Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 9112102, Israel.
Toxins (Basel). 2018 Nov 6;10(11):459. doi: 10.3390/toxins10110459.
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.
在严重的细菌感染中，人类宿主过度强烈的免疫反应往往会导致死亡和疾病。急性中毒性休克是由超抗原毒素引起的，超抗原毒素是一组由革兰氏阳性葡萄球菌和链球菌细菌菌株分泌的多样化蛋白质，其通过数量级的方式过度刺激炎症反应。为了防止受到超抗原毒素的侵害，我们发现除了众所周知的 MHC 类 II 和 T 细胞受体外，主要的共刺激受体 CD28 及其组成型表达的共配体 B7-2（CD86）实际上也是关键的超抗原受体。超抗原结合到这些共刺激受体的同源二聚体界面中，极大地增强了 B7-2/CD28 的结合，导致过度的促炎信号转导。这一发现导致了设计短的受体二聚体界面模拟肽，这些模拟肽可以阻断超抗原的结合，从而起到保护作用，防止死亡。后来发现，这种肽也可以预防革兰氏阴性细菌感染和多微生物败血症。一种这样的 CD28 模拟肽正在进行 3 期临床试验，以防止致命的创伤感染由食人肉细菌。这些针对宿主的治疗方法针对的是人类自身的免疫系统，使病原体不太可能产生耐药性。
