Grant: Project Grant

Outbreaks of emerging viral diseases are increasing at an alarming rate and are a worldwide concern. A notable example of emerging viruses is the Ebola virus that causes severe hemorrhagic fevers in humans and non-human primates with lethality rates that can reach 90% and against which there is currently no antiviral therapy. The threat of unpredictable outbreaks emphasizes the need for the development of therapeutic drugs against Ebola virus. However, fundamental to developing new drugs is the elucidation of the different steps of the life cycle of the virus, such as the discovery of host proteins essential for infection that can be targeted to block virus spread. We have previously identified the receptor of the Ebola virus, the protein Niemann-Pick C1, which resides in late endocytic vesicles. This discovery allowed us to propose a model of infection by which the Ebola virus attaches to the cell surface, is internalized, and is trafficked to intracellular vesicles containing essential host factors such as the Ebola virus receptor triggering entry and delivery of the viral genetic material into the host cell. The requirement of multiple host proteins for viral entry offers several targets for pharmacological inhibition. A promising target includes a protein complex involved in the turnover of endosomal phosphoinositides. Genetic manipulation and chemical inhibition of the complex activity lead to efficient block in Ebola virus infection, suggesting that these proteins and endosomal phosphoinositides are critical for infection. Here, we propose to investigate their roles of in viral trafficking and entry using genetic and chemical biology approaches. The ultimate goal of the proposed research program is the development of urgently needed antiviral therapies against Ebola virus for Canadians and worldwide.