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Signaling in staphylococcal toxic shock syndrome

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S, t, a, p, h, y, l, o, c, o, c, c, u, s a, u, r, e, u, s causes a multitude of “toxin-mediated” diseases, including staphylococcal scalded-skin syndrome (SSSS), toxic shock syndrome (TSS), and food poisoning. These conditions are caused by proteins called superantigens (SAgs). S. aureus can colonize mucosal surfaces, such as the mouth or vagina, although of all colonizing organisms, only about 5-10% produce SAgs. In TSS, toxic shock syndrome toxin 1 (TSST-1) interacts with T cell receptors to induce T cell proliferation and massive cytokine production, which leads to fever, rash, skin peeling, fluid leakage from blood vessels and resultant hypotension. This condition can be fatal if not diagnosed and treated in a timely fashion.
TSST-1 is a simple (12 amino acid), folded protein with a signaling molecule at the carboxy-terminal domain that can be cleaved off. When staphylococci come in contact with a mucosal surface, they secrete α-cytolysins, which disrupt the mucosal barrier, as seen in Figure 1. This allows TSST-1 to reach the deeper mucosal layers, where T cells reside. TSST-1 binds nonspecifically to T cells’ surface receptors. This binding causes T cells to become activated and release highly inflammatory molecules, such as interleukin-1 (IL-1) and tumor-necrosis factor (TNF), beginning the cascade of clinical TSS symptoms. Researchers have demonstrated that genetic variations in T cell binding to TSST-1 may determine the severity of an individual’s disease.
Treatment of TSS involves an antibiotic course, provision of fluids, and intravenous immunoglobulin (IVIg). IVIg is purified antibody collected and pooled from multiple donors; it acts to neutralize TSST-1. In some toxin-mediated staphylococcal infections, a second antibiotic, clindamycin, is added to the treatment regimen for its anti-protein-synthesis effects. With these treatments, mortality from this once uniformly-fatal disease is now less than 25%.
Figure 1. Inflammatory cascade in toxin-mediated staphylococcal infections.
Adapted from Brosnahan et al. Gram-positive bacterial superantigen outside-in signaling causes toxic shock syndrome. FEBS J. Dec 2011; 289(23): 4649-4667
The molecule that allows Staphylococcus aureus’ superantigen TSST-1 to invade through mucosal barriers is:
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