Filoviruses such as Ebola and Marburg viruses are Category A pathogens (pathogens that providethe highest risk to national security and public health) on NIAID's list of emerging infectious diseases due totheir ease of dissemination, high mortality rates, and potential use as bioterrorism weapons. There is a needfor fast acting, easy to use, and more effective medicines to protect against and improve survival from Ebolavirus infection. Vaccines in development require at least 10 days for subjects to develop immunity and thus arenot useful for treating newly infected patients or protecting non-vaccinated healthcare providers and firstresponders in an emergency outbreak situation. Antibiotics and antibody cocktails under study requireintravenous infusion and resistance may develop through random or directed virus mutation. An alternative andpotentially synergistic approach for protecting against Ebola virus infection is to stimulate the innate arm of thehost immune system to resist viral infection. Macrophages and dendritic cells typically are the first cellsinfected by Ebola virus. Upon entry, the virus replicates and expresses proteins that interfere with the hostcell's ability to block viral infection. The virus also causes host cells to secrete proinflammatory cytokines andchemokines that attract other myeloid cells to propagate the infection and results in a dysfunctional immuneresponse unable to control the virus. Interferon gamma (IFNG) quickly (within hours) activates macrophagesand dendritic cells so that they resist infection by Ebola and other viruses, as well as infection by severalCategory A facultative intracellular bacterial pathogens such as Tularemia and Burkholderia. Thus, IFNG hasthe potential to be an effective therapy against several deadly bioterrorism threats. However, IFNG has a veryshort in vivo half-life, poor bioavailability, required intraperitoneal injection for efficacy in preclinical studies, andhas a narrow efficacy window, all of which limit the protein's utility as an Ebola therapy. We created a long-acting human IFNG analog (PEG IFNG) that has superior bioavailability and a longer half-life followingsubcutaneous injection and significantly greater efficacy than IFNG in animals. We hypothesize PEG-IFNG willbe significantly more effective than IFNG at preventing morbidity and mortality from Ebola virus infection bothas a protectant for pre-exposure prophylaxis and as a mitigator for post-exposure prophylaxis. We will test thishypothesis by comparing efficacy of a murine PEG IFNG homolog and murine IFNG administered pre and postinfection for reducing morbidity and mortality from lethal Ebola virus infection in mice, as measured by survival,weight gain and clinical sickness scores. These studies will lead to an effective treatment that confersprotection within hours and which can be administered easily (subcutaneous injection) to patients who recentlycontracted Ebola virus, as well as to first responders and healthcare providers in an emergency outbreaksituation. Stimulating innate immunity using PEG IFNG will protect against Ebola virus and multiple otherintracellular Category A pathogens such as Tularemia and Burkholderia that replicate within macrophages. Narrative. The U.S. government is urgently seeking therapies to protect against and improve survival from Ebola virus and other filoviruses because of their high lethality and potential use as bioterrorism weapons. Current treatments provide only modest survival benefits. We will evaluate whether a novel protein engineered for enhanced bioavailability and pharmacological properties possesses improved ability to stimulate host innate immunity and protect against Ebola virus infection. These studies will lead to an easy to use, effective treatment against Ebola virus as well as a potential treatment against several of the emerging infectious diseases of greatest importance to public health and national security. 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