The role of adipocyte-driven inflammation and leptin pathway in pulmonary viral infections caused by SARS-CoV-2 and influenza A viruses

肥胖大流行是一个重大的全球公共卫生问题，影响着超过40%的美国人口，并与2型糖尿病(T2 DM)密切相关。受影响的人患上严重和危及生命的呼吸道病毒(新冠肺炎或流感)感染的可能性至少高出3倍。目前和未来人类人口中的很大一部分人正在并将面临严重感染这些疾病的极高风险。有必要研究导致肥胖和糖尿病受试者易感性增加的基础机制。长期目标是阐明代谢性疾病影响病毒呼吸道感染致病性的生物学机制。这项建议的总体目标是确定功能失调的脂肪细胞和瘦素途径在形成呼吸道病毒感染的肺固有反应中的作用。我们的中心假设是，脂肪细胞分泌的因子和受损的瘦素信号改变了稳态的肺宿主反应，并增强了呼吸道/肺泡上皮对呼吸道冠状病毒和甲型流感病毒感染的通透性，从而增加了肺损伤，部分原因是病毒复制增加。该项目的基本原理是，对这种反应的剖析可能会产生一个强有力的框架，从而可以开发针对瘦素途径的新的治疗方法，以改善这些感染对高危患者的影响。中心假设将通过追求两个特定的目标来验证：1)研究健康和功能障碍的脂肪细胞和瘦素信号对病毒感染后支气管和肺泡气液界面培养的影响；2)研究瘦素信号在肺先天性反应中的作用及其对甲型流感和SARS-CoV-2体内感染后的临床结局、病毒复制和肺损伤的影响。在第一个目标下，人的呼吸道和肺泡在气液界面上的培养将暴露在来自健康和功能失调的人类脂肪细胞的条件培养液中，并用siRNAs探测以剖析瘦素途径的不同成分。对于第二个目标，瘦素受体-STAT3信号缺陷、瘦素受体-SOCS3信号缺陷和瘦素受体缺陷小鼠将被用来机械地了解瘦素途径在体内对SARS-CoV-2和流感病毒A的肺部反应中的作用。拟议的研究具有创新性，因为它结合了体外和体内的工具来机械地探测瘦素信号途径并了解其在肺部对病毒感染的反应中的作用，这与目前所知的有实质性的偏离。这项拟议的研究具有重要意义，因为揭示瘦素信号通路在呼吸道病毒感染中的确切作用将允许确定宿主途径干预点，以便在高危肥胖症和T2 DM患者中制定精确的干预策略来对抗这些感染。

The “obesity pandemic” is a major global public health issue that affects more than 40% of the US population and is tightly interrelated with type 2 diabetes mellitus (T2DM). Affected people are at least 3 times more likely to develop critical and life-threatening respiratory viral (COVID-19 or influenza) infections. A large proportion of the current and future human population is and will be at very high risk of severely suffering from these infections. There is an indispensable need to study the underpinning mechanisms that drive increased susceptibility in obese and diabetic subjects. The long-term goal is to elucidate the biological mechanisms by which metabolic diseases influence the pathogenicity of viral respiratory infections. The overall objective of this proposal is to determine the effects of dysfunctional adipocytes and the leptin pathway in shaping pulmonary innate responses to respiratory viral infections. Our central hypothesis is that adipocyte secreted factors and impaired leptin signaling alter homeostatic pulmonary host responses and enhance airway/alveolar epithelial permissiveness to respiratory coronaviruses and Influenza virus A infections, with consequently increased lung injury associated in part with higher viral replication. The rationale for this project is that the dissection of such responses is likely to yield a strong framework whereby new therapeutic approaches targeting the leptin pathway can be developed to ameliorate the impact of these infections in at-risk patients. The central hypothesis will be tested by pursuing two specific aims: 1) investigate the influence of healthy and dysfunctional adipocytes and leptin signaling in bronchial and alveolar air-liquid interface cultures following viral infection; and 2) investigate the contributions of leptin signaling on pulmonary innate responses and its effects on clinical outcome, viral replication and lung injury following in vivo Influenza A and SARS-CoV-2 infections. Under the first aim, human airway and alveolar cultures on an air-liquid interface will be exposed to conditioned media derived from healthy and dysfunctional human adipocytes and probed with siRNAs to dissect different components of the leptin pathway. For the second aim, leptin receptor-STAT3 signaling-deficient, leptin receptor-SOCS3 signalingdeficient, and leptin receptor-deficient mice will be employed to mechanistically understand the role of the leptin pathway in in vivo pulmonary responses to SARS-CoV-2 and influenza virus A. The proposed research is innovative as it combines in vitro and in vivo tools to mechanistically probe the leptin signaling pathway and understand its role in pulmonary responses to viral infections, a substantive deviation from what is currently known. The proposed research is significant as unravelling the precise role of the leptin signaling pathway during respiratory viral infection will allow the identification of host pathway intervention points for precise intervention strategies to combat these infections in at-risk obese and T2DM patients.