Post-acute metabolic sequelae of SARS-CoV-2 infection in nonhuman primates

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，由于再次感染的风险，新冠肺炎可能会作为公共卫生问题持续存在 可能逃脱当前疫苗的令人担忧的变种的出现，以及潜在病毒的存在 水库。新冠肺炎的风险和严重性因一些预先存在的疾病而增加， 尤其是糖尿病、心血管疾病和高血压。相反，有越来越多的证据表明 新冠肺炎幸存者的糖代谢改变和新发糖尿病以及血脂异常， 提示新冠肺炎的代谢效应可能是急性后遗症的重要组成部分 新冠肺炎(Sequoia Capital)。因此，新冠肺炎和代谢性疾病之间存在双向关系 哪种代谢性疾病是新冠肺炎增加的独立并存因素 一方面严重，而SARS-CoV-2感染通过代谢产生有害影响 引发新的代谢性疾病或加速已有亚临床疾病进展的重要组织 另一方面是代谢性疾病。最近的研究表明，SARS-CoV-2可以感染胰岛， 包括b细胞和其他内分泌细胞类型，以及脂肪细胞和白色脂肪组织(WAT)免疫 细胞。根据这些数据，我们推测SARS-CoV-2对胰岛和 导致PACS相关代谢病理的WAT功能我们建议解决这个问题 通过追求以下具体目标来实现假设。 特定目标1.确定SARS-CoV-2感染对代谢启动和进展的影响 疾病。 我们将使用现在已经建立的SARS-CoV-2感染的恒河猴临床前模型，在该模型中 瘦削、代谢健康、肥胖、胰岛素抵抗的成年雄性恒河猴将感染 SARS-CoV-2的Delta变种，并跟踪6个月的时间进程，在此期间全面纵向 将对病毒载量、肺部病理、免疫细胞图谱以及葡萄糖和脂代谢进行评估 已执行。此外，WAT免疫细胞的纵向样本和感染的横断面样本 对未感染的胰岛细胞进行单细胞rna-seq分析，以表征细胞的长期变化。 细胞配置文件。在尸检时，将评估胰岛功能，并收集多个组织样本用于 潜在潜在储集层中病毒分布和持久性的确定。拟议的研究代表了 一个独一无二的机会来阐明PASC代谢方面的潜在机制 实验上易于处理的临床前模型，允许在临床研究中进行不可能的评估。

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 likely persist as a public health issue as a result of the risk of reinfection, the emergence of variants of concern that may evade current vaccines, and the potential existence of latent viral reservoirs. The risk for and the severity of COVID-19 are increased by a number of pre-existing conditions, notably diabetes, cardiovascular disease, and hypertension. Conversely, there is increasing evidence of altered glucose metabolism and new-onset diabetes as well as dyslipidemia in COVID-19 survivors, suggesting that metabolic effects of COVID-19 may comprise an important component of post-acute sequelae of COVID-19 (PASC). Thus, there is a bidirectional relationship between COVID-19 and metabolic disease, in which concurrent metabolic disease constitutes an independent comorbid factor that increases COVID-19 severity on the one hand, while SARS-CoV-2 infection exerts deleterious effects through metabolically important tissues to initiate new metabolic disease or accelerate the progression of pre-existing subclinical metabolic disease on the other. Recent studies have shown that SARS-CoV-2 can infect pancreatic islets, including b cells and other endocrine cell types, as well as adipocytes and white adipose tissue (WAT) immune cells. Based on these data, we hypothesize that SARS-CoV-2 exerts direct and indirect effects on islet and WAT function that result in the metabolic pathology associated with PACS We propose to address this hypothesis through pursuit of the following specific aim. Specific Aim1. Determine the effect of SARS-CoV-2 infection on the initiation and progression of metabolic disease. We will employ a now well-established rhesus macaque preclinical model of SARS-CoV-2 infection in which lean, metabolically healthy and obese, insulin-resistant adult male rhesus macaques will be infected with the delta variant of SARS-CoV-2 and followed for a 6-month time course, during which comprehensive longitudinal assessments of viral load, lung pathology, immune cell profiles, and glucose and lipid metabolism will be performed. Additionally, longitudinal samples of WAT immune cells and cross-sectional samples of infected and non-infected islet cells with be analyzed by single-cell RNA-seq to characterize long-term alteration of cellular profiles. At necropsy, 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 metabolic aspects of PASC in an experimentally tractable preclinical model that permits assessments impossible in clinical studies.