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.
Highlights
Ebola virus (EBOV) is a member of the genus Ebolavirus within the Filoviridae family of highly pathogenic viruses
We demonstrate that interferon gamma profoundly inhibits Ebola virus infection of macrophages, which are early cellular targets of Ebola virus
Mouse peritoneal macrophages treated for 48 hours with either granulocyte-macrophage colony stimulating factor (GM-CSF) or macrophage colony stimulating factor (M-CSF) support robust infection by a recombinant EBOV that expresses green fluorescent protein (GFP) [20] (Fig 1A)
Summary
Ebola virus (EBOV) is a member of the genus Ebolavirus within the Filoviridae family of highly pathogenic viruses. Pro-inflammatory molecules recruit other target cells to the site of infection, providing additional cells for virus infection and increasing circulation of inflammatory cells and proteins This uncontrolled amplification of infection and cytokine production results in dysregulation of the inflammatory response, leading to the systemic spread of the virus, excessive cytokine accumulation and circulatory collapse observed in cases of fatal EBOV hemorrhagic fever in humans and non-human primates [3, 4, 6, 8]. Contributing to this amplifying dysregulation, EBOV sustains replication in macrophages and DCs by counteracting early innate immune responses, thereby decreasing effective host responses to the virus [5, 9]. These events in combination with decreased T cell numbers observed in EBOV-infected individuals [10] are thought to lead to poor adaptive immune responses to infection
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