ACE2 and SARS-CoV-2 Expression in the Normal and COVID-19 Pancreas

Abstract

SUMMARYDiabetes is associated with increased mortality from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of the key molecule for SARS-CoV-2 infection of cells, angiotensin-converting enzyme-2 (ACE2). Specifically, we analyzed five public scRNAseq pancreas datasets and performed fluorescence in situ hybridization, Western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) patients. These in silico and ex vivo analyses demonstrated pancreatic expression of ACE2 is prominent in pancreatic ductal epithelium and the microvasculature, with rare endocrine cell expression of this molecule. Pancreata from COVID-19 patients demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression primarily limited to ducts. SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, appears an unlikely central pathogenic feature of COVID-19 as it relates to diabetes.

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).…”

“…Surprisingly, we were not able to observe ACE2 pancreatic islets positive signal using Abcam monoclonal antibody Ab108252, while signal was clearly evident in microvasculature and scattered ductal cells. However, these results are in line with Kusmartseva et al 2020 (57). Of note, Ab108252 monoclonal antibody specifically targets an epitope located in the N-terminal domain of ACE2 protein (200-300aa) which is missing in the recently discovered truncated ACE2 isoform (short-ACE2, 357-805aa) (24,25), thus being capable to recognize only the long-ACE2 isoform.…”

“…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).…”