Amino Acid Residue at Position 79 of Marburg Virus VP40 Confers Interferon Antagonism in Mouse Cells.
Marburg viruses (MARVs) cause highly lethal infections in humans and nonhuman primates. Mice are not generally susceptible to MARV infection; however, if the strain is first adapted to mice through serial passaging, it becomes able to cause disease in this animal. A previous study correlated changes accrued during mouse adaptation in the VP40 gene of a MARV strain known as Ravn virus (RAVV) with an increased capacity to inhibit interferon (IFN) signaling in mouse cell lines. The MARV strain Ci67, which belongs to a different phylogenetic clade than RAVV, has also been adapted to mice and in the process the Ci67 VP40 acquired a different collection of genetic changes than did RAVV VP40. Here, we demonstrate that the mouse-adapted Ci67 VP40 more potently antagonizes IFN-α/β-induced STAT1 and STAT2 tyrosine phosphorylation, gene expression, and antiviral activity in both mouse and human cell lines, compared with the parental Ci67 VP40. Ci67 VP40 is also demonstrated to target the activation of kinase Jak1. A single change at VP40 residue 79 was found to be sufficient for the increased VP40 IFN antagonism. These data argue that VP40 IFN-antagonist activity plays a key role in MARV pathogenesis in mice.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York.
Alicia R
AR
Feagins
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York.
Christopher F
CF
Basler
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism; D008379:Marburg Virus Disease / Q000378:metabolism / Q000821:virology; D029024:Marburgvirus / Q000378:metabolism* / Q000472:pathogenicity*; D051379:Mice; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism*
D000596:Amino Acids; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C080981:VP40 protein, virus; D014763:Viral Matrix Proteins; D016899:Interferon-beta; D053613:Janus Kinase 1
Ci67 strain; Marburg virus; Ravn virus; VP40; interferon; mouse-adapted