Staphylococcal superantigens interact with multiple host receptors to cause serious diseases

Abstract

Staphylococcus aureus strains that cause human diseases produce a large family of pyrogenic toxin superantigens (SAgs). These include toxic shock syndrome toxin-1 (TSST-1), the staphylococcal enterotoxins (SEs), and the SE-like proteins; to date, 23 staphylococcal SAgs have been described. Among the SAgs, three have been highly associated with human diseases (TSST-1, SEB, and SEC), likely because they are produced in high concentrations compared to other SAgs. Another major family of exotoxins produced by S. aureus is the cytolysins, particularly α-, β-, γ-, and δ-toxins, phenol soluble modulins, and leukocidins. This review discusses the association of SAgs with human diseases and particularly the "outside-in" signaling mechanism that leads to SAg-associated diseases. We discuss SAg interactions with three host immune cell receptors, including variable regions of the β-chain of the T cell receptor, MHC II α- and/or β-chains, and an epithelial/endothelial cell receptor that may include CD40. To a lesser extent, we discuss the role of cytolysins in facilitating disease production by SAgs.

Figure 1

Three dimensional structure of TSST-1 as representative of the SAg family. Red amino acids identify two residues within the MHC II contact site; blue amino acids identify three residues within the Vβ2-TCR contact site; purple amino acids identify the dodecapeptide epithelial cells binding site.

Figure 2

“Outside-In signaling mechanism for S. aureus (purple) to cause menstrual, vaginal TSS. S. aureus produces TSST-1 and α-toxin (green pacmen) that are pro-inflammatory for human vaginal epithelial cells, causing them to produce pro-inflammatory chemokines. The chemokines attract components of the innate and adaptive immune systems into the submucosa, disrupting mucosal barrier integrity. Barrier disruption allows TSST-1 to penetrate and massively stimulate CD4⁺ T cell and macrophage proliferation. This leads to production of a cytokine storm, including TNF-α and β, IL-1β, IL-2, IL-6, and interferon γ. These cytokines are critical in producing the defining criteria of TSS (fever, hypotension, rash, skin peeling upon recovery, and a variable multi-organ component.