Temperature-dependent replication and sensitivity to innate immunity of human coronavirus HKU1

The human coronavirus HKU1, causing common colds and occasionally severe illness, remains largely uncharacterized because it has not been successfully grown on immortalized cells. Here, we identify Caco2 cells overexpressing TMPRSS2, the HKU1 receptor, as being highly permissive to infection. HKU1 replicates efficiently, forms syncytia and releases infectious progeny in these cells at 33 °C, the temperature of the nasal cavity, but is attenuated at 37 °C. Viral entry occurs similarly at both temperatures, but subsequent viral RNA synthesis is enhanced at 33 °C. Released virions display higher stability at 33 °C. In Caco2 and primary epithelial nasal cells, HKU1 is sensitive to interferons (IFN), but induction of IFN stimulated genes, such as IFN-Induced Transmembrane Proteins (IFITMs), is delayed at 33 °C. Once expressed, IFITMs comparably inhibit HKU1 fusion at both temperatures. In contrast, SARS-CoV-2 robustly replicates at 37 °C. Thus, cellular permissiveness, innate immunity and viral properties collectively explain why HKU1 replicates more efficiently at nasal temperature. Our results highlight temperature-sensitivity disparities between coronaviruses, likely associated to different pathogenic outcomes. Characterization of the human coronavirus HKU1 is limited due to a lack of infection models. Here, the authors develop a cell model to propagate HKU1 and show that, unlike its relative SARS-CoV-2, it grows better at 33 °C, the temperature of the nasal cavity, than at 37 °C, which is linked to IFN response and viral properties.

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Publication Details

Journal
Nature Communications
Published
2026-07-27
DOI
https://doi.org/10.1038/s41467-026-75779-y
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
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article

Temperature-dependent replication and sensitivity to innate immunity of human coronavirus HKU1

Darragh Duffy, François Bontems, Vincent Michel, Julian Buchrieser et al.
Nature Communications
SARS-CoV-2 and COVID-19 Research
article

Temperature-dependent replication and sensitivity to innate immunity of human coronavirus HKU1

Darragh Duffy, François Bontems, Vincent Michel, Julian Buchrieser, F.A. Rey, Marie‐Anne Rameix‐Welti, Françoise Porrot, Timothée Bruel, Nicoletta Casartelli, Florence Guivel‐Benhassine, Delphine Planas, Isabelle Staropoli, Olivier Schwartz, Etienne Simon‐Lorière, Michael White, Laurence Arowas, Vincent Bondet, Nell Saunders, I. Fernández, Matthieu Prot, Eva Thuillier, Chloé Petiot, Martin Jungbauer-Groznica, Jeanne Postal, Amelie Wileveau, Arnaud Fontanet, Sophie Trouillet-Assant, Jamie Sugrue, Catherine Blanc
article en

Abstract

The human coronavirus HKU1, causing common colds and occasionally severe illness, remains largely uncharacterized because it has not been successfully grown on immortalized cells. Here, we identify Caco2 cells overexpressing TMPRSS2, the HKU1 receptor, as being highly permissive to infection. HKU1 replicates efficiently, forms syncytia and releases infectious progeny in these cells at 33 °C, the temperature of the nasal cavity, but is attenuated at 37 °C. Viral entry occurs similarly at both temperatures, but subsequent viral RNA synthesis is enhanced at 33 °C. Released virions display higher stability at 33 °C. In Caco2 and primary epithelial nasal cells, HKU1 is sensitive to interferons (IFN), but induction of IFN stimulated genes, such as IFN-Induced Transmembrane Proteins (IFITMs), is delayed at 33 °C. Once expressed, IFITMs comparably inhibit HKU1 fusion at both temperatures. In contrast, SARS-CoV-2 robustly replicates at 37 °C. Thus, cellular permissiveness, innate immunity and viral properties collectively explain why HKU1 replicates more efficiently at nasal temperature. Our results highlight temperature-sensitivity disparities between coronaviruses, likely associated to different pathogenic outcomes. Characterization of the human coronavirus HKU1 is limited due to a lack of infection models. Here, the authors develop a cell model to propagate HKU1 and show that, unlike its relative SARS-CoV-2, it grows better at 33 °C, the temperature of the nasal cavity, than at 37 °C, which is linked to IFN response and viral properties.

Nature Communications
Université Claude Bernard Lyon 1 (FR), Conservatoire National des Arts et Métiers (FR), Centre National de la Recherche Scientifique (FR), Institut de Chimie des Substances Naturelles (FR), Inserm (FR), Institut Pasteur (FR), Université Paris Cité (FR), Université Paris-Saclay (FR), Hospices Civils de Lyon (FR), Evolutionary Genomics (United States) (US), Hôpital Lyon Sud (FR), Institut de Recherche Vaccinale (FR), Centre International de Recherche en Infectiologie (FR), Infection et inflammation (FR)
Openalex Percentile: Top 9%
SARS-CoV-2 and COVID-19 Research
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