The Role of Lung Multiciliated Cell MIWI2 in Influenza Pathogenesis

肺多纤毛细胞 MIWI2 在流感发病机制中的作用

• 批准号: 10315467
• 负责人: Jin Yuan
• 金额: $ 6.6万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2022-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315467
• 关键词: Role; Lung; Multiciliated; Cell; MIWI2

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.

项目概要/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同质群体；然而，调查结果 我们的实验室揭示了小鼠和人肺中独特的多纤毛细胞子集，可以将其 以 MIWI2 蛋白的表达为特征，约占所有气道的 5-10% 上皮细胞。 MIWI2 是 Argonaute 家族成员，可结合小非编码 RNA (piRNA) 积极抑制生殖细胞中逆转录病毒元件的表达。虽然多纤毛细胞的功能 衍生的 MIWI2 尚不清楚，我们的初步数据表明 MIWI2 关键参与调节 肺部有外源性病毒。总体而言，关于多纤毛细胞在过程中的作用知之甚少。 病毒感染。特别是，尚不清楚多纤毛细胞是否发挥独特的作用 在最初的感染过程中、病毒传播过程中或帮助协调宿主防御反应过程中。 鉴于 MIWI2 在基因沉默和保护种系基因组免受侵害方面发挥的作用 内源性逆转录病毒，我们测试了气道 MIWI2 也可以调节 外源病毒。我们的初步数据表明，缺乏多纤毛细胞 MIWI2 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显着下降 甲型流感病毒（PR8）。根据这些发现，我们将检验 MIWI2+ 多纤化的假设 细胞促进甲型流感病毒 (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 对 IAV 感染的反应取决于 MIWI2。在目标 2 中，我们将确定是否是 multicilated 细胞 MIWI2 促进 IAV 感染和传播。这些研究的结果将扩展我们的 了解肺中多纤毛细胞的作用和 MIWI2 蛋白的功能。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。