Grant: Operating Grant: Innovative Ebola Research Grants - Ebola biology

The Ebola virus (EboV) causes outbreaks of severe hemorrhagic fevers with lethality rates that can reach 90% and against which there is currently no antiviral therapy. The recent EboV outbreak in West Africa and the unpredictable nature of these outbreaks highlight the urgent need for the development of novel antiviral strategies. EboV hemorrhagic fever is characterized by the suppression of the innate and adaptive immune response and strong pro-inflammatory cytokine production called cytokine storm. During the course of the disease, macrophages are the primary targets of the virus. Macrophages are not only infected and replication sites of the virus but also secrete pro-inflammatory cytokines that potentially contribute to the cytokine storm. Unfortunately, very little is known about EboV infection of human macrophages and the resulting inflammatory response. Understanding how Ebola virus infects and induce inflammation in human macrophages could pave the way for the design of new antiviral therapy. Interestingly, while the entry process is completely dependent on the viral glycoprotein that protrudes from the viral membrane, the virus also induces a viral glycoprotein-dependent inflammatory response in macrophages. Therefore, understanding how the virus, through its glycoprotein, infects and triggers an inflammatory response in macrophages may lead to antiviral drugs that reduce viral spread in addition to further reduce the cytokine storm. Here, we propose to investigate the EboV entry pathway in human macrophages using small molecule inhibitors of infection and characterize the macrophage inflammatory response during entry. Our studies will lead to a detailed understanding of EboV infection and activation of macrophages and will ultimately lead to the development of urgently needed EboV antiviral therapies for Canadians and worldwide.