A VP35 Mutant Ebola Virus Lacks Virulence but Can Elicit Protective Immunity to Wild-Type Virus Challenge

Publication date: 17 September 2019Source: Cell Reports, Volume 28, Issue 12Author(s): Courtney Woolsey, Andrea R. Menicucci, Robert W. Cross, Priya Luthra, Krystle N. Agans, Viktoriya Borisevich, Joan B. Geisbert, Chad E. Mire, Karla A. Fenton, Allen Jankeel, Sneha Anand, Hideki Ebihara, Thomas W. Geisbert, Ilhem Messaoudi, Christopher F. BaslerSummaryZaire ebolavirus (EBOV) VP35 protein is a suppressor of type I interferon (IFN) production, an inhibitor of dendritic cell maturation, and a putative virulence determinant. Here, a recombinant EBOV encoding a mutant VP35 virus (VP35m) is demonstrated to activate RIG-I-like receptor signaling and innate antiviral pathways. When inoculated into cynomolgus macaques, VP35m exhibits dramatic attenuation as compared to wild-type EBOV (wtEBOV), with 20 or 300 times the standard 100% lethal challenge dose not causing EBOV disease (EVD). Further, VP35m infection, despite limited replication in vivo, activates antigen presentation and innate immunity pathways and elicits increased frequencies of proliferating memory T cells and B cells and production of anti-EBOV antibodies. Upon wtEBOV challenge, VP35m-immunized animals survive, exhibiting host responses consistent with an orderly immune response and the absence of excessive inflammation. These data demonstrate that VP35 is a critical EBOV immune evasion factor and provide insights into immune mechanisms of EBOV control.Graphical Abstract

Source: Cell Reports - September 18, 2019 Category: Cytology Source Type: research