Loss of cellular identity after influenza virus infection and effects on pulmonary function

项目摘要/摘要 据估计，每年有20%的全球人口感染流感病毒，尽管感染通常是 高度急性的流感病毒可引起宿主肺生理的长期变化。由于他们的 流感病毒对全球健康的重要性已经得到了很好的研究；然而，所做的工作相对较少 研究受感染的上皮细胞的命运。这主要是因为这一领域的教条长期以来一直 流感病毒完全是细胞病变病毒，即所有被感染的细胞最终都会被杀死。我们是在 有兴趣通过实验确定是否有细胞能够在直接病毒感染后存活并有可能继续 在病毒清除后影响宿主。使用重组甲型流感病毒和乙型流感病毒 病毒(IBV)，随着转基因动物系统对感染细胞命运的监测，我们发现高达3% 的肺上皮细胞被感染，但不会被病毒或随后的免疫反应杀死。而当 某些上皮细胞类型的存活是病毒特异性的，IAV和IBV都能诱导群体的形成 幸存的纤毛细胞。纤毛细胞是一种终末分化的细胞类型，具有良好的特性 形态和转录特征，我们假设这将是一个强大的模型来识别和 询问病毒感染对细胞生理的任何长期影响。我们发现病毒感染会导致 正常纤毛细胞身份的显著丧失，不仅允许基因的正常表达 仅限于其他类型的上皮细胞，但也引起了形态和功能的变化 对保护感染后的肺功能具有重要意义。在这个提案中，我们试图利用 这些观察和实验模型旨在了解病毒如何影响细胞身份，以及 细胞识别灵活性与病毒致病机制的关系。拟议中的实验不仅揭示了 病毒感染可以打破细胞分化的正常规则，但也揭示了一种新的宿主适应性 在急性病毒感染期间维持关键器官功能的机制。从长远来看，这项研究的结果 也可能揭示出可用于治疗以改善流感结果的细胞过程 病毒感染。 好了！

Project Summary/Abstract Influenza viruses infect an estimated 20% of the global population every year and although infection is typically highly acute, influenza viruses can induce prolonged changes to host pulmonary physiology. Due to their importance for global health, influenza viruses are well studied; however relatively little work has been done investigating the fates of infected epithelial cells. This is primarily because the dogma in the field has long held that influenza viruses are exclusively cytopathic viruses, i.e. all infected cells are eventually killed. We were interested in experimentally determining if any cells could survive direct viral infection and potentially continue to affect the host after viral clearance. Using recombinant strains of influenza A virus (IAV) and influenza B virus (IBV), along with transgenic animal systems to monitor the fates of infected cells, we found that up to 3% of the lung epithelium is infected but is not killed by the virus or the subsequent immune response. While the survival of some epithelial cell types was virus specific, both IAV and IBV induced the formation of populations of “survivor” ciliated cells. Ciliated cells are a terminally differentiated cell type with a well characterized morphology and transcriptional profile, which we hypothesized would be a powerful model to identify and interrogate any long-term effects of viral infection on cellular physiology. We found that viral infection induced a striking loss of the normal ciliated cell identity which not only allowed the expression of genes normally restricted to other epithelial cell types, but also caused morphological and functional changes that were important for the preservation of pulmonary function after infection. In this proposal, we attempt to leverage these observations and experimental models to understand how viruses can affect cellular identity, as well as how cellular identity flexibility relates to viral pathogenesis. The proposed experiments will reveal not only how viral infection can break the normal rules of cellular differentiation, but also reveal a novel host adaptive mechanism to maintain critical organ function during acute viral infection. Long term, the results of this study may also reveal cellular processes that can be therapeutically exploited to improve the outcome of influenza virus infection. !