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

流感病毒感染后细胞特性的丧失及其对肺功能的影响

基本信息

批准号：
10438638
负责人：
Nicholas S Heaton
金额：
$ 58.81万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438638
关键词：
Acute Affect Alveolar Anti-Inflammatory Agents Cell Differentiation process Cell physiology Cells Data Disease Epithelial Epithelial Cells Experimental Models Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Immune response Infection Inflammation Influenza A virus Influenza B Virus Influenza Virus Infected Cells Label Long-Term Effects Lung Maintenance Mechanics Mediating Modeling Monitor Morphology Nature Organ Phenotype Physiology Population Primary Cell Cultures Process Proteins Pulmonary Surfactants Recombinants Research Respiration Respiratory physiology Survivors System Techniques Therapeutic Transgenic Animals Viral Viral Pathogenesis Virus Virus Diseases Virus Replication Work alveolar type II cell cell type design experience experimental study flexibility global health improved outcome in vivo influenza infection influenza virus strain influenzavirus interest lung injury novel preservation pulmonary function surfactant transcription factor

项目摘要

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. !

项目总结/摘要据估计，流感病毒每年感染全球20%的人口，尽管感染通常是一种流行性感冒。高度急性的流感病毒可引起宿主肺生理学的长期变化。由于其由于流感病毒对全球健康的重要性，人们对它进行了充分的研究，但所做的工作相对较少研究受感染上皮细胞的命运这主要是因为该领域的教条长期以来一直存在流感病毒完全是致细胞病变的病毒，即所有受感染的细胞最终都会被杀死。我们感兴趣的是通过实验确定是否有细胞可以在直接病毒感染中存活，在病毒清除后影响宿主使用甲型流感病毒（IAV）和乙型流感病毒（B）的重组株沿着转基因动物系统监测感染细胞的命运，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。而某些上皮细胞类型的存活是病毒特异性的，IAV和IBV均诱导群体的形成 “幸存者”的纤毛细胞。纤毛细胞是一种终末分化的细胞类型，具有良好的特征，形态学和转录谱，我们假设这将是一个强大的模型，以确定和询问病毒感染对细胞生理学的任何长期影响。我们发现病毒感染诱导正常纤毛细胞特性的显著丧失，不仅允许基因正常表达，仅限于其他上皮细胞类型，但也引起形态和功能变化，这对感染后肺功能的保护很重要。在这个提案中，我们试图利用这些观察和实验模型，以了解病毒如何影响细胞的身份，以及细胞身份灵活性与病毒发病机制的关系。拟议中的实验不仅将揭示病毒感染可以打破细胞分化的正常规律，也可以揭示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细胞过程，可用于治疗，以改善流感的结果，病毒感染。 !