Viral replication and host response in airway epithelial cells predicts coronavirus pathogenicity and identifies HCoV-229E as an atypical seasonal coronavirus

Abstract

Human coronaviruses (HCoVs) range from mild seasonal strains to pathogenic viruses that cause severe pneumonia. The virological and host determinants that distinguish pathogenic coronaviruses (MERS-CoV, SARS-CoV-2) from seasonal strains (HCoV-229E, HCoV-NL63 and HCoV-OC43) remain poorly defined. To identify determinants of pathogenicity, we systematically compared replication, cellular tropism, innate responses and cytopathogenicity of pathogenic compared with seasonal HCoVs across nasal, bronchial, small airway and embryonic stem cell derived alveolar type II (AT2) epithelial cell cultures. All HCoVs preferentially infected ciliated cells in the upper airway, but only pathogenic viruses replicated to high titres in AT2 cells. Pathogenic HCoVs reprogrammed AT2 function and suppressed key innate immune signatures, consistent with distal lung epithelial dysfunction. In contrast, seasonal HCoVs were associated with limited alveolar replication and milder disruption of AT2 homeostasis. Strikingly, despite modest replication in all cell types, HCoV-229E induced pronounced epithelial injury, cilia loss and strong interferon stimulated gene expression, as well as induction of cellular stress/death programmes resembling those induced by MERS-CoV. These findings highlight the striking differences in cellular responses throughout the airways and between distinct HCoV strains and emphasizes the importance of assessing distal lung tropism and epithelial host responses to evaluate emergent coronaviruses to inform pandemic preparedness strategies.