Impact of obesity on SARS-CoV-2 infection and reciprocal effects of SARS-CoV-2 on metabolic disease

肥胖对 SARS-COV-2 感染的影响以及 SARS-COV-2 对代谢疾病的相互影响

• 批准号: 10583175
• 负责人: Paul Kievit
• 金额: $ 99.42万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583175
• 关键词: 2019-nCoV; Acceleration; Acute; Acute Disease; Address; Adipocytes; Adipose tissue; Adult; Affect; Alveolar; Anatomy; Animals; Antigens; Appearance; Autopsy; Biological Markers; Blood; C-Peptide; COVID-19; COVID-19 impact; COVID-19 pandemic; COVID-19 patient; COVID-19 risk; COVID-19 severity; COVID-19 survivors; Cardiovascular Diseases; Cells; Chronic; Clinical; Data; Diabetes Mellitus; Disease; Endocrine; Endothelial Cells; Exhibits; Foundations; Glucose; Glycosylated hemoglobin A; Heart Diseases; Hospitalization; Human; Hyperinsulinism; Hypertension; Immune; Immune response; Immunohistochemistry; Impairment; Individual; Infection; Inflammation; Insulin; Insulin Resistance; Irrigation; Light; Link; Lipids; Lung; Macaca; Macaca mulatta; Macrophage; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Modeling; Monitor; Morbidity - disease rate; Morphology; Nature; Newly Diagnosed; Nucleic Acids; Obesity; Oral; Outcome; Pancreas; Pathology; Patients; Peripheral; Phase; Post-Acute Sequelae of SARS-CoV-2 Infection; Pre-Clinical Model; Predisposition; Public Health; Pulmonary Pathology; Quantitative Reverse Transcriptase PCR; Recovery; Reporting; Resistance; Respiratory Disease; Respiratory physiology; Risk; Risk Factors; SARS-CoV-2 B.1.617.2; SARS-CoV-2 infection; SARS-CoV-2 variant; Sampling; Serology; Severities; Severity of illness; System; Testing; Therapeutic; Thinness; Time; Tissue Sample; Tissues; Vaccines; Viral; Viral Antigens; Viral Load result; Viral reservoir; Viremia; Virus Latency; Visceral; acute infection; adverse outcome; blood glucose regulation; clinical care; clinical diagnosis; clinical heterogeneity; comorbidity; cytokine; diet-induced obesity; endothelial dysfunction; fasting glucose; glucose metabolism; glucose tolerance; glycemic control; human tissue; insulin secretion; insulin tolerance; islet; lipid metabolism; male; metabolic phenotype; mortality; nasal swab; nonhuman primate; novel; obese person; pandemic disease; patient population; pre-clinical; response; severe COVID-19; subcutaneous; therapy development; vaccination outcome; variants of concern; western diet

