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

Abstract

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 type 2 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 (Il33 -/-), and protease-activated receptor 2 knockout mice (F2rl1-/-). Results: Intratracheal exposure to SplB sensitized the mice and caused 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.