The Role of E3 Ligase MARCH10 in Influenza Virus Infection

PROJECT SUMMARY There are ~1 billion human influenza cases worldwide each year, resulting in up to 650,000 deaths. Influenza virus infects cells of the airways and distal lung, causing acute lung injury. The main class of antiviral drugs recommended for treating influenza works by blocking the viral neuraminidase enzyme on the virus surface to prevent the release of viral particles from infected cells. However, the increasing emergence of drug resistance limits their effectiveness. Therefore, there is an urgent need to identify novel molecular regulators and pathways of the innate immune response in the lung against influenza virus infection. This proposal is driven by our novel finding that the E3 ubiquitin ligase MARCH10, a protein never described in the lungs in the context of influenza virus infection with no known role in pulmonary immunity, is significantly downregulated by influenza virus infection in human and murine lungs. Overexpression of MARCH10 also drastically decreases the viral protein influenza hemagglutinin when lung epithelial cells are infected with influenza virus. We hypothesize that MARCH10, regulated at the transcriptional level, decreases influenza pathogenesis and is a critical regulator of airway epithelial cell host defense. We have proposed the following specific aims to investigate this hypothesis: 1) Determine if influenza virus induces a stage-specific decrease in MARCH10 at the gene transcriptional level and 2) Determine if catalytically active MARCH10 reduces influenza virus pathogenesis via post-transcriptional mechanisms. To accomplish these goals, the principal investigator has developed a five-year training program under the guidance of her mentors, Dr. Rama Mallampalli – an expert in ubiquitin-mediated proteolysis and acute lung injury and Dr. Jacob Yount - an expert in influenza and viral immunology, to acquire training in advanced molecular and cell biology techniques, virology techniques, and small animal model development. The candidate’s training will also be overseen by a Scientific Advisory Committee to lend expertise, provide oversight and evaluate progress, including, Dr. Mallampalli, Dr. Yount, Dr. Estelle Cormet-Boyaka – an expert in lung epithelial cell biology, and Dr. Dan Wozniak – an expert in lung and bacterial pathogenesis. The proposed career development plan will provide the additional training necessary to achieve the principal investigator’s ultimate goal of becoming an independent physician-scientist studying the biological mechanisms by which lung epithelial cells respond to respiratory viral infections and modulate the lung innate immune response and translate these findings into novel therapeutics to prevent and treat viral infections and its associated lung injury.