The COVID-19 global pandemic caused by the novel SARS-CoV-2 coronavirus continues to result in significant morbidity and mortality worldwide. Although effective vaccines and therapeutics have been introduced, COVID-19 will continue to persist as a public health issue as a result of vaccine resistance/hesitancy and risk of reinfection, the emergence of variants of concern that may evade current vaccines, and the potential existence of latent viral reservoirs. The adverse outcomes associated with COVID- 19 are increased by a number of pre-existing conditions, notably diabetes, cardiovascular disease, and hypertension. These conditions share obesity and insulin resistance (IR) as a common underlying feature, which has raised the question of whether obesity per se is an independent risk factor for more severe COVID- 19 outcomes in the absence of clinically diagnosed diabetes, cardiovascular disease, or hypertension. This concept is supported by previously described effects of obesity on respiratory disease and the immune response. Evidence is also accumulating for altered glucose and lipid metabolism and new-onset diabetes in COVID-19 patients that can persist after recovery from acute infection, and that constitutes an important component of post-acute sequelae of COVID-19 (PASC). These data suggest that, while obesity and metabolic disease affect the acute COVID-19, that there are a reciprocal acute and post-acute effects of COVID-19 on metabolic control. We hypothesize that: (1) obesity/IR in the absence of other conditions such as frank diabetes, CVD, or hypertension will increase the severity of SARS-CoV-2 infection and acute disease pathology; and (2) that SARS-CoV-2 infection will exacerbate pre-existing preclinical metabolic disease as reflected in progression to more advanced, clinically evident disease. We propose to address these hypotheses through pursuit of the following specific aims. Specific Aim 1. Determine the effect of pre-existing obesity/IR on the acute response to SARS-CoV-2 infection. Specific Aim 2. Determine the effect of SARS-CoV-2 infection on the post-acute progression of metabolic disease. We will employ a nonhuman primate preclinical model of lean, metabolically healthy and obese, insulin- resistant adult male rhesus macaques infected with SARS-CoV-2 over a 2-week (acute phase) or 6-month (post-acute) course of disease, during which time comprehensive longitudinal assessments of viral load, lung pathology, peripheral and adipose immune cell responses, and glucose and lipid metabolism will be performed. At necropsy following the acute and post-acute studies, islet function will be assessed and multiple tissue samples collected for determination of viral distribution and persistence in potential latent reservoirs. The proposed studies represent a unique opportunity to elucidate the mechanisms underlying the reciprocal relationship between COVID-19 and metabolic disease in an experimentally tractable preclinical model.

新型SARS-CoV-2冠状病毒引发的新冠肺炎全球大流行继续导致 世界范围内的严重发病率和死亡率。尽管有效的疫苗和治疗方法已经 介绍，新冠肺炎将因接种疫苗而继续作为公共卫生问题持续存在 抵抗力/犹豫不决和再次感染的风险，出现可能逃避当前情况的令人担忧的变种 疫苗，以及潜在的病毒库的潜在存在。与COVID相关的不良后果- 19因一些先前存在的疾病而增加，特别是糖尿病、心血管疾病和 高血压。这些疾病都有肥胖和胰岛素抵抗(IR)作为共同的潜在特征， 这引发了肥胖本身是否是更严重的COVID的独立风险因素的问题- 19在没有临床诊断的糖尿病、心血管疾病或高血压的情况下的结果。这 肥胖症对呼吸系统疾病和免疫的影响支持了这一概念 回应。糖脂代谢改变和新发糖尿病的证据也在积累 新冠肺炎患者从急性感染中恢复后能够坚持下去，这构成了一个重要的 新冠肺炎急性后遗症的成分(PASC)。这些数据表明，虽然肥胖和新陈代谢 疾病影响急性新冠肺炎，即新冠肺炎有急性和后急性的相互作用。 代谢控制。我们假设：(1)在没有其他条件的情况下，肥胖/胰岛素抵抗 糖尿病、心血管疾病或高血压会增加SARS-CoV-2感染和急性疾病的严重程度 病理；及(2)SARS-CoV-2感染会加重先前存在的临床前代谢性疾病，如 表现为进展为更晚期、临床明显的疾病。我们建议解决这些问题 假设通过追求以下具体目标来实现。 具体目的1.确定既往肥胖/胰岛素抵抗对SARS-CoV-2感染的急性反应的影响。 特定目的2.确定SARS-CoV-2感染对急性后代谢进展的影响 疾病。 我们将使用一种非人类灵长类临床前模型，研究精瘦、代谢健康和肥胖的胰岛素- 在2周(急性期)或6个月内感染SARS-CoV-2的成年成年恒河猴 (急性后)病程，在此期间全面纵向评估病毒载量、肺 将进行病理学、外周和脂肪免疫细胞反应以及葡萄糖和脂肪代谢。 在急性和急性后研究的尸检中，将评估胰岛功能和多个组织 为确定病毒在潜在潜伏水库中的分布和持久性而收集的样本。这个 拟议的研究为阐明相互作用背后的机制提供了一个独特的机会 在可实验处理的临床前模型中新冠肺炎与代谢性疾病的关系。