Stimulating innate immunity to protect against Ebola virus infection

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Abstract. Filoviruses such as Ebola and Marburg viruses are Category A pathogens (pathogens that provide the highest risk to national security and public health) on NIAID's list of emerging infectious diseases due to their ease of dissemination, high mortality rates, and potential use as bioterrorism weapons. There is a need for fast acting, easy to use, and more effective medicines to protect against and improve survival from Ebola virus infection. Vaccines in development require at least 10 days for subjects to develop immunity and thus are not useful for treating newly infected patients or protecting non-vaccinated healthcare providers and first responders in an emergency outbreak situation. Antibiotics and antibody cocktails under study require intravenous infusion and resistance may develop through random or directed virus mutation. An alternative and potentially synergistic approach for protecting against Ebola virus infection is to stimulate the innate arm of the host immune system to resist viral infection. Macrophages and dendritic cells typically are the first cells infected by Ebola virus. Upon entry, the virus replicates and expresses proteins that interfere with the host cell's ability to block viral infection. The virus also causes host cells to secrete proinflammatory cytokines and chemokines that attract other myeloid cells to propagate the infection and results in a dysfunctional immune response unable to control the virus. Interferon gamma (IFNG) quickly (within hours) activates macrophages and dendritic cells so that they resist infection by Ebola and other viruses, as well as infection by several Category A facultative intracellular bacterial pathogens such as Tularemia and Burkholderia. Thus, IFNG has the potential to be an effective therapy against several deadly bioterrorism threats. However, IFNG has a very short in vivo half-life, poor bioavailability, required intraperitoneal injection for efficacy in preclinical studies, and has 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 following subcutaneous injection and significantly greater efficacy than IFNG in animals. We hypothesize PEG-IFNG will be significantly more effective than IFNG at preventing morbidity and mortality from Ebola virus infection both as a protectant for pre-exposure prophylaxis and as a mitigator for post-exposure prophylaxis. We will test this hypothesis by comparing efficacy of a murine PEG IFNG homolog and murine IFNG administered pre and post infection 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 confers protection within hours and which can be administered easily (subcutaneous injection) to patients who recently contracted Ebola virus, as well as to first responders and healthcare providers in an emergency outbreak situation. Stimulating innate immunity using PEG IFNG will protect against Ebola virus and multiple other intracellular Category A pathogens such as Tularemia and Burkholderia that replicate within macrophages.