The Role of Lung Multiciliated Cell MIWI2 in Influenza Pathogenesis

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Project Summary/Abstract After inhalation, influenza viruses target airway epithelial cells, in particular the multiciliated cell population. These cells were previously thought to be a homogeneous population; however, findings from our lab revealed a unique subset of multiciliated cells in the mouse and human lung that can be distinguished by the expression of the protein MIWI2, and represent approximately 5-10% of all airway epithelial cells. MIWI2 is an Argonaute family member that binds small non-coding RNA (piRNA) to actively repress retroviral element expression in germ cells. While the function of multiciliated cell- derived MIWI2 is not yet known, our preliminary data suggest MIWI2 is critically involved in regulating exogenous viruses in the lung. Overall, very little is known regarding the role of multiciliated cells during viral infection. In particular, it is not clear whether there are unique roles that multiciliated cells play during the initial infection, in viral propagation, or in helping to orchestrate the host defense response. Given the role that MIWI2 plays in gene silencing and defending the germline genome against endogenous retroviruses, we tested the idea that airway MIWI2 could also regulate the expression of exogenous viruses. Our preliminary data show that mice deficient in multiciliated cell MIWI2 exhibit markedly decreased levels of both viral RNAs and infectious viral particles at 7 days of infection with influenza A virus (PR8). In light of these findings, we will test the hypothesis that MIWI2+ multiciliated cells bolster the propagation of influenza A virus (IAV) infection and regulate key immune events that help sustain viral spread. In Aim 1, we will determine whether the multiciliated cell transcriptomic responses to IAV infection are dependent on MIWI2. In Aim 2, we will determine whether multiciliated cell MIWI2 promotes IAV infection and propagation. Results from these studies will expand our knowledge of the role of multiciliated cells and the function of MIWI2 protein in the lung. Importantly, execution of the experimental plan will provide a rich opportunity for the growth and maturation of an early investigator.