Potential for prolonged replication of common acute respiratory viruses in air-liquid interface cultures of primary human airway cells

Abstract

A previous study provides clinical evidence that extended respiratory virus detection can occur in healthy pediatric individuals. However, it remains unclear how long respiratory viruses can survive in the human respiratory tissue. In this study, the replication potential of common respiratory viruses was evaluated using air-liquid interface (ALI) cultures of primary human respiratory epithelial cells. The findings demonstrate that most respiratory viruses can replicate for approximately 100 days in ALI cultures, with some showing prolonged replication for up to 150-200 days. In contrast, influenza and respiratory DNA viruses showed shorter replication periods likely due to virus-induced cell death. Even during the late phase, some samples continued to support viral replication in re-infection experiments, indicating sustained viral viability. ALI cultures, which lack effector immune cells, did not exhibit apparent type I interferon responses during long-term replication, except for transient IFNβ secretion in the early phase of infection, suggesting a state of tolerance that allows prolonged viral replication. Furthermore, genetic analysis revealed that viruses replicating for more than 50-60 days developed genetic variations, indicating an increased risk of mutations during prolonged infection. These results suggest that common respiratory viruses can remain detectable in human respiratory tissues for extended periods. However, transmission within 50-60 days may be preferable to reduce the risk of generating genetic variants. This concern is particularly relevant in immunocompromised individuals, where prolonged infections may facilitate viral evolution and contribute to the emergence of novel variants. IMPORTANCE: This study demonstrates that most common respiratory viruses, excluding influenza and DNA viruses, can replicate and produce infectious progeny for an average of up to 100 days in air-liquid interface (ALI) cultures of primary human respiratory epithelial cells without obvious innate immune responses. These findings imply that extended viral replication may occur in human hosts, potentially supported by the slow turnover of the respiratory epithelium. Notably, replication beyond 50-60 days was associated with the accumulation of genetic variations, suggesting a potential mechanism for the emergence of novel variants. To mitigate this risk, limiting transmission to within 50-60 days may be preferable. This issue is particularly relevant in immunocompromised individuals, where prolonged infection may promote viral evolution. Together, these findings provide insight into the replication dynamics of respiratory viruses in human tissue and highlight the importance of limiting long-term replication to prevent the emergence of new variants.

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