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Toxins 2018, 10(11), 459; https://doi.org/10.3390/toxins10110459

Bacterial Superantigen Toxins, CD28, and Drug Development

Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 9112102, Israel
Received: 18 October 2018 / Revised: 2 November 2018 / Accepted: 4 November 2018 / Published: 6 November 2018
(This article belongs to the Special Issue From Toxins to Drugs)
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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. View Full-Text
Keywords: bacterial superantigen toxins; lethal toxic shock; costimulation; CD28 receptor; CD28 homodimer interface; B7-2 receptor; receptor dimer interface mimetic peptides bacterial superantigen toxins; lethal toxic shock; costimulation; CD28 receptor; CD28 homodimer interface; B7-2 receptor; receptor dimer interface mimetic peptides
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Kaempfer, R. Bacterial Superantigen Toxins, CD28, and Drug Development. Toxins 2018, 10, 459.

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