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

• 批准号: 10213821
• 负责人: Nicholas S Heaton
• 金额: $ 60.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213821
• 关键词: Acute; Affect; Alveolar; Anti-Inflammatory Agents; Antiviral 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

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. !

项目概要/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 流感病毒高度急性，可引起宿主肺部生理机能的长期变化。由于他们的 流感病毒对全球健康很重要，已得到充分研究；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 流感病毒完全是细胞病变病毒，即所有受感染的细胞最终都会被杀死。我们是 有兴趣通过实验确定是否有任何细胞可以在直接病毒感染中存活下来并有可能继续下去 病毒清除后影响宿主。使用甲型流感病毒 (IAV) 和乙型流感病毒的重组毒株 病毒 (IBV) 以及监测受感染细胞命运的转基因动物系统，我们发现高达 3% 肺上皮细胞被感染，但未被病毒或随后的免疫反应杀死。虽然 某些上皮细胞类型的存活是病毒特异性的，IAV 和 IBV 均诱导细胞群的形成 “幸存者”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来识别和 询问病毒感染对细胞生理学的任何长期影响。我们发现病毒感染会诱发 正常纤毛细胞特性的显着丧失，这不仅允许基因正常表达 仅限于其他上皮细胞类型，但也引起了形态和功能的变化 对于感染后肺功能的保护具有重要意义。在本提案中，我们尝试利用 这些观察和实验模型可以了解病毒如何影响细胞身份，以及 细胞身份灵活性与病毒发病机制的关系。拟议的实验不仅将揭示如何 病毒感染可以打破细胞分化的正常规则，同时也揭示了一种新的宿主适应性 急性病毒感染期间维持关键器官功能的机制。从长远来看，本研究的结果 还可能揭示可用于治疗改善流感结果的细胞过程 病毒感染。 ！