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

免疫上皮祖细胞相互作用驱动病毒性肺炎后与年龄相关的发育不良肺修复

• 批准号: 10751699
• 负责人: Harish Narasimhan
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751699
• 关键词: 2019-nCoV; 3-Dimensional; Accounting; Acute; Acute Disease; Address; Adopted; Age; Aging; Alveolar; Area; Bioinformatics; Bronchoalveolar Lavage Fluid; CD8B1 gene; COVID-19; Cell Differentiation process; Cells; Cessation of life; Chronic; Chronic Disease; Coculture Techniques; Coupled; Cytokeratin 8; Data; Data Set; Development; Epithelial Cells; Epithelium; Exhibits; Fibrosis; Genetic; Goals; Healthcare; Healthcare Systems; Human; Immune; Immune System Diseases; Immune response; Immune system; Impairment; In Vitro; Individual; Infection; Inflammation; Influenza; Injury; Interleukin-1 beta; Kinetics; Lung; Lung Capacity; Macrophage; Maintenance; Mediating; Memory; Middle East Respiratory Syndrome; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Natural regeneration; Organoids; Outcome; Pathologic; Pathology; Phase; Population; Post-Acute Sequelae of SARS-CoV-2 Infection; Predisposition; Process; Public Health; Pulmonary Inflammation; Recovery; Reporting; Rhinovirus; Risk; Role; SARS coronavirus; SARS-CoV-2 infection; Severities; Signal Transduction; Stains; System; T memory cell; Techniques; Therapeutic; Time; Tissues; Transitional Cell; Viral; Viral Pneumonia; Viral Respiratory Tract Infection; Virus; Virus Diseases; adverse outcome; aged; alveolar epithelium; care burden; cytokine; high dimensionality; high risk; human old age (65+); improved; in vivo; insight; lung repair; mortality; pandemic disease; progenitor; pulmonary function; repaired; respiratory; self-renewal; single-cell RNA sequencing; spatial integration; transcriptomics

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.

项目总结/摘要 呼吸道病毒感染如SARS-CoV-2和流感是发病和死亡的主要原因， 每年约有200万人死亡， 流行病特别是65岁以上的个体，在急性呼吸道感染期间易受不良后果的影响。 呼吸道疾病。除了急性疾病的严重程度增加外，老年人的风险更高， 发生慢性肺部后遗症-在以下情况下称为“COVID-19急性后后遗症”（PASC） SARS-CoV-2感染。根据研究标准，27-80%的康复者被发现发展为 慢性疾病，因此PASC正在迅速发展成为全世界医疗保健系统的主要负担。 值得注意的是，这种现象不仅限于SARS-CoV-2，而且在其他几种情况下也有报道。 呼吸道病毒感染，包括流感、SARS-CoV-1、MERS、RSV和鼻病毒。增加 老年人对慢性肺部后遗症和不良长期结局的易感性仍然是一个问题。 在所有病毒中保持一致。然而，我们对年龄相关特征的了解有限， 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以前曾报道过以下免疫反应持续失调 呼吸道病毒感染在衰老过程中长期维持组织驻留的CD 8+记忆T-（CD 8 + TRM） 细胞被发现有助于老年肺的慢性病理学。这背后的分子机制 病理活动以前是未知的，但我现在提出的数据表明，CD 8 + TRM细胞在老年人中持续存在， 肺有助于病毒损伤后受损的肺泡再生。在消耗了CD 8 + TRM细胞后， 感染急性期后，我观察到Krt 8+移行细胞的长期维持减少， 肺泡上皮2型（ATII）细胞在分化成ATI细胞之前所采用的中间状态。 结合观察到的ATI细胞的增加，这些数据表明CD 8 + TRM细胞损害了完整的细胞周期。 Krt 8+移行细胞分化为成熟ATI细胞，从而损害肺功能。我也 发现CD 8 + TRM耗竭导致IL-1β水平降低，IL-1 β是一种已知调节Krt 8+过渡性 细胞活性因此，我的总体假设是，在病毒感染后，CD 8 + TRM细胞在老年肺中持续存在， 肺炎有助于慢性IL-1β释放，从而损害Krt 8+移行细胞分化以促进 发育不良的肺修复为了解决我的假设，我建议1）确定CD 8 + TRM细胞的贡献 持续存在于老化的肺中以损害肺泡再生和2）阐明驱动的病理机制 通过CD 8 + TRM细胞促进老年肺的发育不良修复。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巨噬细胞中作用的基本理解。 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。 策略，以促进老年肺功能修复后，严重的病毒性肺炎。