Myeloid Cell Leukemia-1 knockout leads to increased viral propagation of Respiratory Syncytial Virus and influenza virus in mouse embryonic fibroblast cells and A549 cells: implications in cancer therapy

Introduction: Respiratory Syncytial Virus (RSV) remains a significant global health burden, particularly affecting young children, elderly individuals, and immunocompromised patients. The antiapoptotic protein Myeloid Cell Leukemia-1 (Mcl-1) is rapidly upregulated following RSV infection; however, its functional significance in viral pathogenesis remains poorly defined. 

Methods: We investigated the role of Mcl-1 during RSV infection using Mcl-1 knockout mouse embryonic fibroblasts (ΔMcl-1 MEFs) and human alveolar epithelial (A549) cells subjected to small interfering RNA (siRNA)-mediated Mcl-1 knockdown. Viral replication was quantified by plaque assays, and phenotypic effects were assessed through syncytia formation and apoptosis assays. To assess broader implications, influenza A virus replication was also evaluated in ΔMcl-1 MEFs and Mcl-1–silenced A549 cells. 

Results: RSV replication was significantly enhanced in ΔMcl-1 MEFs compared to wild-type (WT) controls, with increased viral titers, larger syncytia formation, and elevated apoptosis during the late stages of infection. Consistent results were observed in A549 cells following Mcl-1 knockdown, where RSV titers increased by more than 3 log₁₀. Influenza A virus replication was also markedly elevated in ΔMcl-1 MEFs and siRNA-treated A549 cells, suggesting that Mcl-1 exerts a broad antiviral effect across multiple respiratory viruses. 

Discussion: These findings indicate that Mcl-1 upregulation during RSV and influenza virus infection functions as a critical host antiviral defense mechanism, rather than a viral evasion strategy. Clinically, our results raise concerns regarding therapies that target Mcl-1, such as certain anticancer treatments, which may inadvertently increase susceptibility to severe viral infections. Careful monitoring and potential prophylactic antiviral interventions may be warranted in patients receiving Mcl-1 inhibitor therapies.