Shocking superantigens promote establishment of bacterial infection.

Streptococcus pyogenes, also referred to as group A Streptococcus (GAS), is an exclusive human pathogen causing diseases ranging from uncomplicated infections of the throat and skin to severe invasive infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome (STSS). Asymptomatic carriage, particularly in the nasoand oropharyngeal mucosa, is common. GAS is equipped with an arsenal of virulence factors (e.g., surface-associated and secreted factors that contribute to disease pathogenesis) (1). Among the secreted virulence factors, superantigens (SAgs) have been recognized as key factors mediating the systemic excessive inflammatory response associated with STSS (2). SAgs belong to a family of proteins that activate T cells in an unconventional manner bypassing the normal rules for antigen processing and presentation. SAgs bind without prior cellular processing to the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and to the variable β-chains of the T-cell receptor on CD4 and CD8 T cells. In this way, the fine MHCpeptide specificity of T cells is bypassed, allowing for activation of numerous Vβ-specific T cells and an overzealous inflammatory response. This cytokine storm is harmful to the host and underlies conditions such as STSS (2). While the role of SAgs in STSS is well established, a lingering question has been why the bacteria secrete such powerful immunostimulatory factors. To date, 14 distinct SAgs have been identified and most clinical strains express several, thus showing a redundancy of these toxins (3). In PNAS, Zeppa et al. (4) provide evidence that SAgs promote GAS nasopharyngeal colonization and infection in a Vβ-specific T-cell–dependent manner. Passive immunization with antibodies against the SAg streptococcal pyrogenic exotoxin A (SpeA) or vaccination with a SpeA toxoid devoid of superantigenic activity provided antibody-dependent protection against nasopharyngeal infection. In addition, the authors discovered an antibody-independent protective mechanism involving SAg-triggered T-cell responses that enhanced GAS infection, thereby offering an explanation as to the bacterial benefit of a SAgtriggered T-cell response (ref. 4; Fig. 1). The concept that SAgs are critical in the establishment of GAS infection was first proposed by Kasper et al. (5), who showed that mice expressing human MHC class II molecules (e.g., mice susceptible to the action of SAgs) were easily colonized by GAS, whereas the wild-type mice readily cleared the infection. The enhanced colonization and infection was attributed to the SAg SpeA. In PNAS, the study by Zeppa et al. (4) provides additional mechanistic insight into the role of SAg as a colonizing factor. First, the authors show that passive immunization of humanized mice with anti-SpeA serum resulted in a reduced bacterial burden in the nasopharynx. Similarly, direct vaccination with inactive SpeA toxoid lacking SAg activity resulted in a strong anti-SpeA humoral response and protection against nasopharyngeal infection. However, vaccination with either SpeA or the staphylococcal SAg staphylococcal enterotoxin B (SEB) also afforded protection against GAS infection despite the absence of anti-SpeA antibodies, hence also suggesting an antibody-independent protective mechanism. The authors then explored whether T-cell responses contributed to the protective effect, and they provide evidence of the involvement of the SpeA-targeted T-cell subset, namely, CD3Vβ8 lymphocytes, which were reduced and less responsive in SpeAor SEB-vaccinated mice. Thus, the data indicate that the T-cell response elicited by the SAg contributed to the noted enhanced bacterial infection. This was further supported by the finding that depletion of either CD8 T cells alone or in combination with CD4 T cells resulted in a reduced nasopharyngeal GAS burden, although an exaggerated bacterial burden for Streptococcus pneumoniae, a non-SAg–producing bacteria. As an additional potential explanation, the authors link the observed effects to the inflammatory state during bacterial infection. Mice lacking CD4 T cells, CD8 T cells, or both showed reduced levels of inflammation during bacterial infection, which was linked to bacterial clearance. Similarly, SpeAand SEBvaccinated mice that were protected against GAS, infection showed a reduced inflammatory response (4). The authors propose that SAgs target and activate Vβspecific T cells, resulting in an inflammatory milieu and