Differential beta‐coronavirus infection dynamics in human bronchial epithelial organoids

Abstract

The lower respiratory system serves as the target and barrier for beta‐coronavirus (beta‐CoV) infections. In this study, we explored beta‐CoV infection dynamics in human bronchial epithelial (HBE) organoids, focusing on HCoV‐OC43, SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2. Utilizing advanced organoid culture techniques, we observed robust replication for all beta‐CoVs, particularly noting that SARS‐CoV‐2 reached peak viral RNA levels at 72 h postinfection. Through comprehensive transcriptomic analysis, we identified significant shifts in cell population dynamics, marked by an increase in goblet cells and a concurrent decrease in ciliated cells. Furthermore, our cell tropism analysis unveiled distinct preferences in viral targeting: HCoV‐OC43 predominantly infected club cells, while SARS‐CoV had a dual tropism for goblet and ciliated cells. In contrast, SARS‐CoV‐2 primarily infected ciliated cells, and MERS‐CoV showed a marked affinity for goblet cells. Host factor analysis revealed the upregulation of genes encoding viral receptors and proteases. Notably, HCoV‐OC43 induced the unfolded protein response pathway, which may facilitate viral replication. Our study also reveals a complex interplay between inflammatory pathways and the suppression of interferon responses during beta‐CoV infections. These findings provide insights into host‐virus interactions and antiviral defense mechanisms, contributing to our understanding of beta‐CoV infections in the respiratory tract.