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

doi:10.1016/j.celrep.2019.08.047

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

Microbiology And Immunology

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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 language	English (US)
Pages (from-to)	3032-3046.e6
Journal	Cell Reports
Volume	28
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2019.08.047
State	Published - Sep 17 2019

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2019.08.047

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Woolsey, C., Menicucci, A. R., Cross, R. W., Luthra, P., Agans, K. N., Borisevich, V., Geisbert, J. B., Mire, C. E., Fenton, K. A., Jankeel, A., Anand, S., Ebihara, H., Geisbert, T. W., Messaoudi, I., & Basler, C. F. (2019). A VP35 Mutant Ebola Virus Lacks Virulence but Can Elicit Protective Immunity to Wild-Type Virus Challenge. Cell Reports, 28(12), 3032-3046.e6. https://doi.org/10.1016/j.celrep.2019.08.047

Woolsey, C, Menicucci, AR, Cross, RW, Luthra, P, Agans, KN, Borisevich, V, Geisbert, JB, Mire, CE, Fenton, KA, Jankeel, A, Anand, S, Ebihara, H, Geisbert, TW, 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

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

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

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T1 - A VP35 Mutant Ebola Virus Lacks Virulence but Can Elicit Protective Immunity to Wild-Type Virus Challenge

AU - Woolsey, Courtney

AU - Menicucci, Andrea R.

AU - Cross, Robert W.

AU - Luthra, Priya

AU - Agans, Krystle N.

AU - Borisevich, Viktoriya

AU - Geisbert, Joan B.

AU - Mire, Chad E.

AU - Fenton, Karla A.

AU - Jankeel, Allen

AU - Anand, Sneha

AU - Ebihara, Hideki

AU - Geisbert, Thomas W.

AU - Messaoudi, Ilhem

AU - Basler, Christopher F.

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N2 - 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.

AB - 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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KW - interferon

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

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Keywords

ASJC Scopus subject areas

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