A VP35 Mutant Ebola Virus Lacks Virulence but Can Elicit Protective Immunity to Wild-Type Virus Challenge
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. Basler
Affiliations
Courtney Woolsey
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA
Andrea R. Menicucci
Department of Molecular Biology and Biochemistry, College of Biological Sciences, University of California, Irvine, Irvine, CA 92697, USA
Robert W. Cross
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA
Priya Luthra
Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA
Krystle N. Agans
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA
Viktoriya Borisevich
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA
Joan B. Geisbert
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA
Chad E. Mire
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA
Karla A. Fenton
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA
Allen Jankeel
Department of Molecular Biology and Biochemistry, College of Biological Sciences, University of California, Irvine, Irvine, CA 92697, USA
Sneha Anand
Department of Molecular Biology and Biochemistry, College of Biological Sciences, University of California, Irvine, Irvine, CA 92697, USA
Hideki Ebihara
Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
Thomas W. Geisbert
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA; Corresponding author
Ilhem Messaoudi
Department of Molecular Biology and Biochemistry, College of Biological Sciences, University of California, Irvine, Irvine, CA 92697, USA; Corresponding author
Christopher F. Basler
Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; Corresponding author
Summary: Zaire 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. : Woolsey et al. demonstrate that immune evasion functions of the Ebola virus VP35 protein are critical for virulence in non-human primates. A VP35 mutant Ebola virus does not cause lethal disease and instead elicits adaptive immune responses that can protect animals from wild-type Ebola virus challenge. Keywords: Ebola, filovirus, primate, VP35, RIG-I, RLR signaling, interferon, innate immunity, pathogenesis
