SARS-CoV-2 infects an in vitro model of the human developing pancreas through endocytosis
Wojciech J. Szlachcic,
Agnieszka Dabrowska,
Aleksandra Milewska,
Natalia Ziojla,
Katarzyna Blaszczyk,
Emilia Barreto-Duran,
Marek Sanak,
Marcin Surmiak,
Katarzyna Owczarek,
Dariusz Grzanka,
Julia Durzynska,
Krzysztof Pyrc,
Malgorzata Borowiak
Affiliations
Wojciech J. Szlachcic
Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznanskiego 6, 61-614 Poznan, Poland
Agnieszka Dabrowska
Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
Aleksandra Milewska
Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland
Natalia Ziojla
Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznanskiego 6, 61-614 Poznan, Poland
Katarzyna Blaszczyk
Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznanskiego 6, 61-614 Poznan, Poland
Emilia Barreto-Duran
Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland
Marek Sanak
Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, 30-688 Kraków, Poland
Marcin Surmiak
Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, 30-688 Kraków, Poland
Katarzyna Owczarek
Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland
Dariusz Grzanka
Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
Julia Durzynska
Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznanskiego 6, 61-614 Poznan, Poland
Krzysztof Pyrc
Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; Corresponding author
Malgorzata Borowiak
Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznanskiego 6, 61-614 Poznan, Poland; Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Corresponding author
Summary: Recent studies showed that SARS-CoV-2 can infect adult human pancreas and trigger pancreatic damage. Here, using human fetal pancreas samples and 3D differentiation of human pluripotent cells into pancreatic endocrine cells, we determined that SARS-CoV-2 receptors ACE2, TMPRSS2, and NRP1 are expressed in precursors of insulin-producing pancreatic β-cells, rendering them permissive to SARS-CoV-2 infection. We also show that SARS-CoV-2 enters and undergoes efficient replication in human multipotent pancreatic and endocrine progenitors in vitro. Moreover, we investigated mechanisms by which SARS-CoV-2 enters pancreatic cells, and found that ACE2 mediates the entry, while NRP1 and TMPRSS2 do not. Surprisingly, we found that in pancreatic progenitors, SARS-CoV-2 enters cells via cathepsin-dependent endocytosis, which is a different route than in respiratory tract. Therefore, pancreatic spheroids might serve as a model to study candidate drugs for endocytosis-mediated viral entry inhibition and to investigate whether SARS-CoV-2 infection may affect pancreas development, possibly causing lifelong health consequences.
