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

Cell Rep. 2019 Sep 17;28(12):3032-3046.e6. doi: 10.1016/j.celrep.2019.08.047.

Abstract

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.

Keywords: Ebola; RIG-I; RLR signaling; VP35; filovirus; innate immunity; interferon; pathogenesis; primate.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes* / immunology
  • B-Lymphocytes* / pathology
  • Chlorocebus aethiops
  • Ebolavirus* / genetics
  • Ebolavirus* / immunology
  • Ebolavirus* / pathogenicity
  • Hemorrhagic Fever, Ebola* / genetics
  • Hemorrhagic Fever, Ebola* / immunology
  • Hemorrhagic Fever, Ebola* / pathology
  • Hemorrhagic Fever, Ebola* / prevention & control
  • Macaca fascicularis
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / pathology
  • Vero Cells
  • Viral Regulatory and Accessory Proteins* / genetics
  • Viral Regulatory and Accessory Proteins* / immunology
  • Virulence Factors* / genetics
  • Virulence Factors* / immunology

Substances

  • VP35 protein, filovirus
  • Viral Regulatory and Accessory Proteins
  • Virulence Factors