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

Meagan PrescottMaciej MaselkoManoj Kumar Pastey^*

• Oregon State University, Corvallis, United States

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 upregulated shortly after RSV infection; however, the implications of this upregulation have not been clearly defined. In this study, 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 treated with small interfering RNA (siRNA) targeting Mcl-1. Our results demonstrated significantly enhanced RSV replication in ΔMcl-1 MEFs compared to wild-type (WT) controls, as evidenced by increased viral titers, larger syncytia formation, and elevated apoptosis during the late stages of infection. Consistent findings were observed in human A549 cells following Mcl-1 knockdown, with RSV titers increasing dramatically by over 3 log₁₀. Additionally, influenza A virus exhibited similar enhancement in replication in ΔMcl-1 MEFs and in anti-Mcl-1 siRNA treated A549 cells, suggesting a broader antiviral role for Mcl-1. These findings imply that Mcl-1 upregulation during RSV and influenza virus infection represents a critical host antiviral response rather than a viral evasion strategy. Clinically, these data raise concerns regarding therapies targeting Mcl-1, such as certain cancer treatments, as they may inadvertently increase patient susceptibility to severe viral infections. Thus, our results advocate for careful clinical monitoring and potential prophylactic antiviral measures for patients undergoing Mcl-1 inhibitor therapies.