Diverse Cellular Tropisms and Immune Responses during Beta-Coronavirus Infections in Human Bronchial Epithelial Organoids

Abstract The lower respiratory system serves as the primary target and barrier for beta-coronavirus (beta-CoV) infections. We investigated the interactions between four distinct beta-CoVs [HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2 (Omicron)] in human bronchial epithelial (HBE) organoids using single-cell RNA sequencing (scRNA-seq). Our findings revealed diverse viral tropisms: SARS-CoV and SARS-CoV-2 mainly infected ciliated cells, while HCoV-OC43 and MERS-CoV preferred club and goblet cells, respectively. Notably, genes encoding the host receptor BSG (CD147) and proteases (TMPRSS2, cathepsin B/D, and SPCS1) associated with beta-CoV infections were upregulated by all four virus infections, particularly in club cells. Transcriptomic profiling showed that these viruses commonly induced inflammation via TNF-α/NF-кB signaling and reduced interferon responses. However, host-defense pathways like the unfolded protein response, ER-related calcium regulation, and oxidative stress response exhibited cell-type and virus-dependent regulations. Notably, in contrast to SARS-CoV infection, HCoV-OC43 infected cells induce the upregulation of IFNα-related interferon-stimulated genes (ISGs) particularly in club and goblet cells, potentially suppressing viral replication despite widespread infection. Taken together, our study redefines our understanding of beta-CoVs cellular tropism and highlights the intricate interplay between these cells and the host's immune defense mechanisms.