title: 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-α/β) and IFN-γ 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-α/β and the IFN-α/β-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.
authors.affiliation: Department Microbiology, Box 1124, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Valmas
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors*; D016899:Interferon-beta / Q000037:antagonists & inhibitors*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D053613:Janus Kinase 1 / Q000378:metabolism; D029024:Marburgvirus / Q000472:pathogenicity*; D051379:Mice; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C080981:VP40 protein, virus; D014763:Viral Matrix Proteins; D016899:Interferon-beta; D007371:Interferon-gamma; D053613:Janus Kinase 1