Impact of Changes in Human Airway Epithelial Cellular Composition and Differentiation on SARS-CoV-2 Infection Biology

The consequences of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can range from asymptomatic to fatal disease. Variations in epithelial susceptibility to SARS-CoV-2 infection depend on the anatomical location from the proximal to distal respiratory tract. However, the cellular biology underlying these variations is not completely understood. Thus, air-liquid interface cultures of well-differentiated primary human tracheal and bronchial epithelial cells were employed to study the impact of epithelial cellular composition and differentiation on SARS-CoV-2 infection by transcriptional (RNA sequencing) and immunofluorescent analyses. Changes of cellular composition were investigated by varying time of differentiation or by using specific compounds. We found that SARS-CoV-2 primarily infected not only ciliated cells but also goblet cells and transient secretory cells. Viral replication was impacted by differences in cellular composition, which depended on culturing time and anatomical origin. A higher percentage of ciliated cells correlated with a higher viral load. However, DAPT treatment, which increased the number of ciliated cells and reduced goblet cells, decreased viral load, indicating the contribution of goblet cells to infection. Cell entry factors, especially cathepsin L and transmembrane protease serine 2, were also affected by differentiation time. In conclusion, our study demonstrates that viral replication is affected by changes in cellular composition, especially in cells related to the mucociliary system. This could explain in part the variable susceptibility to SARS-CoV-2 infection between individuals and between anatomical locations in the respiratory tract. (c) 2023 The Author(s). Published by S. Karger AG, Basel

Automated summary

The cellular biology underlying the variations in epithelial susceptibility to SARS-CoV-2 infection in different anatomical locations of the respiratory tract is not completely understood. This study used air-liquid interface cultures of primary human tracheal and bronchial epithelial cells to investigate the impact of cellular composition and differentiation on SARS-CoV-2 infection. The results showed that SARS-CoV-2 primarily infected ciliated cells, goblet cells, and transient secretory cells. The viral replication was influenced by differences in cellular composition, especially the percentage of ciliated cells. Moreover, the study found that the differentiation time affected the cell entry factors. These findings provide insights into the variable susceptibility to SARS-CoV-2 infection between individuals and anatomical locations in the respiratory tract.