Immune-epithelial progenitor interactions drive age-associated dysplastic lung repair post viral pneumonia

项目摘要/摘要 SARS-CoV-2和流感等呼吸道病毒感染是发病率和死亡率的主要原因， 每年约有200万人死亡，医疗保健负担更高 大流行。尤其是65岁以上的人，在急性发作期间容易出现不良后果。 呼吸系统疾病。除了急性疾病的严重性增加外，老年人患上 发生慢性肺部后遗症--称为“新冠肺炎急性后遗症”(PASC) SARS-CoV-2感染。根据研究标准，27%-80%的康复者被发现患有 慢性疾病，因此PASC正在迅速发展成为全球医疗系统的主要负担。 值得注意的是，这种现象不仅限于SARS-CoV-2，而且在其他几种病毒之后也有报道 呼吸道病毒感染包括流感、SARS-CoV-1、MERS、RSV和鼻病毒。增加了 老年人对慢性肺部后遗症和不良长期后果的易感性仍然是一个 所有病毒都具有一致的功能。然而，我们对年龄相关特征的洞察有限 负责急性病毒损伤后慢性肺部后遗症的发展和维持。 我们的实验室和其他实验室之前曾报道过以下持续的免疫反应失调 衰老过程中的呼吸道病毒感染。组织常驻CD8+记忆性T-(CD8+TRM)的长期维持 细胞被发现在老年肺的慢性病理中起作用。这背后的分子机制 病理活动以前是未知的，但我现在提供的数据表明，CD8+TRM细胞在老年人中持续存在 肺是病毒损伤后肺泡再生受损的原因之一。当CD8+TRM细胞耗尽时 感染急性期后，我观察到Krt8+移行细胞的长期维持减少- 肺泡上皮2型(ATII)细胞分化为ATI细胞之前的一种中间状态。 再加上观察到的ATI细胞的增加，这些数据表明CD8+TRM细胞损害了完整的 Krt8+移行细胞分化为成熟的ATI细胞，从而损害肺功能。我也是 发现CD8+TRM耗竭导致IL-1β水平降低，这是一种已知调节Krt8+过渡性细胞因子的细胞因子 细胞活动。因此，我的总体假设是CD8+TRM细胞在病毒感染后持续存在于老年肺中。 肺炎促进慢性IL-1β释放从而损害Krt8+移行细胞分化促进 肺发育不良修复术。为了解决我的假设，我建议1)确定CD8+TRM细胞的贡献 2)阐明老年肺泡再生受损的病理机制 CD8+TRM细胞促进老年肺发育不良修复了解这种免疫上皮祖细胞 相互作用将加深我们对免疫系统在肺泡中的作用的基本理解 再生和肺修复。此外，拟议的研究将为开发治疗方法铺平道路。 促进重症病毒性肺炎后老年肺功能修复的策略。

PROJECT SUMMARY/ABSTRACT Respiratory viral infections such as SARS-CoV-2 and influenza are a leading cause of morbidity and mortality, accounting for approximately 2 million deaths per year and an even higher healthcare burden during pandemics. Individuals over the age of 65 in particular, are susceptible to adverse outcomes during acute respiratory illness. In addition to increased severity of acute disease, aged individuals are at higher risk of developing chronic pulmonary sequelae – termed “post-acute sequelae of COVID-19” (PASC) in the context of SARS-CoV-2 infection. Depending on the study criteria, 27-80% of convalescents have been found to develop chronic disease and thus PASC is quickly developing into a major burden on healthcare systems worldwide. Notably, this phenomenon is not only limited to SARS-CoV-2 and has been reported following several other respiratory viral infections including influenza, SARS-CoV-1, MERS, RSV and rhinovirus. Increased susceptibility of aged individuals to chronic pulmonary sequelae and adverse long-term outcomes remains a consistent feature across all viruses. However, we have limited insight into the age-associated features responsible for the development and maintenance of chronic pulmonary sequelae following acute viral injury. Our lab and others have previously reported persistent dysregulation of immune responses following respiratory viral infections during aging. Long-term maintenance of tissue resident CD8+ memory T- (CD8+ TRM) cells was found to contribute to chronic pathology in aged lungs. The molecular mechanisms underlying this pathological activity were previously unknown, but I now present data that CD8+ TRM cells persisting in aged lungs contribute to impaired alveolar regeneration post viral injury. Upon depletion of CD8+ TRM cells in the post-acute phase of infection, I observe a reduction in the long-term maintenance of Krt8+ transitional cells – an intermediate state adopted by alveolar epithelial type 2 (ATII) cells prior to differentiation into ATI cells. Coupled with the observed increase in ATI cells, these data indicate that CD8+ TRM cells impair the complete differentiation of Krt8+ transitional cells into mature ATI cells, thereby compromising pulmonary function. I also found that CD8+ TRM depletion results in reduced IL-1β levels, a cytokine known to regulate Krt8+ transitional cell activity. Thus, my overall hypothesis is that CD8+ TRM cells persisting in aged lungs following viral pneumonia contribute to chronic IL-1β release and thus impair Krt8+ transitional cell differentiation to promote dysplastic lung repair. To address my hypothesis, I propose to 1) determine the contributions of CD8+ TRM cells persisting in aged lungs to impaired alveolar regeneration and 2) elucidate the pathological mechanisms driven by CD8+ TRM cells to promote dysplastic repair of aged lungs. Understanding this immune-epithelial progenitor interaction would deepen our fundamental understanding of the role of the immune system in alveolar regeneration and lung repair. Moreover, the proposed studies would pave the way for developing therapeutic strategies to promote functional repair of aged lungs following severe viral pneumonia.