The Role of Lung Multiciliated Cell MIWI2 in Influenza Pathogenesis

项目总结/摘要 吸入后，流感病毒靶向气道上皮细胞，特别是多纤毛细胞 人口这些细胞以前被认为是一个同质的群体;然而，研究结果表明， 揭示了小鼠和人类肺中一个独特的多纤毛细胞亚群， 其特征在于蛋白质MIWI 2的表达，并且占所有气道的大约5- 10 上皮细胞MIWI 2是Argonaute家族成员，其结合小的非编码RNA（皮尔纳）， 主动抑制生殖细胞中的逆转录病毒元件表达。多纤毛细胞的功能- 衍生的MIWI 2尚不清楚，我们的初步数据表明MIWI 2在调节 肺中的外源性病毒。总的来说，关于多纤毛细胞在细胞周期中的作用知之甚少。 病毒感染特别是，目前尚不清楚多纤毛细胞是否发挥着独特的作用 在初始感染期间，在病毒传播中，或在帮助协调宿主防御反应中。 鉴于MIWI 2在基因沉默和保护生殖系基因组免受 内源性逆转录病毒，我们测试了气道MIWI 2也可以调节 外源性病毒我们的初步数据显示，缺乏多纤毛细胞MIWI 2的小鼠表现出 感染7天后，病毒RNA和感染性病毒颗粒的水平均显著降低， 甲型流感病毒（PR 8）。根据这些发现，我们将检验MIWI 2+多纤毛的假设， 细胞支持甲型流感病毒（IAV）感染的传播，并调节关键的免疫事件， 帮助维持病毒传播。在目标1中，我们将确定多纤毛细胞转录组是否与多纤毛细胞转录组相关。 对IAV感染的应答依赖于MIWI 2。在目标2中，我们将确定是否有多分支 细胞MIWI 2促进IAV感染和繁殖。这些研究的结果将扩大我们的 了解多纤毛细胞的作用和MIWI 2蛋白在肺中的功能。重要的是， 实验计划的实施将为一个国家的成长和成熟提供丰富的机会。 早期调查员

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.