Expression of SARS-CoV-2 Entry Factors in the Pancreas of Normal Organ Donors and Individuals with COVID-19

Abstract

Diabetes 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 angiotensin-converting enzyme 2 (ACE2), the key entry factor for SARS-CoV-2 infection. Specifically, we analyzed five public scRNA-seq 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) cases. These in silico and ex vivo analyses demonstrated prominent expression of ACE2 in pancreatic ductal epithelium and microvasculature, but we found rare endocrine cell expression at the mRNA level. Pancreata from individuals with COVID-19 demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression that was primarily limited to ducts. These results suggest SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, is an unlikely central pathogenic feature of COVID-19-related diabetes.

Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning

“…Related findings were reported independently by Kusmartseva et al. (2020) by employing IHC, western blotting, in situ hybridization, and RNA-seq databases.…”

“…A similar pattern of ACE2 protein expression was obtained using 4 independently validated ACE2 antisera; ACE2 was predominantly localized to the ductal epithelium and pancreatic blood vessels in several dozen pancreata obtained from neonates, children, adolescents, middle age, and older human subjects. Moreover, ACE2 expression localized to the ductal epithelium and vascular endothelium, and SARS-CoV-2 nucleocapsid protein was detected in ducts, but not islets, in pancreata (two with pre-existing T2D) obtained from COVID-19+ individuals ( Kusmartseva et al., 2020 ).…”

Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications

“…Analyses of severe COVID-19-induced biochemical alterations in the liver have shown the elevation of liver enzymes, such as alanine aminotransferases and aspartate aminotransferases, and significantly lower albumin levels [ 43 , 44 ] and thus, liver markers should be monitored continuously during COVID-19 evolvement. ACE2 and TMPRSS2 are highly expressed in gallbladder [ 17 ], whereas regarding pancreas ACE2 is expressed in exocrine tissue microvasculature and in a subset of pancreatic ducts with TMPRSS2 expression being restricted to ductal cells [ 45 , 46 ]. Notably, both ACE2 and TMPRSS2 are rarely expressed in single pancreatic β cells from donors with or without diabetes [ 45 , 46 ] suggesting that SARS-CoV-2 cannot directly infect β cells.…”

“…ACE2 and TMPRSS2 are highly expressed in gallbladder [ 17 ], whereas regarding pancreas ACE2 is expressed in exocrine tissue microvasculature and in a subset of pancreatic ducts with TMPRSS2 expression being restricted to ductal cells [ 45 , 46 ]. Notably, both ACE2 and TMPRSS2 are rarely expressed in single pancreatic β cells from donors with or without diabetes [ 45 , 46 ] suggesting that SARS-CoV-2 cannot directly infect β cells.…”

Pandemics and pathology: a reflection on influenza, HIV/AIDS and SARS (COVID-19) pandemic infections

“…Lastly there appears to be a precipitation of type 1 diabetes and/or a worsening of known type 2 diabetes directly due to COVID virus infection; this emerges from diabetologists who have noted in 2020 a marked increase in severe diabetes presentations with no other evident explanation. This is probably not due to infection of pancreatic beta cells by COVID-19 28 but the scenario is under investigation.…”