Balancing epithelial cell resistance and resilience to respiratory viral infections

平衡上皮细胞抵抗力和对呼吸道病毒感染的抵抗力

• 批准号: 10555886
• 负责人: Jose Manuel Ordovas-Montanes
• 金额: $ 86.99万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555886
• 关键词: 2019-nCoV; Airway Disease; Anabolism; Antiviral Response; Antiviral resistance; Area; Basal Cell; Biogenesis; Biology; COVID-19; COVID-19 pandemic; COVID-19 patient; Cachexia; Cardiovascular system; Cell Survival; Cell physiology; Cells; Cholesterol; Clinical; Complement; Coupled; Data; Defect; Development; Disease; Epithelial Cells; Epithelium; Equilibrium; Genes; Genetic study; Glycoproteins; Goblet Cells; Health; Histologic; Host Defense; Host resistance; Human; Immunity; Impairment; Individual; Infection; Infiltration; Inflammatory; Influenza; Integration Host Factors; Interferons; Investigation; Knowledge; Laboratories; Lead; Light; Lipids; Metabolic; Modeling; Molecular; Mus; Mutation; Outcome; Overweight; Oxidoreductase; Pathogenesis; Pathogenicity; Persons; Phenotype; Population; Predisposition; Publishing; RNA Viruses; Regenerative capacity; Research; Resistance; Respiratory Disease; Respiratory System; Respiratory distress; Risk; STAT1 gene; Secretory Cell; Sensory; Severity of illness; Signal Transduction; Specialized Epithelial Cell; Structure of mucous membrane of nose; System; Testing; Therapeutic; Tissues; Up-Regulation; Vaccination; Vaccines; Variant; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Virus Replication; Work; Zinc; airway epithelium; assault; cellular resilience; cholesterol biosynthesis; cohort; design; epidemiology study; epithelial stem cell; flu; in vivo; influenza infection; influenzavirus; innovation; lipid metabolism; lipidomics; mortality; nasopharyngeal swab; novel; novel therapeutic intervention; obese person; progenitor; prophylactic; prospective; recruit; resilience; resistance mechanism; respiratory; respiratory virus; response; screening; seasonal influenza; severe COVID-19; single-cell RNA sequencing; stability testing; stem cells

PROJECT SUMMARY The COVID-19 pandemic has highlighted how one respiratory RNA virus can induce a tremendous diversity of host outcomes. While we have made progress in understanding clinical, cellular, and molecular correlates of disease severity, few studies have assessed if or how specific factors present at baseline may induce severe disease. There is a tremendous knowledge gap in whether correlates of disease severity represent causal factors (i.e. if presence at baseline lead to more severe infection), or may actually represent generally beneficial attempts at restoring tissue function (i.e. a resilience mechanism), that are detrimental only in select host contexts. Despite distinct biology of SARS-CoV-2 and influenza, epidemiological studies have noted that overweight and obese individuals are at greater risk for severe infection, implicating lipid metabolism, and further genetic studies have found mutations in the Type I/III interferon system in severe cases. Importantly, treating the underlying causes of severe viral respiratory diseases will require a deeper understanding of the epithelial cell states that contribute to diverse outcomes to design host-directed therapies that complement vaccination campaigns and avoid long- lasting damage to the respiratory and cardiovascular systems. Recently through single-cell RNA-sequencing (scRNA-seq) of nasopharyngeal swabs, we have discovered that a muted interferon antiviral response combined with an increase in intracellular cholesterol biosynthesis potential in respiratory epithelial cells characterizes severe vs. mild-moderate COVID-19. In this same study, we also revealed diversified subsets of secretory and goblet cells with uncharacterized functional potential, overlapping with subsets we had previously identified in a study of seasonal influenza. Our published data, together with that of our colleagues, mandate further investigation into how pre-existing antiviral and cholesterol biosynthetic cell states in human respiratory epithelial cells dictate host outcomes to respiratory viral infection. In light of these findings, we hypothesize that baseline cholesterol biosynthesis in respiratory epithelial cells is a critical host resilience mechanism which becomes pathogenic in the absence of effective antiviral resistance mechanisms. This overarching hypothesis can only be tested through a shift in the conceptual and experimental approaches we traditionally deploy (New Research Direction). Successfully testing our hypothesis will address (Aim 1) whether cholesterol biosynthesis dictates the maximum potential interferon response in airway epithelial cells, or whether a muted interferon response underlies enhanced cholesterol biosynthesis in mice. Furthermore, it will identify novel contributions of airway epithelial cells to local and organismal lipid metabolism. Our work will also test (Aim 2) the stability of metabolic and antiviral cellular phenotypes in human epithelial progenitor cells. Successful completion of our plan will lead to the development of non-invasive screening approaches to better ascertain risk of susceptible populations to respiratory viruses, and of prophylactic and therapeutic strategies to achieve optimal balance of host defense strategies in the respiratory tract.

项目摘要 2019冠状病毒病大流行突出表明，一种呼吸道RNA病毒可以诱导多种多样的 东道主的成果。虽然我们在理解临床、细胞和分子相关性方面取得了进展， 疾病严重程度，很少有研究评估基线时存在的特定因素是否或如何可能诱导严重的 疾病在疾病严重程度的相关性是否代表因果因素方面存在巨大的知识缺口 (i.e.如果基线时存在导致更严重的感染），或者实际上可能代表通常有益的尝试 在恢复组织功能（即弹性机制），这是有害的，只有在选定的主机环境。尽管 SARS-CoV-2和流感的独特生物学，流行病学研究指出，超重和肥胖 个体有更大的严重感染风险，涉及脂质代谢，进一步的遗传研究表明， 在严重病例中发现了I/III型干扰素系统的突变。重要的是，治疗根本原因 严重病毒性呼吸道疾病的发生将需要更深入地了解上皮细胞状态， 设计宿主导向疗法，补充疫苗接种活动，避免长期 对呼吸系统和心血管系统造成持久性损害。 最近通过鼻咽拭子的单细胞RNA测序（scRNA-seq），我们发现， 干扰素抗病毒应答减弱，同时细胞内胆固醇生物合成潜力增加 在呼吸道上皮细胞中的特征是严重与轻中度COVID-19。在这项研究中，我们还 揭示了分泌细胞和杯状细胞的多样化亚群，具有未表征的功能潜力，重叠 与我们之前在一项季节性流感研究中发现的亚群进行比较。我们公布的数据，加上 我们的同事，授权进一步调查如何预先存在的抗病毒和胆固醇生物合成细胞， 人类呼吸道上皮细胞的状态决定了呼吸道病毒感染的宿主结果。 根据这些发现，我们假设呼吸道上皮细胞胆固醇生物合成的基线是 一种关键的宿主恢复机制，在缺乏有效的抗病毒耐药性的情况下成为致病性 机制等这一总体假设只能通过概念和实验的转变来检验。 我们传统上采用的方法（新研究方向）。成功验证我们的假设将解决 (Aim 1）胆固醇生物合成是否决定了气道上皮细胞中最大潜在干扰素反应 细胞，或者减弱的干扰素反应是否是小鼠胆固醇生物合成增强的基础。此外，委员会认为， 它将确定气道上皮细胞对局部和有机体脂质代谢的新贡献。我们的工作将 还测试（目的2）人上皮祖细胞中代谢和抗病毒细胞表型的稳定性。 我们计划的成功完成将导致非侵入性筛查方法的发展，以更好地 确定易感人群对呼吸道病毒的风险，以及预防和治疗策略， 在呼吸道中实现宿主防御策略的最佳平衡。