The S. aureus serine protease-like protein B (SplB) in murine allergic lung disease

Abstract

Asthma is a chronic inflammatory disease that is characterized by wheezing, coughing, chest tightness, and shortness of breath. Allergic asthma is the most common form of asthma and is characterized by a type 2 immune response. Genetic and environmental factors, such as microbial colonization, play a role in the onset of asthma. Staphylococcus aureus (S. aureus) is a gram-positive opportunistic pathogen that is well-known for its Janus-faced behavior. On the one hand, S. aureus is a major cause of community-acquired and nosocomial infections. On the other hand, nearly 30% of the human population is colonized without visible adverse effects. Asthma patients are more frequently colonized with S. aureus than healthy persons, however, the causality of this relationship is unknown. S. aureus secretes several virulence factors that promote allergic sensitization. Among them are the serine protease-like proteins (Spls). Recent epidemiological studies indicate that especially SplB induces an allergic immune response in humans. In this thesis, we characterize the allergenic properties of SplB in a murine model of chronic allergic airway inflammation (AAI). We induced AAI in C57BL/6J wild-type, IL 33 ko, PAR2 ko and Rag2 ko mice through repeated intratracheal (i.t.) inoculation of recombinant SplB. We also exposed C57BL/6J wild-type mice i.t. to an enzymatically inactive mutant of SplB. We observed severe eosinophil infiltration in the lungs of SplB-sensitized mice, as well as high SplB-specific serum IgE titers. Remarkably, SplB induced these asthma symptoms without the need for adjuvants. Characterization of the pathomechanisms revealed that the proteolytic activity of SplB as well as a functional adaptive immune system were essential for the development of murine asthma. The soluble protease sensor IL-33 was necessary for eosinophil tissue invasion, whereas the membrane-bound protease sensor PAR2 was dispensable. Based on these results we propose a new hypothesis about the relationship between asthma and S. aureus colonization. Previously, it has been debated whether asthma facilitates S. aureus colonization, and/or whether S. aureus favors sensitization to environmental allergens. We have identified the S. aureus virulence factor SplB as a potent allergen. Therefore, we propose that S. aureus is capable of inducing allergic airway inflammation on its own