Host factor PLAC8 is required for pancreas infection by SARS-CoV-2

Ibarguen Gonzalez, L.; Heller, S.; DeDiego, M. L.; Lopez-Garcia, D.; Gomez-Valero, A. M.; Barth, T. F.; Gallego, P.; Fernandez-Cardenas, I.; Alzate-Pinol, S.; Crespi, C.; Mena-Guerrero, J. A.; Cisneros-Barroso, M. E.; Ugalde, A. P.; Bretones, G.; Steenblock, C.; Kleger, A.; Barcelo, C.

doi:10.1101/2023.08.18.553908

bioRxiv · 10.1101/2023.08.18.553908

Host factor PLAC8 is required for pancreas infection by SARS-CoV-2

Ibarguen Gonzalez, L.·Heller, S.·DeDiego, M. L.·Lopez-Garcia, D.·Gomez-Valero, A. M.·Barth, T. F.·Gallego, P.·Fernandez-Cardenas, I.·Alzate-Pinol, S.·Crespi, C.·Mena-Guerrero, J. A.·Cisneros-Barroso, M. E.·Ugalde, A. P.·Bretones, G.·Steenblock, C.·Kleger, A.·Barcelo, C.

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Abstract

BackgroundAlthough 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) MethodsWe 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 infection experiments in PLAC8 knock-out PDAC cell lines with full SARS-CoV-2 virus. ResultsWe 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. 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. ConclusionOur 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. Plain language summaryPrevious studies have shown that the pancreas is infected by SARS-CoV-2. However, none of these studies have described measurable pancreatic damage associated to COVID-19 severity and the pathogenesis of pancreatic SARS-CoV-2 infection remains largely unknown. Novel host factors have been proposed for SARS-CoV-2 infection of mainly the airway epithelium, none of them studied in the pancreas. Our study shows clinically relevant pancreatic damage associated with SARS-CoV-2 infiltration and assesses the predictive potential of circulating pancreatic enzymes to stratify patients according to COVID-19 severity and predict clinical outcomes in a cohort of 120 patients. Our data show that host factor Placenta-associated protein 8 (PLAC8) expression is linked to SARS-CoV-2 infection in postmortem analysis of COVID-19 patients and functionally demonstrated the full requirement of PLAC8 for SARS-CoV-2 pancreatic infection and viral replication. Our data confirm the human pancreas as a SARS-CoV-2 target with signs of injury unveiling the measurement of pancreatic enzymes for prognosis value and demonstrating that host factor PLAC8 is required for SARS-CoV-2 pancreatic infection defining new stratification and target opportunities for COVID-19-associated pancreatic pathogenesis.

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Ibarguen Gonzalez, L., Heller, S., DeDiego, M. L., Lopez-Garcia, D., Gomez-Valero, A. M., Barth, T. F., Gallego, P., Fernandez-Cardenas, I., Alzate-Pinol, S., Crespi, C., Mena-Guerrero, J. A., Cisneros-Barroso, M. E., Ugalde, A. P., Bretones, G., Steenblock, C., Kleger, A., Barcelo, C.. 2023-08-21. Host factor PLAC8 is required for pancreas infection by SARS-CoV-2. https://doi.org/10.1101/2023.08.18.553908

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