title: Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance.
abstract: Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Rasmussen
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA. Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okumura
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Martin T
authors.initials: MT
authors.lastname: Ferris
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Green
authors.affiliation: Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA.
authors.forename: Friederike
authors.initials: F
authors.lastname: Feldmann
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Kelly
authors.affiliation: Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA.
authors.forename: Dana P
authors.initials: DP
authors.lastname: Scott
authors.affiliation: Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA.
authors.forename: David
authors.initials: D
authors.lastname: Safronetz
authors.affiliation: Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Haddock
authors.affiliation: Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: LaCasse
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Thomas
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Sova
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Carter
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Darla R
authors.initials: DR
authors.lastname: Miller
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Ginger D
authors.initials: GD
authors.lastname: Shaw
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Korth
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Fernando Pardo-Manuel
authors.initials: FP
authors.lastname: de Villena
authors.affiliation: Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA.
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA. Washington National Primate Research Center, Seattle, WA, USA. honey@uw.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D000483:Alleles; D000818:Animals; D001777:Blood Coagulation / Q000235:genetics; D002199:Capillary Permeability / Q000235:genetics; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D019142:Hemorrhagic Fever, Ebola / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000235:genetics*; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics; D042787:Receptor, TIE-2 / Q000235:genetics*
chemical_list: D042787:Receptor, TIE-2; C079086:Tek protein, mouse