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Endokrine In-vitro-Modelle zur Untersuchung der Pathophysiologie und Diabetes bei SARS-CoV-2 / COVID-19

Fachliche Zuordnung Virologie
Endokrinologie, Diabetologie, Metabolismus
Förderung Förderung in 2021
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 458701159
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

SARS-CoV-2 can infect multiple organs. While severe COVID-19 is mainly associated with impairment of the respiratory system, gastrointestinal, cardiovascular and neuronal systems as well as metabolism can be affected. In the early phase of the pandemic, clinical reports of patients with severe COVID-19 suffering from deregulation of blood glucose levels e.g. hyperglycemia, ketoacidosis emerged. Moreover, patients with pre-existing diabetes were susceptible to an increased risk of severe disease course. This suggests an impairment of insulin-producing beta-cells but it was under debate (i) if viral entry factors enabling pancreatic infection are expressed in pancreatic cells, (ii) if pancreatic cells can be infected in vivo and (iii) what mechanisms are impairing the function of insulin-producing cells. Our study aimed at addressing these open questions to better understand disease pathomechanisms and to develop targeted interventions. We used human pancreatic tissue to characterize expression of entry factors ACE2 and TMPRSS2 that help viral particles to enter into specific cell types. Stainings revealed expression in digestive exocrine and hormone-producing endocrine compartment of the pancreas with prevalence in insulin-producing beta cells. This expression is the basis for subsequent pancreatic infection with SARS-CoV-2. To test the susceptibility of insulin-producing beta-cells, we incubated human islets of Langerhans (hormone-producing pancreatic unit) not meeting standards for transplantation with SARS-CoV-2 and revealed viral replication and release. Furthermore, these infected islets showed morphological, transcriptional and functional changes. First, the number of granules storing insulin was decreased. Second, genes normally expressed in pancreatic cells were reduced, while those important for cellular defense mechanisms were increased. Third, stimulated insulin release was impaired after viral infection. Finally, we characterized pancreatic tissue from deceased COVID-19 patients. Interestingly, we detected viral protein in exocrine cells of the pancreas but in only a few insulin-producing beta-cells. However, clusters of infected cells localized close to islets of Langerhans. Given the expression pattern of the viral entry proteins, we wondered why only few insulin-expressing cells have been infected. Therefore, we used a second marker, NKX6.1, specific for mature beta-cells and found viral protein in these cells indicating that SARS-CoV-2 might lead to hormone loss. In summary, our results support that SARS-CoV-2 infection in the pancreas can occur in severe COVID-19 cases and that the observed changes in the endocrine compartment could explain the deregulation of blood glucose levels in some patients. However, limited sample size prohibits final conclusions and demands additional studies to completely understand involved pathomechanisms. With this study we published pioneering work, which was discussed worldwide in the press (e.g. Die Welt, Deutsches Ärzteblatt, New York Times, NIH Director’s Blog) and on twitter, and was chosen as the most cited paper of 2021 in Nature Metabolism. Moreover, this work ranks in the top 5% of research outputs scored by Altmetrics (Web-based online attention and activity score) underlining the importance of our findings in the research community.

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