Virus World

Background: Although COVID-19 initially caused great concern about respiratory symptoms, mounting evidence shows that also the pancreas is productively infected by SARS-CoV-2. However, the severity of pancreatic SARS-CoV-2 infection and its pathophysiology are still under debate. Here we investigated the consequences of SARS-CoV-2 pancreatic infection and the role of the host factor Placenta-associated protein (PLAC8).

Methods: We analyzed plasma levels of pancreatic enzymes and inflammatory markers in a retrospective cohort study of 120 COVID-19 patients distributed in 3 severity-stratified groups. We studied the expression of SARS-CoV-2 and PLAC8 in the pancreas of deceased COVID-19 patients as well as in non-infected donors. We performed pseudovirus infection experiments in PLAC8 knock-out PDAC cell lines and validated results with SARS-CoV-2 virus.

Findings: We found that analysis of circulating pancreatic enzymes aided the stratification of patients according to COVID-19 severity and predict outcomes. Interestingly, we found an association between PLAC8 expression and SARS-CoV-2 infection in postmortem analysis of COVID-19 patients. Functional experiments demonstrated the requirement of PLAC8 in SARS-CoV-2 pancreatic infection by pseudovirus. Furthermore, using full SARS-CoV-2 infectious virus inoculum from Wuhan-1 and BA.1 strains, we demonstrated that PLAC8 is necessary for productive infection of PDAC cell lines. Finally, we observed an overlap between PLAC8 and SARS-CoV-2 immunoreactivities of the pancreas of deceased patients.

Interpretation: Our data indicate the human pancreas as a SARS-CoV-2 target with plausible signs of injury and demonstrate that the host factor PLAC8 is required for SARS-CoV-2 pancreatic infection, thus defining new target opportunities for COVID-19-associated pancreatic pathogenesis.

To be published in The Lancet (Sept. 2023):

http://dx.doi.org/10.2139/ssrn.4564662 

Emerging evidence points towards an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While pre-existing diabetes is associated with severe COVID-19, it is unclear if COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic β-cells can be infected by SARS-CoV-2 and cause β-cell depletion. We found that the SARS-CoV-2 receptor, ACE2 and related entry factors (TMPRSS2, NRP1, TRFC) are expressed in β-cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic β-cells in patients who succumbed to COVID-19 and selectively infects human islet β-cells in vitro. We demonstrated SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion, and induces β-cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic β-cell signaling, similar to that observed in Type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce β-cell killing.

Published in Cell Metabolism (May 18, 2021):

https://doi.org/10.1016/j.cmet.2021.05.013