Background. Postinfluenza Staphylococcus aureus pneumonias are increasingly recognized as a major form of life-threatening infections.

Methods. A mouse model of postinfluenza S. aureus pneumonia was developed. Mice were intranasally infected with bacteria alone or bacteria plus virus. Infection was assessed by mouse survival, lung histopathology, bacterial density in the lungs, and cellular response to infection.

Results. Mice infected with both influenza virus and S. aureus showed higher mortality, greater lung parenchymal damage, and greater bacterial density at metastatic tissue sites than mice infected with only S. aureus. At 4 h, more polymorphonuclear leukocytes and fewer CD11c⁺ cells were found in lung samples from mice infected with virus and bacteria than in those from mice infected with bacteria. α-Hemolysin and protein A were maximally expressed 4 h after infection, and Panton-Valentine leukocidin was maximally expressed 72 h after infection, with higher levels of α-hemolysin expression in mice infected with bacteria alone. Interferon γ expression was higher in tissue collected from mice infected with virus plus bacteria than in those from bacteria-infected mice.

Conclusions. The results from this model demonstrate diverse effects caused by antecedent influenza virus infection, which have a profound influence on the morbidity and mortality associated with S. aureus pneumonia.