The VP35 protein shapes immune responses and promotes virulence of Ebola virus in nonhuman primates

Specific determinants of the high lethality caused by Ebola virus (EBOV) remain incompletely understood. The EBOV VP35 protein inhibits RIG-I-like receptor (RLR) signaling to suppress type I interferon (IFN) production and impair dendritic cell (DC) maturation. To assess the contribution of VP35-mediated immune evasion functions to EBOV pathogenesis, a recombinant VP35 mutant EBOV (VP35m) was compared to wildtype EBOV (wtEBOV) in cell culture and cynomolgus macaques. VP35m activated RLR signaling and IFN responses but grew to comparable titers as wtEBOV in cell culture. In infected macaques, which model severe human EBOV disease (EVD), VP35m replicated to low levels unlike wtEBOV and failed to cause illness at either of two doses. Instead, VP35m activated antigen presentation and innate immunity pathways, triggered robust adaptive immune responses, and protected animals from a wtEBOV challenge. These data demonstrate that VP35 is an immune evasion factor that makes critical contributions to the severity of EVD.