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

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.