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

非人灵长类动物感染 SARS-CoV-2 后急性代谢后遗症

• 批准号: 10554898
• 负责人: Paul Kievit
• 金额: $ 128.66万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-31 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554898
• 关键词: 2019-nCoV; Acute; Address; Adipocytes; Adipose tissue; Adult; Affect; Antibody Therapy; Antigens; Attenuated; Autopsy; B-Lymphocytes; Biopsy; Bronchoalveolar Lavage; C-Peptide; COVID-19; COVID-19 impact; COVID-19 pandemic; COVID-19 patient; COVID-19 severity; COVID-19 survivors; Cardiovascular Diseases; Cells; Chronic; Clinical Research; Coronavirus; Data; Development; Diabetes Mellitus; Dyslipidemias; Endocrine; Exhibits; Functional disorder; Future; Glucose; Glucose tolerance test; Glycosylated hemoglobin A; HIV; HIV Envelope Protein gp120; Health; Heterogeneity; Human; Hyperinsulinism; Hypertension; Immune; Infection; Inflammation; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Intestines; Islet Cell; Islets of Langerhans; Light; Lipids; Liver; Lung diseases; Macaca mulatta; Metabolic; Metabolic Diseases; Metabolic dysfunction; Modeling; Monitor; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Obesity; Oral; Pathology; Peripheral; Phase; Population; Post-Acute Sequelae of SARS-CoV-2 Infection; Pre-Clinical Model; Prediabetes syndrome; Process; Proteins; Public Health; Pulmonary Pathology; Reporting; Risk; SARS-CoV-2 B.1.617.2; SARS-CoV-2 infection; SARS-CoV-2 variant; Sampling; Therapeutic; Therapeutic Agents; Thinness; Time; Tissue Sample; Tissues; Toxic effect; Transcript; Treatment Efficacy; Vaccine Therapy; Vaccines; Viral; Viral Load result; Viral Proteins; Viral reservoir; Viremia; Virus Latency; Virus Replication; Virus Shedding; adipokines; base; cell type; comorbidity; diet-induced obesity; fasting glucose; glucose metabolism; insulin secretion; islet; lipid metabolism; lymph nodes; male; mortality; nonhuman primate; novel; novel therapeutic intervention; pandemic disease; preclinical evaluation; prevent; respiratory; response; single cell analysis; single-cell RNA sequencing; transcriptome; 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 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.

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 介绍，COVID-19可能会持续作为一个公共卫生问题，由于再感染的风险， 可能逃避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COVID-19的风险和严重程度因一些预先存在的情况而增加， 尤其是糖尿病、心血管疾病和高血压。相反，越来越多的证据表明， COVID-19幸存者的葡萄糖代谢改变和新发糖尿病以及血脂异常， 这表明COVID-19的代谢效应可能是急性后后遗症的重要组成部分 COVID-19（PASC）。因此，COVID-19和代谢疾病之间存在双向关系， 哪种并发代谢疾病构成增加COVID-19的独立共病因素 严重性，而SARS-CoV-2感染通过代谢产生有害影响， 引发新的代谢疾病或加速既存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。 细胞基于这些数据，我们假设SARS-CoV-2对胰岛细胞产生直接和间接的影响， WAT功能导致与PACS相关的代谢病理学，我们建议解决这一问题 通过追求以下具体目标的假设。 具体目标1。确定SARS-CoV-2感染对代谢启动和进展的影响 疾病 我们将采用一种现已建立的SARS-CoV-2感染的恒河猴临床前模型， 精瘦的、代谢健康的和肥胖的、胰岛素抵抗的成年雄性恒河猴将感染 SARS-CoV-2的delta变体，并随访6个月的时间过程，在此期间， 将评估病毒载量、肺病理学、免疫细胞谱以及葡萄糖和脂质代谢， 执行。此外，WAT免疫细胞的纵向样品和感染的受试者的横截面样品也是如此。 和未感染的胰岛细胞通过单细胞RNA-seq进行分析，以表征长期变化 细胞图谱尸检时，将评估胰岛功能，并采集多个组织样本， 确定病毒在潜在潜伏宿主中的分布和持久性。拟议的研究代表 这是一个独特的机会，可以阐明PASC代谢方面的机制， 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。