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Influenza A virus infection causes considerable morbidity and mortality each year globally, and secondary bacterial infection further exacerbates the severity and fatality of the initial viral infection. Mast cells have substantial roles in protecting the respiratory tract mucosa, while their role in viral and bacterial co-infection remains unclear. The present study revealed that secondary Staphylococcus aureus infection significantly aggravated the activation of mast cells during the initial H1N1 infection both in vivo and in vitro, which was closely related to the increased inflammatory lung injury and mortality. Meanwhile, the secondary S. aureus infection suppressed autophagy and promoted inflammatory mediators released by mast cells through activating the PI3K/Akt signaling pathway. Blocking PI3K/Akt pathway by LY294002, an inhibitor of Akt phosphorylation, could rescue autophagy and inhibit the release of inflammatory mediators. Furthermore, based on the influenza A viral and secondary bacterial infected mice model, we showed that the combination of LY294002 and antiviral drug oseltamivir could effectively reduce the inflammatory damage and pro-inflammatory cytokines releasing in lungs, recovering body weight loss and improving the survival rate from the co-infections. In conclusion, secondary bacterial infection can inhibit autophagy and stimulate mast cell activation through the PI3K/Akt pathway, which might explain why secondary bacterial infection would cause severe and fatal consequences following an initial influenza A viral infection.