The Role of Staphylococcus aureus and Its Toxins in the Pathogenesis of Allergic Asthma

Abstract

Bronchial asthma is one of the most common chronic diseases worldwide and affects more than 300 million patients. Allergic asthma affects the majority of asthmatic children as well as approximately 50% of adult asthmatics. It is characterized by a Th2-mediated immune response against aeroallergens. Many aspects of the overall pathophysiology are known, while the underlying mechanisms and predisposing factors remain largely elusive today. Over the last decade, respiratory colonization with Staphylococcus aureus (S. aureus), a Gram-positive facultative bacterial pathogen, came into focus as a risk factor for the development of atopic respiratory diseases. More than 30% of the world’s population is constantly colonized with S. aureus in their nasopharynx. This colonization is mostly asymptomatic, but in immunocompromised patients, it can lead to serious complications including pneumonia, sepsis, or even death. S. aureus is known for its ability to produce a wide range of proteins including toxins, serine-protease-like proteins, and protein A. In this review, we provide an overview of the current knowledge about the pathophysiology of allergic asthma and to what extent it can be affected by different toxins produced by S. aureus. Intensifying this knowledge might lead to new preventive strategies for atopic respiratory diseases.

Keywords: Staphylococcus aureus; Staphylococcus aureus enterotoxin B; allergen; allergic asthma; atopic diseases; microbial colonization; serine protease-like protein; staphylococcal protein A; toxic-shock-syndrome toxin 1; toxin-specific IgE-sensitization.

Figure 1

Key effector cells and soluble mediators in the pathogenesis of allergic asthma. After detection, internalization, and processing by dendritic cells, peptide fragments of the allergen are presented via MHII to naïve CD4⁺ T cells. These become activated, differentiate into Th2 cells, and produce huge amounts of typical type 2 cytokines, such as IL-4, IL-5, and IL-13. IL-4 and IL-13 promote class switching in B cells into IgE-producing plasma cells. Allergen-specific IgE antibodies bind to specific Fcε-receptors on the surfaces of basophils and mast cells. Following prior sensitization against a specific allergen, the respiratory tract is re-challenged with the allergen and allergen-specific Th2 cells are activated. Due to the cross-linking of membrane-bound, allergen-specific IgE antibodies by the allergen, the degranulation of basophils and mast cells is triggered, and mediators such as histamines or leukotrienes are released, further enhancing the allergic reaction. Blood eosinophils are recruited to the airway epithelium due to, amongst other chemoattractants, increased IL-5 concentrations. In addition to their barrier function, airway epithelial cells are able to produce a variety of cytokines, such as IL-25, IL-33 and thymic lymphopoeitin (TSLP), which further enhance the allergic reaction via the activation of basophils, mast cells, and innate lymphoid cells type 2 (ILC2). References are in the main text. Created with BioRender.com.

Figure 2

Processes in the pathogenesis of allergic asthma affected by different toxins produced by S. aureus. S. aureus is known for its ability to produce a variety of proteins, including several toxins. Belonging to the family of superantigens produced by S. aureus, the toxic shock syndrome toxin-1 (TSST-1; green pentagon) mainly affects B cell immunity by enhancing the number of B cells and thereby the amount of produced IgE antibodies (indicated by white arrows in green pentagons). Another member of the superantigen family, the S. aureus enterotoxin B (SEB; red pentagon) is presumably able to affect pathogenesis in multiple ways. In human studies, asthmatic individuals showed increased SEB-specific IgE-levels, as well as stronger asthmatic symptoms. In murine studies, it has been shown that intranasal SEB-administration can have either ameliorating or aggravating effects on allergic airway inflammation and affects various key effector cells and mediators involved in pathogenesis. White arrows in red pentagons indicate SEB-mediated effects. Serine-protease-like proteases (Spls; yellow pentagon) are a family of six proteases produced by S. aureus, which could also affect the pathogenesis of allergic asthma. In asthmatic patients, significantly higher Spl-specific IgE-levels have been observed, and in a murine study, it has been shown that SplD is especially able to induce an asthma-like phenotype after intratracheal administration (indicated by white arrows in yellow pentagons). The S. aureus protein A (SpA; blue pentagons) is referred to as a B cell superantigen, and in atopic patients, it triggers strong B cell proliferation and increased production of IgE antibodies. Those effects mediated by SpA are indicated through white arrows in blue pentagons. References in the main text. Created with BioRender.com.