The effects of cells that survive direct influenza A virus infection on lung repair

项目摘要/摘要 甲型流感病毒(IAV)是一种急性的细胞病变病毒，感染一系列不同类型的细胞，但主要是 肺上皮细胞。病毒感染会对近端和肺泡的呼吸道造成广泛的损害。 因为病毒在细胞培养中的生长是高度溶解细胞的，并且病毒通过以下方式从宿主中完全消除 获得性免疫系统，长期以来一直被认为没有受感染的细胞能够直接存活 感染。这一假设的一个派生结果是，病毒在感染后不能影响宿主 病毒感染的解决。 我最近开发了一种表达Cre重组酶的IAV，它使我能够永久地标记每一个感染的 细胞和跟随它们的命运。用这种病毒和转基因报告鼠系，我鉴定了一个种群 在直接和有效的病毒感染中存活下来的上皮俱乐部细胞。这些细胞不仅可以消除所有 病毒的痕迹并存活下来，但对这些细胞的进一步表征显示，这些细胞获得了 存活后，转录谱发生改变，通常是炎症性的。这些细胞的特定耗竭 上皮再生增强，表明病毒消退后存活细胞延迟了肺修复 感染。 我的初步数据表明，IAV感染导致了一群 转录重新编程的存活细胞，在肺修复中具有重要的抑制作用。尽最大努力 据我所知，存活细胞群体对肺修复的贡献从未被研究过。在这 建议，我将分析IAV的毒株特异性如何影响体内存活的俱乐部细胞的数量。我 然后将定义存活细胞如何影响未感染的基础/祖细胞行为以及跟踪命运 在肺修复期间存活者俱乐部细胞的数量。我将具体评估幸存的俱乐部细胞对 修复较大的和肺泡上皮。拟议中的工作将探索一种完全未被研究的 肺修复的调节剂，并可能识别新的机制，以治疗促进上皮再生 在病毒感染之后。

Project Summary/Abstract Influenza A virus (IAV) is an acute, cytopathic virus that infects a range of different cell types, but principally lung epithelial cells. Viral infection causes extensive damage to both the proximal and alveolar airways. Because virus growth is highly cytolytic in cell culture, and the virus is completely eliminated from the host by the adaptive immune system, it has long been believed that no infected cells are able to survive direct IAV infection. A derivative of this assumption is that the virus is incapable of influencing the host after the resolution of viral infection. I recently developed a Cre recombinase-expressing IAV, which allowed me to permanently label every infected cell and follow their fates. With this virus and transgenic reporter mouse lines, I identified a population of epithelial club cells that survived direct and productive viral infection. Not only can these cells eliminate all traces of the virus and survive, but further characterization of these cells revealed that the cells acquire an altered, and generally inflammatory, transcriptional profile after surviving. Specific depletion of these cells enhanced epithelial regeneration, indicating that survivor cells delay lung repair after the resolution of viral infection. The implication of my preliminary data is that IAV infection leads to the generation of a population of transcriptionally reprogrammed survivor cells that have important inhibitory roles in lung repair. To the best of my knowledge, the contribution of survivor cell populations to lung repair has never been studied. In this proposal, I will assay how the strain specificity of IAV influences the numbers of surviving club cells in vivo. I will then define how survivor cells influence uninfected basal/progenitor cell behavior as well as track the fates of survivor club cells during lung repair. I will specifically evaluate the effects of surviving club cells on the repair of both the larger and alveolar epithelium. The proposed work will explore a completely unstudied regulator of lung repair, and may identify novel mechanisms to therapeutically enhance epithelial regeneration after viral infections.