The Role of Lung Multiciliated Cell MIWI2 in Influenza Pathogenesis

项目摘要/摘要 流感病毒吸入后，攻击呼吸道上皮细胞，特别是多纤毛细胞。 人口。这些细胞以前被认为是同质的群体；然而，研究结果 在小鼠和人的肺中发现了一种独特的多纤毛细胞亚群，这种细胞可以 以MIWI2蛋白的表达为特征，约占所有呼吸道的5%-10% 上皮细胞。MIWI2是Argavit家族成员，可与小分子非编码RNA(PiRNA)结合 主动抑制生殖细胞中逆转录病毒元件的表达。而多纤毛细胞的功能- 衍生的MIWI2尚不清楚，我们的初步数据表明MIWI2参与了关键的调控 肺内的外源病毒。总体而言，对多纤毛细胞在体内的作用知之甚少。 病毒感染。特别是，目前还不清楚多纤毛细胞是否扮演着独特的角色 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方面。 鉴于MIWI2在基因沉默和保护生殖系基因组中所起的作用 内源性逆转录病毒，我们测试了MIWI2也可以调节其表达的想法 外源病毒。我们的初步数据显示，缺乏多纤毛细胞MIWI2的小鼠表现出 病毒RNA和感染性病毒颗粒水平在感染后7天显著下降 甲型流感病毒(PR8)。根据这些发现，我们将检验MIWI2+多纤毛的假设 细胞支持甲型流感病毒(IAV)感染的繁殖，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是否转录 对IAV感染的反应取决于MIWI2。在目标2中，我们将确定多纤毛 MIWI2细胞可促进IAV的感染和繁殖。这些研究的结果将扩大我们的 了解多纤毛细胞的作用和MIWI2蛋白在肺中的功能。重要的是 实验计划的实施将为企业的成长和成熟提供丰富的机会 早期的调查员。

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.