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

由新型SARS-CoV-2冠状病毒引起的COVID-19全球大流行继续导致 世界范围内发病率和死亡率都很高。虽然有效的疫苗和治疗方法已经被 据介绍，由于疫苗的使用，COVID-19将继续作为公共卫生问题存在。 耐药性/犹豫和再感染的风险，可能逃避目前流行的令人担忧的变异的出现， 疫苗，以及潜在的病毒储存库的存在。与COVID相关的不利后果- 19是增加了一些预先存在的条件，特别是糖尿病，心血管疾病， 高血压这些病症共有肥胖和胰岛素抵抗（IR）作为共同的潜在特征， 这引发了一个问题，即肥胖本身是否是导致更严重COVID的独立风险因素- 在没有临床诊断的糖尿病、心血管疾病或高血压的情况下的19个结果。这 这一概念得到了先前描述的肥胖对呼吸系统疾病和免疫系统疾病的影响的支持。 反应关于葡萄糖和脂质代谢改变以及新发糖尿病的证据也在不断积累， COVID-19患者从急性感染中恢复后可以持续存在，这构成了重要的 COVID-19急性后遗症（PASC）的组成部分。这些数据表明，虽然肥胖和代谢 疾病影响急性COVID-19，COVID-19对急性和急性后影响是相互的， 代谢控制我们假设：（1）肥胖/IR在没有其他条件，如坦率 糖尿病、心血管疾病或高血压将增加SARS-CoV-2感染和急性疾病的严重程度 病理学;和（2）SARS-CoV-2感染将加剧预先存在的临床前代谢疾病， 反映为进展为更晚期的临床明显疾病。我们建议解决这些问题 通过追求以下具体目标的假设。 具体目标1。确定既存肥胖/IR对SARS-CoV-2感染急性反应的影响。 具体目标2。确定SARS-CoV-2感染对急性期后代谢性疾病进展的影响 疾病 我们将采用非人灵长类动物临床前模型，该模型具有瘦肉、代谢健康和肥胖、胰岛素- 抗SARS-CoV-2的成年雄性恒河猴感染2周（急性期）或6个月 （急性后）病程，在此期间对病毒载量、肺 将进行病理学、外周和脂肪免疫细胞应答以及葡萄糖和脂质代谢。 在急性和急性后研究后尸检时，将评估胰岛功能， 采集样本，用于确定潜在潜伏宿主中的病毒分布和持久性。的 拟议的研究代表了一个独特的机会，阐明相互作用的机制， COVID-19和代谢疾病之间的关系在实验上易于处理的临床前模型。

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.