Lung MIWI2 and the host defense against Influenza A virus

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Abstract Influenza is one of the most common respiratory infections globally and has led to an alarming number of deaths annually. Seasonal vaccines and therapies vary in efficacy among higher risk patients although they currently serve as the only countermeasures. This presents a critical need to further understand the host response to influenza in order to uncover pathways that can be targeted using novel therapies. One of the target cells of Influenza A virus (IAV) are the multiciliated cells of the lung airway. Our lab had previously discovered a subset of multiciliated cells defined by the expression of MIWI2, an Argonaute family protein most commonly studied in mammalian testes. MIWI2 binds to PIWI-interacting RNA (piRNA) and suppresses retrotransposon activity in germline cells to maintain genome integrity. However, MIWI2 expression in somatic cells is not well understood. In order to understand lung MIWI2, we used a MIWI2-TdTomato heterozygote (haplo-sufficient) and a homozygote (deficient) knock-in reporter mouse model. Mice deficient in MIWI2 exhibited a markedly decrease burden of Influenza A virus suggesting that MIWI2 plays a critical role in regulating viral pathogenesis and the immune response. Incorporating an HA-mNeon reporter IAV, we ruled out the possibility that MIWI2 multiciliated cells were preferentially infected as we observed no differences in viral tropism between MIWI2 haplo-sufficient and deficient mice. Recently, we identified the presence of an immune cell population that also expresses MIWI2, raising the prospect that this heretofore unrecognized hematopoietic cell could be key to MIWI2 dependent immune function. Taken together, we hypothesize that a MIWI2 expressing cell in the lung critically modulates the host response to IAV infection. We will examine our central hypothesis by pursuing two aims. In the first Aim, we will use bone marrow transplantations and cell-specific deletion of MIWI2 mouse models to determine the identity of the MIWI2 expressing cell population that modulates the immune response during an IAV infection. In the second Aim, we will employ single cell sequencing to elucidate MIWI2-dependent pathways that critically regulate the lung’s antiviral immune response. Overall, the work proposed here will expand our understanding of the viral pathogenesis of IAV as well as uncover novel pathways that are involved in the lung’s host immune response. These studies will also provide functional information regarding the action of Argonaute proteins in somatic cells. Most importantly, this serves as a platform for an integrated and cogent training plan that will support my development as an independent researcher.