Abstract

Marburg viruses (MARVs) cause highly lethal infections in humans and nonhuman primates. Mice are not gen-erally 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 adap-tation 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 po-tently antagonizes IFN-α/β–induced STAT1 and STAT2 tyrosine phosphorylation, gene expression, and antivi-ral 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 suf-ficient for the increased VP40 IFN antagonism. These data argue that VP40 IFN-antagonist activity plays a key role in MARV pathogenesis in mice.