The S. aureus serine protease-like protein B (SplB) is a potent allergen causing eosinophilic airway inflammation in mice

Background Asthma is associated with Staphylococcus aureus colonization. Two hypotheses were proposed to explain this phenomenon: (1) the allergic environment in asthma favors S. aureus colonization and (2) S. aureus colonization creates a pro-allergic environment. Since several S. aureus virulence factors, such as the serine protease–like protein (Spl) B, elicit a TH2-biased immune response, we asked whether the pathogen itself can cause asthma. Objective Test the ability of recombinant SplB of S. aureus to sensitize mice and induce allergic airway inflammation (AAI). Methods Mice were treated with repeated intratracheal inoculations of either catalytically active SplB or an inactive mutant. AAI was assessed by evaluating airway hypersensitivity, immune cell infiltration, cytokines, mucus production, fibrosis, and specific serum IgE. We compared the outcome between wild-type and gene-deficient C57BL/6J mice, including recombination-activating gene knockout mice (Rag2 -/- ), interleukin-33 knockout mice (IL-33 -/- ), and protease-activated receptor 2 knockout mice (PAR2 -/- ). Results Intratracheal exposure to SplB sensitized the mice and caused severe eosinophilic airway inflammation and hyperresponsiveness. The development of asthma required both the proteolytic activity of SplB and a functional adaptive immune system. The soluble protease sensor IL-33 was necessary for eosinophil tissue invasion, whereas the membrane-bound protease sensor PAR2 was not. Conclusion The serine protease SplB of S. aureus is a potent allergen. Based on this finding we propose a third mechanism to explain the relationship between S. aureus colonization and asthma: S. aureus can release allergens, such as SplB, that sensitize individuals and lead to the development of asthma. Key Messages The SplB protease, which is secreted by S. aureus , is a potent allergen that induces severe eosinophilic airway inflammation. SplB’s allergenicity depends on its enzymatic activity and on the host’s adaptive immune system. The IL-33, a soluble protease sensor, is required for eosinophilic airway inflammation but not for the SplB-specific IgE response. The membrane protease sensor PAR2 was only required for lung fibrosis. Bacterial proteases may be an underestimated cause of idiopathic asthma. Capsule summary The protease SplB, produced by the bacterium Staphylococcus aureus , induces allergic airway inflammation in mice, suggesting that S. aureus may promote asthma in human patients. These findings imply that bacterial allergens could play a significant role in idiopathic asthma.