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

脂肪细胞驱动的炎症和瘦素通路在 SARS-CoV-2 和甲型流感病毒引起的肺部病毒感染中的作用

• 批准号: 10832290
• 负责人: Mariano Carossino
• 金额: $ 25.9万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-24 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10832290
• 关键词: 2019-nCoV; Adipocytes; Affect; Air; Alveolar; Biological; Biology; COVID-19; Clinical; Coronavirus; Disease; Dissection; Exposure to; Future; Goals; Human; Immune response; Impairment; In Vitro; Infection; Inflammation; Influenza; Influenza A virus; Intervention; Leptin; Life; Liquid substance; Lung; Metabolic Diseases; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathogenicity; Pathway interactions; Patients; Persons; Population; Predisposition; Public Health; Research; Risk; Role; SARS-CoV-2 infection; STAT3 gene; Shapes; Signal Pathway; Signal Transduction; Small Interfering RNA; Testing; Viral; Viral Respiratory Tract Infection; Virus Diseases; Virus Replication; alveolar epithelium; combat; diabetic; high risk; in vivo; innovation; leptin receptor; lung injury; novel therapeutic intervention; pandemic disease; permissiveness; respiratory; response; tool

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.

“肥胖大流行”是一个主要的全球公共卫生问题，影响了美国40％以上的人口，并且与2型糖尿病（T2DM）密切相关。受影响的人产生关键和威胁生命的呼吸道病毒（COVID-19或影响）感染的可能性至少高3倍。当前和未来的人口中，很大一部分人口将会受到严重遭受这些感染的高风险。不可或缺的需要研究促进肥胖和糖尿病受试者易感性的基础机制。长期目标是阐明代谢疾病影响病毒呼吸道感染的致病性的生物学机制。该提案的总体目的是确定功能失调的脂肪细胞和瘦素途径在塑造肺部对呼吸道病毒感染的肺部先天反应中的影响。我们的中心假设是，脂肪细胞分泌的因素和瘦素信号受损会改变稳态肺宿主反应，并增强气道/肺泡上皮上皮允许对呼吸道冠状病毒和流感病毒的感染，导致与较高病毒复制相关的肺部损伤增加。该项目的理由是，这种反应的解剖可能会产生一个强大的框架，从而可以开发出针对瘦素途径的新治疗方法，以减轻这些感染对处于危险患者的影响。中央假设将通过追求两个具体目的来检验：1）病毒感染后，研究健康和功能障碍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部先天反应的贡献及其对临床结果，病毒复制和肺部损伤的影响。在第一个目标下，人类气道和空气界面上的肺泡培养物将暴露于来自健康和功能障碍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成分。 For the second aim, leptin receptor-STAT3 signaling-deficient, leptin receptor-SOCS3 signaling-deficient, and leptin receiver-deficiency mice will be employed to mechanically understand the role of the leptin pathway in in vivo pulmonary responses to SARS-CoV-2 and influenceza virus A. The proposed research is innovative as it combines in vitro and in vivo tools to mechanically probe the leptin信号通路并了解其在肺部对病毒感染的反应中的作用，这与目前已知的事物是实质性的。在呼吸病毒感染期间，瘦素信号通路的精确作用将允许确定宿主途径干预点，以确定精确的干预策略，以对抗高危肥胖和T2DM患者中的这些感染。