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

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

30 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
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

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Funding

This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) and NIH grant U19A109945 (to C.F.B. I.M. and T.W.G.). Preparation of the Ebola virus seed stock was supported by NIAID/NIH grant U19AI109711 to T.W.G. Operations support of the Galveston National Laboratory was supported by NIAID/NIH grant UC7AI094660. We thank Daniel Deer for assistance in performing the nonhuman primate studies. We also thank the UTMB Animal Resource Center for husbandry of laboratory animals and Natalie Dobias (Department of Microbiology and Immunology, UTMB) for expert assistance with histology and immunohistochemistry assays. We thank Drs. Yize (Henry) Li and Susan R. Weiss (Department of Microbiology, Perelman School of Medicine, University of Pennsylvania) for kindly providing the parental and MAVS KO A549 cells. C.W. A.R.M. R.W.C. P.L. K.N.A. V.B. J.B.G. C.E.M. K.A.F. H.E. A.J. S.A. and T.W.G. conducted the experiments; C.W. A.R.M. R.W.C. P.L. K.N.A. V.B. J.B.G. C.E.M. H.E. T.W.G. I.M. and C.F.B. analyzed the data; C.W. R.W.C. P.L. H.E. T.W.G. I.M. and C.F.B. designed the experiments; and C.W. A.R.M. T.W.G. I.M. and C.F.B. wrote the paper with input from all co-authors. The authors declare no competing interests. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) and NIH grant U19A109945 (to C.F.B., I.M., and T.W.G.). Preparation of the Ebola virus seed stock was supported by NIAID/NIH grant U19AI109711 to T.W.G. Operations support of the Galveston National Laboratory was supported by NIAID/NIH grant UC7AI094660 . We thank Daniel Deer for assistance in performing the nonhuman primate studies. We also thank the UTMB Animal Resource Center for husbandry of laboratory animals and Natalie Dobias (Department of Microbiology and Immunology, UTMB) for expert assistance with histology and immunohistochemistry assays. We thank Drs. Yize (Henry) Li and Susan R. Weiss (Department of Microbiology, Perelman School of Medicine, University of Pennsylvania) for kindly providing the parental and MAVS KO A549 cells.

Funders	Funder number
C.E.M.
C.F.B.
C.W.
NIH-NIAID
National Institutes of Health (NIH)	U19A109945
National Institute of Allergy and Infectious F32-AI286447 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI168214 Jason W. Rosch Diseases National Institute of Allergy and Infectious P30 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R00-AI166116 Christopher D. Radka Diseases National Institute of Allergy and Infectious T32-AI106700 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI192221 Jason W. Rosch Diseases National Inst...	UC7AI094660, U19AI109711, U19AI109945
The Pennsylvania State University
University of Texas Medical Branch at Galveston	Henry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2019.08.047

Cite this

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

@article{ba4439a674a5404bbb9863554520af9d,

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.",

keywords = "Ebola, RIG-I, RLR signaling, VP35, filovirus, innate immunity, interferon, pathogenesis, primate",

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.\}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = sep,

day = "17",

doi = "10.1016/j.celrep.2019.08.047",

language = "English",

volume = "28",

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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

TY - JOUR

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.

PY - 2019/9/17

Y1 - 2019/9/17

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.

KW - Ebola

KW - RIG-I

KW - RLR signaling

KW - VP35

KW - filovirus

KW - innate immunity

KW - interferon

KW - pathogenesis

KW - primate

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UR - https://www.scopus.com/pages/publications/85071901123#tab=citedBy

U2 - 10.1016/j.celrep.2019.08.047

DO - 10.1016/j.celrep.2019.08.047

M3 - Article

C2 - 31533029

AN - SCOPUS:85071901123

SN - 2211-1247

VL - 28

SP - 3032-3046.e6

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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