title: Interferon-γ Inhibits Ebola Virus Infection.
abstract: Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.
authors.affiliation: Department of Microbiology, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Rhein
authors.affiliation: Department of Internal Medicine, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Powers
authors.affiliation: Department of Microbiology, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Kai
authors.initials: K
authors.lastname: Rogers
authors.affiliation: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors.forename: Manu
authors.initials: M
authors.lastname: Anantpadma
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Brajesh K
authors.initials: BK
authors.lastname: Singh
authors.affiliation: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Iowa Institute for Human Genetics, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bair
authors.affiliation: Department of Microbiology, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: Miller-Hunt
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sinn
authors.affiliation: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Davey
authors.affiliation: Department of Internal Medicine, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Martha M
authors.initials: MM
authors.lastname: Monick
authors.affiliation: Department of Microbiology, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Wendy
authors.initials: W
authors.lastname: Maury
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D029043:Ebolavirus / Q000187:drug effects*; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D012367:RNA, Viral / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C573415:IFNG protein, human; D012367:RNA, Viral; D007371:Interferon-gamma