title: VSVΔG/EBOV GP-induced innate protection enhances natural killer cell activity to increase survival in a lethal mouse adapted Ebola virus infection.
abstract: Members of the species Zaire ebolavirus cause severe hemorrhagic fever with up to a 90% mortality rate in humans. The VSVΔG/EBOV GP vaccine has provided 100% protection in the mouse, guinea pig, and nonhuman primate (NHP) models, and has also been utilized as a post-exposure therapeutic to protect mice, guinea pigs, and NHPs from a lethal challenge of Ebola virus (EBOV). EBOV infection causes rapid mortality in human and animal models, with death occurring as early as 6 days after infection, suggesting a vital role for the innate immune system to control the infection before cells of the adaptive immune system can assume control. Natural killer (NK) cells are the predominant cell of the innate immune response, which has been shown to expand with VSVΔG/EBOV GP treatment. In the current study, an in vivo mouse model of the VSVΔG/EBOV GP post-exposure treatment was used for a mouse adapted (MA)-EBOV infection, to determine the putative VSVΔG/EBOV GP-induced protective mechanism of NK cells. NK depletion studies demonstrated that mice with NK cells survive longer in a MA-EBOV infection, which is further enhanced with VSVΔG/EBOV GP treatment. NK cell mediated cytotoxicity and IFN-γ secretion was significantly higher with VSVΔG/EBOV GP treatment. Cell mediated cytotoxicity assays and perforin knockout mice experiments suggest that there are perforin-dependent and -independent mechanisms involved. Together, these data suggest that NK cells play an important role in VSVΔG/EBOV GP-induced protection of EBOV by increasing NK cytotoxicity, and IFN-γ secretion.
authors.affiliation: 1 Department of Medical Microbiology and Immunology, University of Alberta , Edmonton, Canada .
authors.forename: Kinola J N
authors.initials: KJ
authors.lastname: Williams
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Qiu
authors.forename: Lisa
authors.initials: L
authors.lastname: Fernando
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
authors.forename: Judie B
authors.initials: JB
authors.lastname: Alimonti
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D004337:Drug Carriers; D046129:Ebola Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D029043:Ebolavirus / Q000235:genetics / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016019:Survival Analysis; D018116:Vesiculovirus / Q000235:genetics*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D004337:Drug Carriers; D046129:Ebola Vaccines; D014759:Viral Envelope Proteins; C113189:envelope glycoprotein, Ebola virus; D007371:Interferon-gamma