Synthesis of glycerol phosphate lipoteichoic acid in Staphylococcus aureus

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Abstract
Streptococcal toxic shock syndrome (STSS) is a rapidly progressing, life-threatening, systemic reaction to invasive infection caused by group A streptococci (GAS). GAS superantigens are key mediators of STSS through their potent activation of T cells leading to a cytokine storm and consequently vascular leakage, shock, and multiorgan failure. Mucosal-associated invariant T (MAIT) cells recognize MR1-presented antigens derived from microbial riboflavin biosynthesis and mount protective innate-like immune responses against the microbes producing such metabolites. GAS lack de novo riboflavin synthesis, and the role of MAIT cells in STSS has therefore so far been overlooked. Here we have conducted a comprehensive analysis of human MAIT cell responses to GAS, aiming to understand the contribution of MAIT cells to the pathogenesis of STSS. We show that MAIT cells are strongly activated and represent the major T cell source of IFNγ and TNF in the early stages of response to GAS. MAIT cell activation is biphasic with a rapid TCR Vβ2-specific, TNF-dominated response to superantigens and a later IL-12- and IL-18-dependent, IFNγ-dominated response to both bacterial cells and secreted factors. Depletion of MAIT cells from PBMC resulted in decreased total production of IFNγ, IL-1β, IL-2, and TNFβ. Peripheral blood MAIT cells in patients with STSS expressed elevated levels of the activation markers CD69, CD25, CD38, and HLA-DR during the acute compared with the convalescent phase. Our data demonstrate that MAIT cells are major contributors to the early cytokine response to GAS, and are therefore likely to contribute to the pathological cytokine storm underlying STSS. Significance Bacterial toxins belonging to the family of superantigens are potent immunostimulatory antigens capable of activating T cells in a nonconventional manner. This results in an overzealous activation of immune cells and release of pathologic levels of pro-inflammatory cytokines, which underlies severe disease manifestations such as streptococcal toxic shock syndrome. Here, we provide evidence that mucosal-associated invariant T (MAIT) cells are major contributors to the overall cytokine response elicited by group A streptococci. Both streptococcal superantigens and surface-attached bacterial factors activate MAIT cells, but through different mechanisms. Furthermore, activated MAIT cells could be detected in patients during the acute phase of streptococcal toxic shock syndrome. Thus, this study identifies an actor and potential target for intervention in streptococcal toxic shock syndrome.