Grant: Project Grant - Priority Announcement: Infection and Immunity

Killer cells of the immune system are important for eliminating most virus infections and serve as a natural defense against tumor cells. We want to understand how killer cells crawl through the body to seek and destroy infected cells and cancer cells. We predicted that a particular protein called leupaxin would be important for controlling either the migration or function of killer cells. We showed that leupaxin localizes to the front end of migrating cells and to the contact zone where killer cells bind to their target cell, consistent with a role for leupaxin in these processes. To directly test its role, we generated a model system where the leupaxin was genetically deleted so that we could study immune responses to viruses and to cancer in its absence. Our preliminary data show that deleting leupaxin causes less severe symptoms in response to influenza virus infection. This was surprising as we predicted the response would be worse. Many of the symptoms of influenza infection are related to damage caused by immune cells responding to the virus and not due to the virus itself. While killer cells contribute to the clearance of influenza virus, too many of these cells could cause some of the symptoms associated with influenza infection. Our hypothesis is that leupaxin contributes to the entry or retention of killer cells and other cells that promote damage in the lungs. By having fewer cells, virus may still be eliminated efficiently, but with less severe disease. To test our hypothesis, we will examine numbers of killer cells and relevant cells in the lungs before and after infection. We will also use genetic mechanisms to pinpoint the function that is responsible for the improved recovery from influenza infection. We want to understand how this improved response occurs to potentially translate the results into therapeutics to improve the outcome after influenza infection, and perhaps other inflammatory diseases.