Abstract
SARS-CoV-2 infects epithelial cells of the human gastrointestinal (GI) tract and causes related symptoms. HIV infection impairs gut homeostasis and is associated with an increased risk of COVID-19 fatality. To investigate the potential link between these observations, we analyzed single-cell transcriptional profiles and SARS-CoV-2 entry receptor expression across lymphoid and mucosal human tissue from chronically HIV-infected individuals and uninfected controls. Absorptive gut enterocytes displayed the highest coexpression of SARS-CoV-2 receptors ACE2, TMPRSS2, and TMPRSS4, of which ACE2 expression was associated with canonical interferon response and antiviral genes. Chronic treated HIV infection was associated with a clear antiviral response in gut enterocytes and, unexpectedly, with a substantial reduction of ACE2 and TMPRSS2 target cells. Gut tissue from SARS-CoV-2–infected individuals, however, showed abundant SARS-CoV-2 nucleocapsid protein in both the large and small intestine, including an HIV-coinfected individual. Thus, upregulation of antiviral response genes and downregulation of ACE2 and TMPRSS2 in the GI tract of HIV-infected individuals does not prevent SARS-CoV-2 infection in this compartment. The impact of these HIV-associated intestinal mucosal changes on SARS-CoV-2 infection dynamics, disease severity, and vaccine responses remains unclear and requires further investigation.
Highlights
Gastrointestinal (GI) tract symptoms are observed in up to 60% of COVID-19 patients and precede respiratory symptoms [1]
In this study we performed single-cell transcriptomic profiling across different human tissue sites and identified high expression of SARS-CoV-2 entry receptors within absorptive enterocytes from the small intestine that we confirmed by in situ protein staining
ACE2, TMPRSS2, and TMPRSS4 expression was highest in the duodenum followed by the lung, with little or no expression detected in the tonsil, liver, lymph node, and blood, consistent with published studies [20, 25, 33, 34]
Summary
Gastrointestinal (GI) tract symptoms are observed in up to 60% of COVID-19 patients and precede respiratory symptoms [1]. SARS-CoV-2 can be detected within intestinal tissues [2, 3], and about 30% of COVID-19 patients harbor detectable viral RNA in their stool [4], which is associated with more severe GI symptoms [1]. Studies of human small intestinal organoids show that the mature enterocytes are the major source for SARS-CoV-2 replication [2, 6, 9]. These cells coexpress the serine proteases TMPRSS2 and TMPRSS4, which promote SARS-CoV-2 spike protein fusion and viral entry into enterocytes [6]
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