT tyrosine phosphorylation, to inhibit IFNα/β or IFNγ-induced gene expression and to inhibit the induction of an antiviral state by IFNα/β. Global loss of STAT and Jak tyrosine phosphorylation in response to both IFNα/β and IFNγ is reminiscent of the phenotype seen in Jak1-null cells. Consistent with this model, MARV infection and MARV VP40 expression also inhibit the Jak1-dependent, IL-6-induced tyrosine phosphorylation of STAT1 and STAT3. Finally, expression of MARV VP40 is able to prevent the tyrosine phosphorylation of Jak1, STAT1, STAT2 or STAT3 which occurs following over-expression of the Jak1 kinase. In contrast, MARV VP40 does not detectably inhibit the tyrosine phosphorylation of STAT2 or Tyk2 when Tyk2 is over-expressed. Mutation of the VP40 late domain, essential for efficient VP40 budding, has no detectable impact on inhibition of IFN signaling. This study shows that MARV inhibits IFN signaling by a mechanism different from that employed by the related EBOV. It identifies a novel function for the MARV VP40 protein and suggests that MARV may globally inhibit Jak1-dependent cytokine signaling.

West Nile Virus Differentially Modulates the Unfolded Protein Response To Facilitate Replication and Immune Evasion

“…This protein also has a hydrophobic C terminus (20) which may be inducing UPR signaling. In addition, Marburg virus VP40 is a hydrophobic, peripheral membrane protein (23) that has also been demonstrated to inhibit STAT1 and Jak1 phosphorylation (49). Interestingly, our data also showed that NS5 (a cytoplasmic protein) is also able to modestly inhibit IFN signaling but does not elicit significant UPR signaling, suggesting an alternative mechanism by which the antiviral response may be regulated (5).…”

Structural basis for Marburg virus VP35–mediated immune evasion mechanisms

“…Despite overall similarities in genome size and organization, virion structure, and disease characteristics (3), EBOV and MARV exhibit important differences, including their strategies for immune evasion (4). For example, although EBOV viral protein (VP) 24 and MARV VP40 counter IFN signaling, neither MARV VP24 nor EBOV VP40 appears to function similarly to its corresponding counterparts with regard to immune evasion (5)(6)(7)(8)(9)(10).…”

Host Cell Factors Involved in Filovirus Infection

“…However, it has been shown that marburgvirus blocks IFN signaling by a mechanism distinct from that of ebolavirus. Marburgvirus matrix protein VP40 has the capacity to inhibit phosphorylation of JAK1 and Tyk2 and abrogates transcriptional activation of interferon-stimulated genes [110] (Fig. 3).…”