Date Published: November 12, 2015
Publisher: Public Library of Science
Author(s): Bethany A. Rhein, Linda S. Powers, Kai Rogers, Manu Anantpadma, Brajesh K. Singh, Yasuteru Sakurai, Thomas Bair, Catherine Miller-Hunt, Patrick Sinn, Robert A. Davey, Martha M. Monick, Wendy Maury, Matthias Johannes Schnell.
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.
Ebola virus (EBOV) is a member of the genus Ebolavirus within the Filoviridae family of highly pathogenic viruses. These viruses cause a severe hemorrhagic fever syndrome in humans and non-human primates (NHP). EBOV infection frequently is associated with high mortality rates and is responsible for the devastating 2014 West African EBOV outbreak [1, 2]. This outbreak has generated a renewed emphasis on the development and approval of safe, effective prophylactics and therapeutics against the virus.
Our results are the first to demonstrate the ability of IFNγ to protect animals both prophylactically and therapeutically against EBOV infection and suggest that this FDA-approved drug may be a useful antiviral for individuals with recent high-risk exposure. IFNγ treatment profoundly inhibited EBOV infection of peritoneal macrophages in tissue culture, consistent with the protection conferred by IFNγ and evidence that this cell type is an important early target for virus replication. Since antiviral efficacy required the presence of IFNγ receptor, but not the type I receptor, IFNγ control of EBOV infection occurs independently of type I IFN responses. Thus, we sought to identify specific IFNγ-stimulated genes involved in its antiviral effect. In addition to previously characterized ISGs, we identified three novel IFNγ-stimulated factors, GBP5, RARRES3 and VAMP5. To date, GBP5, RARRES3 or VAMP5 has not been shown to control negative strand RNA virus infection. Finally, we demonstrated that the recombinant BSL2-level virus, EBOV GP/rVSV, recapitulates our findings with EBOV, arguing that studies with this BSL2 model virus may serve as a safer and cost effective alternative for initial evaluations of novel anti-filoviral agents.