SEC11A identified as a critical host factor for HMPV through virus-induced alternative splicing

Alternative splicing (AS) significantly increases the diversity of the eukaryotic proteome, and alterations in AS induced by viruses have emerged as a novel approach to studying virus-host interactions. Human metapneumovirus (HMPV) interacts with host cells through multiple mechanisms, directly or indirectly utilising various host systems to facilitate infection and replication. In this study, the BEAS-2B human normal lung epithelial cell line was used as the cell model for HMPV infection. The host gene alternative splicing events following HMPV infection were then characterised using RNA sequencing. Selected alternative splicing events were confirmed and the associated genes evaluated for their effect on HMPV replication in knockout cell lines. HMPV replication was found to be greatly reduced in cells lacking the SEC11A gene, suggesting that the SEC11A gene is a critical host factor for HMPV infection. Notably, the SEC11A splicing pattern was not altered during infection with other respiratory viruses. In summary, this study reveals that SEC11A, which encodes the core catalytic subunit of the signal peptidase complex (SPC), is an essential host factor for HMPV infection. We observed a specific exon-skipping event in its mRNA precursor that occurs within the regulatory region upstream of the coding sequence. This atypical splicing site suggests that the virus may regulate SEC11A expression by interfering with the host splicing machinery. These findings provide new insights into HMPV pathogenesis and lay the groundwork for further exploration of HMPV-host interactions and the development of potential host-directed antiviral therapies.