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

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.