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

Courtney Woolsey, Andrea R. Menicucci, Robert Cross, Priya Luthra, Krystle N. Agans, Viktoriya Borisevich, Joan B. Geisbert, Chad Mire, Karla A. Fenton, Allen Jankeel, Sneha Anand, Hideki Ebihara, Thomas Geisbert, Ilhem Messaoudi, Christopher F. Basler

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3032-3046.e6
JournalCell Reports
Volume28
Issue number12
DOIs
StatePublished - Sep 17 2019

Fingerprint

Ebolavirus
Viruses
Virulence
Immunity
Interferon Type I
T-cells
Antiviral Agents
Anti-Idiotypic Antibodies
Animals
Cells
Antigens
Data storage equipment
Proteins
Immune Evasion
Democratic Republic of the Congo
Antigen Presentation
Immunologic Factors
Macaca
Ebola virus nucleoprotein VP35
Innate Immunity

Keywords

  • Ebola
  • filovirus
  • innate immunity
  • interferon
  • pathogenesis
  • primate
  • RIG-I
  • RLR signaling
  • VP35

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

A VP35 Mutant Ebola Virus Lacks Virulence but Can Elicit Protective Immunity to Wild-Type Virus Challenge. / Woolsey, Courtney; Menicucci, Andrea R.; Cross, Robert; Luthra, Priya; Agans, Krystle N.; Borisevich, Viktoriya; Geisbert, Joan B.; Mire, Chad; Fenton, Karla A.; Jankeel, Allen; Anand, Sneha; Ebihara, Hideki; Geisbert, Thomas; Messaoudi, Ilhem; Basler, Christopher F.

In: Cell Reports, Vol. 28, No. 12, 17.09.2019, p. 3032-3046.e6.

Research output: Contribution to journalArticle

Woolsey, C, Menicucci, AR, Cross, R, Luthra, P, Agans, KN, Borisevich, V, Geisbert, JB, Mire, C, Fenton, KA, Jankeel, A, Anand, S, Ebihara, H, Geisbert, T, Messaoudi, I & Basler, CF 2019, 'A VP35 Mutant Ebola Virus Lacks Virulence but Can Elicit Protective Immunity to Wild-Type Virus Challenge', Cell Reports, vol. 28, no. 12, pp. 3032-3046.e6. https://doi.org/10.1016/j.celrep.2019.08.047
Woolsey, Courtney ; Menicucci, Andrea R. ; Cross, Robert ; Luthra, Priya ; Agans, Krystle N. ; Borisevich, Viktoriya ; Geisbert, Joan B. ; Mire, Chad ; Fenton, Karla A. ; Jankeel, Allen ; Anand, Sneha ; Ebihara, Hideki ; Geisbert, Thomas ; Messaoudi, Ilhem ; Basler, Christopher F. / A VP35 Mutant Ebola Virus Lacks Virulence but Can Elicit Protective Immunity to Wild-Type Virus Challenge. In: Cell Reports. 2019 ; Vol. 28, No. 12. pp. 3032-3046.e6.
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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.",
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