SUMMARY 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 signaling-deficient, 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.