Swine Influenza Virus Triggers Ferroptosis In A549 Cells To Enhance Virus Replication

Abstract Background: Recently, Influenza A virus (IAV) has been found to induce several programmed cell death pathways that play essential roles in host defense. Indeed, cell death caused by viral infection may be a mixed pattern of cell death instead of a certain single mode. Ferroptosis is a novel form of regulated cell death (RCD) that is mainly mediated by iron-dependent lipid peroxidation. Basis on the proteomic data, we wonder whether IAV can cause ferroptosis in host cells. Method: In this study, a quantitative proteomics approach based on an iTRAQ combined with LC–MS/MS was used to profile expressed proteins in A549 cells infected with H1N1 SIV. Meanwhile, we measured the intracellular iron content, reactive oxygen species (ROS) release and lipid peroxidation in response to SIV infection. At last, drug experiment was used to investigate effects of ferroptosis on modulating SIV survival. Results: Bioinformatics analysis revealed several proteins closely relevant to iron homeostasis and transport are identified and ferroptosis signaling pathway are highly enriched in response to SIV infection. In our experiment, we found that aberrant expression of iron-binding proteins disrupts labile iron uptake and storage after SIV infection. Meanwhile, SIV infection inhibited system Xc − /GPX4 axis that result in GSH depletion and the accumulation of lipid peroxidation products. Notably, cell death caused by SIV as a result of iron-dependent lipid peroxidation can be partially rescued by ferroptosis inhibitor. Additionally, blockade of the ferroptotic pathway by Fer-1 treatment decreased viral titers and inflammatory response. Conclusion: This study revealed a new mode of cell death induced by IAV infection, which might improve the understanding of the underlying mechanism involved in interaction of virus and host cells.