Bacterial Superantigen Toxins, CD28, and Drug Development

Abstract

During severe bacterial infections, death and disease are often caused by an overly strong immune response of the human host. Acute toxic shock is induced by superantigen toxins, a diverse set of proteins secreted by Gram-positive staphylococcal and streptococcal bacterial strains that overstimulate the inflammatory response by orders of magnitude. The need to protect from superantigen toxins led to our discovery that in addition to the well-known MHC class II and T cell receptors, the principal costimulatory receptor, CD28, and its constitutively expressed coligand, B7-2 (CD86), previously thought to have only costimulatory function, are actually critical superantigen receptors. Binding of the superantigen into the homodimer interfaces of these costimulatory receptors greatly enhances B7-2/CD28 engagement, leading to excessive pro-inflammatory signaling. This finding led to the design of short receptor dimer interface mimetic peptides that block the binding of superantigen and thus protect from death. It then turned out that such a peptide will protect also from Gram-negative bacterial infection and from polymicrobial sepsis. One such CD28 mimetic peptide is advancing in a Phase 3 clinical trial to protect from lethal wound infections by flesh-eating bacteria. These host-oriented therapeutics target the human immune system itself, rendering pathogens less likely to become resistant.

Keywords: B7-2 receptor; CD28 homodimer interface; CD28 receptor; bacterial superantigen toxins; costimulation; lethal toxic shock; receptor dimer interface mimetic peptides.

Figure 1

Mechanism of action of superantigen toxins and of mimetic peptide antagonists. (A) The superantigen acts to induce an inflammatory cytokine storm. In the prototypical superantigen SEB, the conserved β-strand/hinge/α-helix superantigen domain (magenta) points away from the binding sites for MHC-II molecule and TCR that were omitted for clarity; the extracellular domain of CD28 shows the homodimer interface (red and green) and the site where its B7 coligands bind (yellow) and the extracellular domain of B7-2 shows the crystallographic homodimer interface (brown). Normal immune stimulation leads to a moderate CD28–B7-2 interaction between antigen-presenting cell and T cell and to moderate cytokine induction (left). However, when the superantigen engages the homodimer interface of CD28 and of B7-2 (middle), this potently enhances CD28–B7-2 engagement, resulting in an inflammatory cytokine storm (right) [8]. (B) Short peptide mimetics of the β-strand/hinge/α-helix superantigen domain [1] or of the homodimer interfaces in CD28 [7] or in B7-2 [8] act as competitors that prevent access of the superantigen to its CD28 and B7-2 host targets (middle) and thereby abrogate excessive signaling through the CD28/B7-2 axis (right).