Abstract
Superantigens (SAgs) are potent microbial toxins that function to activate large numbers of T cells in a T cell receptor (TCR) Vβ-specific manner, resulting in excessive immune system activation. Staphylococcus aureus possesses a large repertoire of distinct SAgs, and in the context of host-pathogen interactions, staphylococcal SAg research has focused primarily on the role of these toxins in severe and invasive diseases. However, the contribution of SAgs to colonization by S. aureus remains unclear. We developed a two-week nasal colonization model using SAg-sensitive transgenic mice expressing HLA-DR4, and evaluated the role of SAgs using two well-studied stains of S. aureus. S. aureus Newman produces relatively low levels of staphylococcal enterotoxin A (SEA), and although we did not detect significant TCR-Vβ specific changes during wild-type S. aureus Newman colonization, S. aureus Newman Δsea established transiently higher bacterial loads in the nose. S. aureus COL produces relatively high levels of staphylococcal enterotoxin B (SEB), and colonization with wild-type S. aureus COL resulted in clear Vβ8-specific T cell skewing responses. S. aureus COL Δseb established consistently higher bacterial loads in the nose. These data suggest that staphylococcal SAgs may be involved in regulating bacterial densities during nasal colonization.
Highlights
Staphylococcus aureus is recognized as a major human pathogen causing a range of illnesses from superficial skin infections to invasive diseases including bacteremia, sepsis, pneumonia, and endocarditis [1].Within the healthcare setting, S. aureus infections are serious, including infection by methicillin-resistant S. aureus (MRSA) strains, and this pathogen is the most significant cause of serious infections in the United States [1,2,3,4].Despite the massive burden of disease, asymptomatic carriage by S. aureus is pervasive within human populations, being found most typically on the skin and in the nasal cavity
The sea deletion mutant was generated in S. aureus Newman as previously described, and has been characterized as lacking superantigenic activity [26]
Our findings reveal that different SAgs may play distinctive roles during colonization as staphylococcal enterotoxin A (SEA) only transiently altered colony forming units (CFU) for S. aureus Newman nasal colonization, while staphylococcal enterotoxin B (SEB) production reduced S. aureus COL colonization throughout all experimental time points
Summary
Staphylococcus aureus is recognized as a major human pathogen causing a range of illnesses from superficial skin infections to invasive diseases including bacteremia, sepsis, pneumonia, and endocarditis [1]. S. aureus typically resides within the vestibulum nasi of the anterior nares and has been found colonizing the cornified layer of stratified squamous epithelium, keratinized surfaces and mucous debris, as well as hair follicles of the human nose [6] Given these anatomical findings, it is not surprising that S. aureus is able to bind to both keratinized cells and desquamated nasal epithelia. As SAg-mediated T cell activation is not dependent on the antigenic peptide presented in the MHC class II molecule, this response can activate very large numbers of the exposed T cell population and may, in rare cases, lead to a ‘cytokine storm’ disease known as the toxic shock syndrome (TSS) These toxins have been implicated in many other diseases including infectious endocarditis, Kawasaki disease, atopic dermatitis, and various autoimmune diseases [16,17]. In order to test this hypothesis, we created isogenic SAg deletions of two well-characterized strains of S. aureus, and tested these strains against their wild-type counterparts in a SAg-sensitized murine model of staphylococcal nasal colonization
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