Vital Role of PINK1/Parkin-Mediated Mitophagy of Pulmonary Epithelial Cells in Severe Pneumonia Induced by IAV and Secondary Staphylococcus aureus Infection

Influenza A virus (IAV) infection causes considerable morbidity and mortality worldwide, and the secondary bacterial infection further exacerbates the severity and fatality of the initial viral infection. Mitophagy plays an important role in host resistance to pathogen infection and immune response, while its role on pulmonary epithelial cells with viral and bacterial co-infection remains unclear. The present study reveals that the secondary Staphylococcus aureus infection significantly increased the viral and bacterial loads in human lung epithelial cells (A549) during the initial H1N1 infection. Meanwhile, the secondary S. aureus infection triggered more intense mitophagy in A549 cells by activating the PINK1/Parkin signaling pathway. Notably, mitophagy could contribute to the proliferation of pathogens in A549 cells via the inhibition of cell apoptosis. Furthermore, based on an influenza A viral and secondary bacterial infected mouse model, we showed that activation of mitophagy was conducive to the proliferation of virus and bacteria in the lungs, aggravated the inflammatory damage and severe pneumonia at the same time, and eventually decreased the survival rate. The results elucidated the effect and the related molecular mechanism of mitophagy in pulmonary epithelial cells following IAV and secondary S. aureus infection for the first time, which will provide valuable information for the pathogenesis of virus/bacteria interaction and new ideas for the treatment of severe pneumonia.