Adipose Tissue Inflammation in Influenza Infection Severity

流感感染严重程度中的脂肪组织炎症

基本信息

批准号：
10462898
负责人：
Pablo Alarcon
金额：
$ 4.12万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462898
关键词：
2019-nCoV Address Adipocytes Adipose tissue Affect Attention Cell physiology Cells Chronic Clinical Collaborations Communicable Diseases Complex Critical Thinking Data Disease Epidemiology Epithelial Cells Exhibits Future Immune Immune response Infection Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Influenza Influenza A virus Interferon Type I Interferon-alpha Interferon-beta Interferons Interleukin-6 Knock-out Knockout Mice Knowledge Learning Link Literature Lung Lung diseases Mediating Molecular Molecular and Cellular Biology Mus Obese Mice Obesity Outcome Pathogenesis Pathogenicity Pathology Persons Phenotype Physicians Predisposition Preventive Process Production Property Pulmonary Edema Receptor Signaling Reporter Research Respiratory Tract Infections Risk Factors Scientist Severities Severity of illness Shapes Structure of parenchyma of lung Testing Therapeutic Thinness Tissues Virus career development cell type cytokine defined contribution genetic signature high risk human disease influenza infection mortality new therapeutic target novel obese person pandemic disease pathogenic virus prognostic receptor skills tool transcriptome trend virtual

项目摘要

ABSTRACT The obesity pandemic continues unabated, afflicting >500 million people worldwide. Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to Influenza infection. Altered immune cell function (e.g. cytokine production) is often perceived as a key causative factor for increased lung tissue damage. However, the contribution of adipocytes, the dominantly altered cell type in obesity with immune-like properties, to Influenza pathogenesis remains largely ignored. Notably, obesity promotes adipocyte skewing towards a proinflammatory state and amplifies their immune-like contribution. Here we propose to examine the contribution of adipocyte inflammatory capacity to influenza disease pathogenesis. Our novel preliminary data strongly suggest that influenza-induced type I interferon (IFN) sensing skews adipocyte-specific inflammatory capacity, and promotes systemic and tissue inflammation that correlates with disproportionate lung tissue damage in mice. Our preliminary findings indicate that: Obese mice infected with influenza, compared to lean controls, exhibit: (a) increased mortality; (b) more severe lung tissue pathology; (c) increased lung edema; and (d) elevated lung IL-6 levels. Further, we show that influenza infection: (e) directly shapes white adipose tissue (WAT) immune cell infiltration and increases WAT type I IFN/IFNAR axis activation; and (f) induces adipocyte IL-6 inflammatory responses. Lastly, we show that: (g) obesity amplifies adipocyte inflammatory vigor via the type I IFN/IFNAR axis; (h) adipocytes contribute to systemic inflammatory cytokine production; and (i) adipocyte-secreted factors exacerbate lung epithelial cell inflammation. Our data and existing literature support a novel hypothesis that IFNAR-dependent activation of adipocyte inflammatory capacity promotes adipocyte IL-6 production and amplifies influenza infection-driven lung disease severity in obesity. We propose to test this hypothesis by: (i) determining the impact of Influenza infection on adipocyte inflammatory capacity and lung tissue damage in obesity (Aim 1); (ii) determining the contribution of adipocyte-centric IL-6 production on Influenza-associated tissue damage in obesity (Aim 2). Our studies will enhance the knowledge of adipocyte-driven inflammatory vigor and the impact of such inflammation on human disease. Considering the global trend towards a more obese population, defining the contribution of these cellular inflammatory processes will provide a robust platform for discovery of novel therapeutic targets to reduce the clinical burden of influenza.

抽象的肥胖症流行趋势有增无减，困扰着全球超过 5 亿人。流行病学证据将肥胖确定为增加流感感染易感性和严重程度的独立危险因素。免疫细胞功能的改变（例如细胞因子的产生）通常被认为是免疫细胞增加的关键因素。肺组织损伤。然而，脂肪细胞（肥胖症中主要改变的细胞类型）的贡献免疫样特性，导致流感发病机制仍然在很大程度上被忽视。值得注意的是，肥胖会促进脂肪细胞偏向促炎状态并增强其免疫样贡献。在此我们建议检查脂肪细胞炎症能力对流感疾病发病机制的贡献。我们的小说初步数据强烈表明，流感诱导的 I 型干扰素 (IFN) 传感会扭曲脂肪细胞特异性炎症能力，并促进与不成比例的肺相关的全身和组织炎症小鼠的组织损伤。我们的初步研究结果表明：与感染流感的肥胖小鼠相比，精益控制，表现出： (a) 死亡率增加； (b) 更严重的肺组织病理学； (c) 肺水肿加重； (d) 肺部 IL-6 水平升高。此外，我们表明流感感染：（e）直接塑造白色脂肪组织（WAT）免疫细胞浸润并增加 WAT I 型 IFN/IFNAR 轴激活； (f) 诱导脂肪细胞 IL-6 炎症反应。最后，我们表明：（g）肥胖会增强脂肪细胞的炎症活力通过 I 型 IFN/IFNAR 轴； (h) 脂肪细胞有助于全身炎症细胞因子的产生；和（一）脂肪细胞分泌因子加剧肺上皮细胞炎症。我们的数据和现有文献支持脂肪细胞炎症能力的 IFNAR 依赖性激活促进的新假设脂肪细胞 IL-6 的产生并放大了肥胖症中流感感染驱动的肺部疾病的严重程度。我们建议通过以下方式检验这一假设：（i）确定流感感染对脂肪细胞炎症的影响肥胖症的容量和肺组织损伤（目标 1）； (ii) 确定以脂肪细胞为中心的 IL-6 的贡献生产对肥胖中流感相关组织损伤的影响（目标 2）。我们的学习将增强知识脂肪细胞驱动的炎症活力以及此类炎症对人类疾病的影响。考虑到全球人口肥胖趋势，定义了这些细胞炎症过程的贡献将为发现新的治疗靶点以减轻流感的临床负担提供一个强大的平台。