title: Loss of Interleukin 1 Receptor Antagonist Enhances Susceptibility to Ebola Virus Infection.
abstract: The current outbreak of Ebola virus (EBOV) infection in West Africa is unprecedented, with nearly 26 000 confirmed cases and >10 000 deaths. Comprehensive data on the pathogenesis of EBOV infection are lacking; however, recent studies suggested that fatal EBOV infections are characterized by dysregulation of the innate immune response and a subsequent cytokine storm. Specifically, several studies suggested that hypersecretion of interleukin 1 receptor antagonist (IL-1Ra) correlates with lethal EBOV infections. To examine the significance of IL-1Ra in EBOV infections, we infected mice that lack the gene encoding IL-1Ra, Il1rn (IL-1RN-KO), and mice with wild-type Il1rn (IL-1RN-WT) with a mouse-adapted EBOV (MA-EBOV). Infected IL-1RN-KO mice lost more weight and had a lower survival rate than IL-1RN-WT mice infected with MA-EBOV. In addition, IL-1RN-KO mice infected with wild-type EBOV, which does not cause lethal infection in adult immunocompetent mice, such as C57BL/6 mice, experienced greater weight loss than IL-1RN-WT mice infected with wild-type EBOV. Further studies revealed that the levels of 6 cytokines in spleens-IL-1α, IL-1β, interleukin 12p40, interleukin 17, granulocyte colony-stimulating factor, and regulated on activation, normal T-cell expressed and secreted-were significantly different between IL-1RN-KO mice and IL-1RN-WT mice infected with MA-EBOV. Collectively, our data suggest that IL-1Ra may have a protective effect upon EBOV infection, likely by damping an overactive proinflammatory immune response.
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hill-Batorski
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison.
authors.forename: Peter
authors.initials: P
authors.lastname: Halfmann
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana.
authors.forename: Andrea
authors.initials: A
authors.lastname: Marzi
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison Division of Virology, Department of Microbiology and Immunology, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo.
authors.forename: Tiago J S
authors.initials: TJ
authors.lastname: Lopes
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Neumann
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana.
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison Division of Virology, Department of Microbiology and Immunology, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000354:Africa, Western; D000818:Animals; D016207:Cytokines / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology*; D029043:Ebolavirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000821:virology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016207:Cytokines; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D016179:Granulocyte Colony-Stimulating Factor
keywords: Ebola virus; IL-1Ra; Il1rn; interleukin 1 receptor antagonist