@article{510c992acab945a6a72c7b96210fb1d6,
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 = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = sep,
day = "17",
doi = "10.1016/j.celrep.2019.08.047",
language = "English (US)",
volume = "28",
pages = "3032--3046.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}