Temperature and developmental stage govern intestinal susceptibility to human coronavirus 229E
Abstract
Human coronaviruses have been primarily associated with upper respiratory tract infections, yet cases of gastrointestinal symptoms in COVID-19 patients have highlighted their potential to cause systemic disease. Here, we detail the infection of intestinal epithelia by an endemic, low-pathogenic human coronavirus, human alphacoronavirus 229E, using patient-derived human intestinal enteroids (HIEs) from donors of various ages. Using fetal, pediatric, and adult HIEs, we investigated how physiologically relevant temperatures: 37 °C and 32 °C, reflecting gastrointestinal and upper-airway conditions, respectively, modulate epithelial responses and viral infection dynamics. We show that there is temperature-dependent transcriptional reprogramming, indicating strong temperature-dependent regulation of virus replication and epithelial responses. Among the seasonal coronaviruses tested, only HCoV-229E productively infects HIEs. At 32 °C, HCoV-229E replicates efficiently in enteroids from all donor ages and releases high titers of infectious progeny. In contrast, at 37 °C, productive replication is largely confined to fetal and a subset of pediatric tissues, revealing a developmental and temperature-sensitive restriction on infection. Confocal and flow cytometry analyses identify enterocytes as the primary target cells for HCoV-229E. Furthermore, we show that camostat, a serine protease inhibitor, significantly reduces HCoV-229E replication in HIEs, confirming a critical role for host serine protease activity. Collectively, these findings establish HIEs as a relevant model for HCoV-229E–host interactions and reveal temperature- and age-dependent determinants governing intestinal permissiveness to this seasonal coronavirus.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Aleksandra Synowiec
Virogenetics Laboratory of Virology, Małopolska Centre of Biotechnology, Jagiellonian University
Laurensius Kevin Lie
Virogenetics Laboratory of Virology, Małopolska Centre of Biotechnology, Jagiellonian University
Katarzyna Owczarek
Nina Johannesson
OrganoVIR Labs, Emma Children’s Hospital, Department of Pediatric Infectious Diseases, Amsterdam University Medical Center, Academic Medical Center, Amsterdam Institute for Infection and Immunity, Amsterdam Institute for Reproduction and Development, University of Amsterdam
Nina Mickiewicz
Virogenetics Laboratory of Virology, Małopolska Centre of Biotechnology, Jagiellonian University
Heng-Chang Chen
Quantitative Virology Research Group, Population Diagnostics Center, Łukasiewicz Research Network–PORT Polish Center for Technology Development
Artur Szczepański
Virogenetics Laboratory of Virology, Małopolska Centre of Biotechnology, Jagiellonian University
Madison S. Strine
Renata B. Filler
Department of Laboratory Medicine, Yale School of Medicine
Maciej Borowiec
Department of Clinical and Laboratory Genetics, Medical University of Lodz
Michał Pietrusiński
Department of Clinical and Laboratory Genetics, Medical University of Lodz
Izabela Dróżdż
Department of Clinical and Laboratory Genetics, Medical University of Lodz
Agnieszka Robaszkiewicz
Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz
Michał Bochenek
Virogenetics Laboratory of Virology, Małopolska Centre of Biotechnology, Jagiellonian University
Matthias Zilbauer
Department of Pediatrics, School of Clinical Medicine, University of Cambridge
Justyna Rymarowicz
Department of General Surgery, Jagiellonian University Medical College
Michał Pędziwiatr
Department of General Surgery, Jagiellonian University Medical College
Liza Konnikova
Pediatrics Department, Yale University School of Medicine
Craig B. Wilen
Department of Laboratory Medicine, Yale School of Medicine
Dasja Pajkrt
OrganoVIR Labs, Emma Children’s Hospital, Department of Pediatric Infectious Diseases, Amsterdam University Medical Center, Academic Medical Center, Amsterdam Institute for Infection and Immunity, Amsterdam Institute for Reproduction and Development, University of Amsterdam
Katja C. Wolthers
OrganoVIR Labs, Department of Medical Microbiology, Amsterdam University Medical Center, Academic Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam
Carlemi Calitz
OrganoVIR Labs, Emma Children’s Hospital, Department of Pediatric Infectious Diseases, Amsterdam University Medical Center, Academic Medical Center, Amsterdam Institute for Infection and Immunity, Amsterdam Institute for Reproduction and Development, University of Amsterdam
Adithya Sridhar
OrganoVIR Labs, Emma Children’s Hospital, Department of Pediatric Infectious Diseases, Amsterdam University Medical Center, Academic Medical Center, Amsterdam Institute for Infection and Immunity, Amsterdam Institute for Reproduction and Development, University of Amsterdam
Krzysztof Pyrc