Buonpane Rebecca A, Churchill Hywyn R O, Moza Beenu, Sundberg Eric J, Peterson Marnie L, Schlievert Patrick M, Kranz David M
Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA.
Nat Med. 2007 Jun;13(6):725-9. doi: 10.1038/nm1584. Epub 2007 May 21.
Exotoxins of Staphylococcus aureus belong to a family of bacterial proteins that act as superantigens by activating a large subset of the T-cell population, causing massive release of inflammatory cytokines. This cascade can ultimately result in toxic shock syndrome and death. Therapeutics targeting the early stage of the pathogenic process, when the superantigen binds to its receptor, could limit the severity of disease. We engineered picomolar binding affinity agents to neutralize the potent toxin staphylococcal enterotoxin B (SEB). A single immunoglobulin-like domain of the T-cell receptor (variable region, Vbeta) was subjected to multiple rounds of directed evolution using yeast display. Soluble forms of the engineered Vbeta proteins produced in Escherichia coli were effective inhibitors of SEB-mediated T-cell activation and completely neutralized the lethal activity of SEB in animal models. These Vbeta proteins represent an easily produced potential treatment for diseases mediated by bacterial superantigens.
金黄色葡萄球菌的外毒素属于一类细菌蛋白，通过激活大部分T细胞群体作为超抗原起作用，导致炎性细胞因子大量释放。这种级联反应最终可导致中毒性休克综合征和死亡。在超抗原与其受体结合的致病过程早期进行靶向治疗，可能会限制疾病的严重程度。我们设计了皮摩尔结合亲和力的试剂来中和强效毒素葡萄球菌肠毒素B（SEB）。利用酵母展示技术，对T细胞受体的单个免疫球蛋白样结构域（可变区，Vβ）进行了多轮定向进化。在大肠杆菌中产生的工程化Vβ蛋白的可溶性形式是SEB介导的T细胞激活的有效抑制剂，并在动物模型中完全中和了SEB的致死活性。这些Vβ蛋白代表了一种易于生产的、针对由细菌超抗原介导的疾病的潜在治疗方法。
