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.

由新型SARS-COV-2冠状病毒引起的19009年全球大流行，继续导致 全世界的大量发病率和死亡率。虽然有效的疫苗和治疗方法已经 引入，Covid-19将继续作为疫苗的公共卫生问题继续存在 抵抗/犹豫和恢复风险，可能逃避当前的关注变体的出现 疫苗以及潜在的潜在病毒储存剂。与covid相关的不良结果 19次先前存在的疾病增加了19个，尤其是糖尿病，心血管疾病和 高血压。这些疾病具有肥胖和胰岛素抵抗（IR）作为共同的基础特征， 这就提出了一个问题，即肥胖本身是否是更严重的covid-的独立危险因素 在没有临床诊断的糖尿病，心血管疾病或高血压的情况下，结果19的结果。这 概念由先前描述的肥胖对呼吸道疾病和免疫的影响支持 回复。证据也积累了改变葡萄糖和脂质代谢和新发糖尿病的证据 从急性感染中恢复后可以持续存在的Covid-19患者，这构成了重要的 COVID-19（PASC）急性后遗症的成分。这些数据表明，肥胖和代谢 疾病会影响急性covid-19，即19. 代谢控制。我们假设：（1）在没有其他条件（例如弗兰克）的情况下肥胖/IR 糖尿病，CVD或高血压会增加SARS-COV-2感染和急性疾病的严重程度 病理; （2）SARS-COV-2感染会加剧预先存在的临床前代谢疾病 反映在进展为更先进的临床上的疾病中。我们建议解决这些问题 通过追求以下特定目标来假设。 具体目标1。确定肥胖/IR预先存在的对SARS-COV-2感染的急性反应的影响。 具体目标2。确定SARS-COV-2感染对代谢后急性进展的影响 疾病。 我们将采用一个非人类的灵长类动物临床前模型，用于瘦，代谢健康和肥胖，胰岛素 在2周（急性期）或6个月内感染了SARS-COV-2的抗性成年雄性猕猴 （急性后）疾病的病程，在此期间，病毒负荷的全面纵向评估，肺 将进行病理，外周和脂肪免疫细胞反应，以及葡萄糖和脂质代谢。 急性和急性研究后的尸检，将评估胰岛功能并进行多个组织 收集的样品以确定潜在潜在储层中的病毒分布和持久性。这 拟议的研究代表了阐明倒数机制的独特机会 在实验性促成的临床前模型中，19与代谢疾病之间的关系。