Visualizing the resolution of innate immune responses during influenza infection

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Evidence from recent major epidemics suggests that both direct viral cytopathicity and inflammation-mediated tissue damage are equally important factors that potentiate the host lethality. Thus, the therapeutic strategy to bridle excessive immune damage has been proposed for severe respiratory infections. While clearance of influenza-infected cells is primarily mediated by cytotoxic CD8+ T cells, the now well-established dependency of anti-viral host responses on both innate and adaptive immune compartments suggests that harnessing the innate immunity might form a basis for the development of effective vaccines and novel therapeutic approaches. Early recruitment of leukocytes from the blood to sites of tissue infection is a hallmark of innate immune responses. However, it is currently not known how apoptotic immune cells are removed within inflamed tissues during the resolution phase – a process fundamental to our understanding and manipulation of inflammatory diseases. Despite recent advances in studies concerning phagocytic removal of apoptotic cells, the visualization of the dynamic cell clearance process in vivo has been extremely challenging. Here we propose to develop a novel intravital multi-photon microscopy (IV-MPM) system to address critical knowledge gaps regarding the function and fate of innate immune cells during the influenza infection, and their roles in anti-viral immune responses. We will (1) develop the IV-MPM system to visualize in situ neutrophil efferocytosis during resolution of influenza infection in the upper (trachea) and lower (lung) airway, and (2) develop a novel tissue-resident phagocyte fate-mapping assay to study the immunological consequence of the neutrophil efferocytosis. With these new approaches in a mouse influenza infection model, we will be able to identify novel interactions between innate and adaptive immune systems during the influenza infection. Given the importance of dynamic immune modulatory properties during viral infections, the development of novel research tools to elucidate the relationship between innate immunity and effector T cell interactions at the site of infection is critical for deciphering the basis of productive and nonproductive adaptive immune responses and for advancing our capacity to develop new universal vaccines that rely on such cell mediated responses.