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

“肥胖流行病”是一个主要的全球公共卫生问题，影响超过40%的美国人口，并与2型糖尿病（T2 DM）密切相关。受影响的人发生严重和危及生命的呼吸道病毒（COVID-19或流感）感染的可能性至少增加3倍。目前和未来的人口中有很大一部分处于并将处于严重遭受这些感染的非常高的风险中。研究肥胖和糖尿病受试者易感性增加的基础机制是必不可少的。长期目标是阐明代谢性疾病影响病毒性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障碍的脂肪细胞和瘦素途径在塑造肺部先天性反应呼吸道病毒感染的影响。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肺宿主反应，增强了气道/肺泡上皮对呼吸道冠状病毒和流感病毒A感染的容许性，因此增加了肺损伤，部分与更高的病毒复制有关。该项目的基本原理是，解剖这种反应可能会产生一个强大的框架，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。通过追求两个具体目标来检验中心假设：1）研究病毒感染后支气管和肺泡气-液界面培养物中健康和功能障碍的脂肪细胞和瘦素信号传导的影响; 2）研究瘦素信号传导对肺先天性应答的贡献及其对体内甲型流感和SARS-CoV-2感染后的临床结果、病毒复制和肺损伤的影响。在第一个目标下，将空气-液体界面上的人气道和肺泡培养物暴露于来自健康和功能失调的人脂肪细胞的条件培养基，并用siRNA探测以剖析瘦素途径的不同组分。对于第二个目标，将采用瘦素受体-STAT 3信号缺陷、瘦素受体-SOCS 3信号缺陷和瘦素受体缺陷小鼠来机械地理解瘦素途径在体内对SARS-CoV-2和流感病毒A的肺应答中的作用。拟议的研究是创新的，因为它结合了体外和体内工具，以机械地探测瘦素信号通路，并了解其在肺部对病毒感染的反应中的作用，这与目前已知的有实质性的偏差。拟议的研究具有重要意义，因为阐明瘦素信号通路在呼吸道病毒感染期间的确切作用将允许确定宿主通路干预点，以制定精确的干预策略，以对抗高危肥胖和T2 DM患者的这些感染。

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.