Staphylococcus aureus superantigens drive a concentration-dependent neutrophilic or eosinophilic pulmonary inflammation in mouse models of cystic fibrosis.

Staphylococcus aureus (SA), the most common cystic fibrosis (CF) respiratory pathogen, is uniquely capable of producing superantigen (SAg) exotoxins, which are recognized as the most potent activators of the immune system and inducers of inflammation. Although a high frequency of CF SA isolates can produce SA-SAgs, their role in the immunopathogenesis of CF lung disease is unexplored. Therefore, to investigate the role of SA-SAgs in pulmonary inflammation in vivo, we crossed HLA-DR3 transgenic mice with CF gut corrected (HLA-DR3.CFGC) mice and βENaC transgenic (HLA-DR3.ENAC) mice expressing the epithelial Na+ channel β subunit, driven by the Clara cell secretory protein promoter, both accepted mouse models of CF. Intratracheal challenge with purified SA-SAgs (staphylococcal enterotoxin A, B, or C) induced a more robust pulmonary inflammatory response in HLA-DR3.ENAC transgenic mice compared with HLA-DR3.CFGC and B6.ENAC mice in a SA-SAg type- and concentration-dependent manner. Lower concentration of SA-SAg favored eosinophilic lung inflammatory response, whereas higher concentration elicited a neutrophilic lung inflammation and higher mortality in the short-term exposure model. Intratracheal infection with a sublethal inoculum of a clinical SA isolate producing staphylococcal enterotoxin B (SEB), but not the isogenic mutant strain lacking SEB, also induced a type 2 eosinophilic lung inflammatory response. In addition, intratracheal exposure to SA-SAgs or infection with the SA-producing SEB resulted in the airway/lung recruitment of atypical granulocytes expressing both Siglec F+ and Ly6G+ (SigF+Ly6G+), which are expressed by eosinophils and neutrophils, respectively. In conclusion, we demonstrated for the first time that SA-SAgs could drive pulmonary inflammation in CF.