SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells

Abstract

Summary/AbstractReports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This model would require binding and entry of SARS-CoV-2 into host cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. ACE2 and TMPRSS2 transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from any of these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of ACE2 and TMPRSS2 co-expression in islet endocrine cells makes it unlikely that SARS-CoV-2 directly affects pancreatic islet β cells.

SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic β-Cells and in the Human Pancreas Microvasculature

“…Our results indicate that ACE2 is expressed also in the pancreatic islets, and this expression is mostly located in b-cells as compared to a-cells. These results are in contrast with the two recent preprint manuscripts (57,58) which failed to observe ACE2 expression in pancreatic islet endocrine cells. Such discrepancies may be explained by a resulting sum of differences in primary antibodies sensitivity, different epitopes targeted, tissue sections preparation and pretreatment, as well as immunodetection methodology sensitivity (immunohistochemistry vs. immunofluorescence).…”

“…Therefore, a pancreatic islet local vascular damage and inflammation due to SARS-CoV-2 direct infection of ACE2 + pancreatic pericyte cells is a potential contributory factor for islet dysfunction. Of note, two recent preprint manuscripts also indicated the presence of ACE2 expression in pancreatic microvasculature (57,58).…”

SARS-CoV-2 receptor Angiotensin I-Converting Enzyme type 2 (ACE2) is expressed in human pancreatic β-cells and in the human pancreas microvasculature

“…Our results indicate that ACE2 is expressed also in the pancreatic islets and this expression is mostly located in β-cells as compared to α-cells. These results are in contrast with the two recent preprint manuscripts (56,57) which failed to observe ACE2 expression in pancreatic islet endocrine cells. Such discrepancies may be explained by a resulting sum of differences in primary antibodies sensitivity, different epitopes targeted, tissue sections preparation and pre-treatment, as well as immunodetection methodology sensitivity (immunohistochemistry vs. immunofluorescence).…”

“…Therefore, a pancreatic islet local vascular damage and inflammation due to SARS-CoV-2 direct infection of ACE2 + pancreatic pericyte cells is a potential contributory factor for islet dysfunction. Of note, two recent preprint manuscripts also indicated the presence of ACE2 expression in pancreatic microvasculature (56,57).…”

Beta-cells from patients with COVID-19 and from isolated human islets exhibit ACE2, DPP4, and TMPRSS2 expression, viral infiltration and necroptotic cell death

“…The expression of ACE2 in the pancreas is a matter of debate and contradictory results have been reported. For example, three different studies showed a higher expression of ACE2 in the exocrine duct cells than in the islets [17][18][19] , whereas another study showed that ACE2 is preferentially expressed by beta-cells 15 . By single cell sequencing, we have shown that in pancreata from mice, both DPP4 and ACE2 are highly expressed in delta-cells followed by betaand alpha-cells (unpublished data, NATMETAB-A20093633).…”