A Link Between Obesity and Coronavirus Disease 2019

Martinez-Colòn GJ, Ratnasari K, Chen H, et al. SARS-CoV-2 infects human adipose tissue and elicits an inflammatory response consistent with severe COVID-19. bioRxiv 2021.10.24.465626; doi: https:// doi.org/10.1101/2021.10.24.465626. Adipose tissue has previously been shown to serve as a reservoir for influenza A virus as well as human immunodeficiency virus, and obesity is associated with unfavorable outcomes of influenza A virus infection [1]. Obesity is also a strong independent risk factor for coronavirus disease 2019 (COVID-19) infection, as well as for disease severity and associated mortality. Although obesity, especially with associated insulin resistance, is known to be a proinflammatory and hypercoagulable state, the reasons for the detrimental relationship between obesity and COVID-19 have remained undefined. In order to examine the potential role of adipose tissue in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the pathophysiology of the inflammatory response in COVID19, Martinez-Colòn et al secured freshly obtained subcutaneous, visceral, pericardial, and epicardial tissues from individuals undergoing bariatric or cardiac surgery. In addition, they obtained multiple samples from autopsy material of patients who died with COVID-19. Stromal vascular cells (SVCs) were separated from mature adipocytes by collagenase digestion of these tissues. The investigators demonstrated in vitro infection of SVCs and, by flow cytometry, that viral N protein expression was primarily restricted to macrophages. Angiotensin-converting enzyme 2 (ACE-2) expression was, however, very limited in SVCs, with its detection in only approximately 3% of macrophages and with none detected in other tissue types. The macrophages that were infectable were predominantly (85%) type C2, while >11% were C12. Infected C2 macrophages had enrichment of interleukin 10–associated signaling pathways as well as of chemokine and other pathways associated with the innate immune system. At the same time, there was reduced enrichment in host cell translation machinery. Both freshly isolated mature adipocytes and adipocytes differentiated in in vitro culture were susceptible to infection. Genomic RNA and positive sense subgenomic RNA consistent with productive infection were detected. Preadipocytes were not infected but had undergone proinflammatory activation as associates of infected SVCs. In vivo infection of adipose tissue was also demonstrated. SARS-CoV-2 was detected in epicardial, visceral, and subcutaneous adipose tissue as well as in lung, heart, and kidney. The highest concentrations were found in lung, followed by adipose tissue. The investigators have provided evidence that contributes to our understanding of the relationship between obesity and COVID-19 risk. They demonstrated that SARS-CoV-2 primarily infects macrophages in SVCs and that it enters these cells by a means that appears to be independent of host cell ACE-2 expression. This leads to upregulation of proinflammatory pathways and secretion of cytokines and vascular factors by affected adipose tissues.