Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
Vaccine. 2012 Jul 20;30(34):5099-109. doi: 10.1016/j.vaccine.2012.05.067. Epub 2012 Jun 9.
Staphylococcus aureus causes significant illnesses throughout the world, including toxic shock syndrome (TSS), pneumonia, and infective endocarditis. Major contributors to S. aureus illnesses are secreted virulence factors it produces, including superantigens and cytolysins. This study investigates the use of superantigens and cytolysins as staphylococcal vaccine candidates. Importantly, 20% of humans and 50% of rabbits in our TSS model cannot generate antibody responses to native superantigens. We generated three TSST-1 mutants; G31S/S32P, H135A, and Q136A. All rabbits administered these TSST-1 toxoids generated strong antibody responses (titers>10,000) that neutralized native TSST-1 in TSS models, both in vitro and in vivo. These TSST-1 mutants lacked detectable residual toxicity. Additionally, the TSST-1 mutants exhibited intrinsic adjuvant activity, increasing antibody responses to a second staphylococcal antigen (β-toxin). This effect may be due to TSST-1 mutants binding to the immune co-stimulatory molecule CD40. The superantigens TSST-1 and SEC and the cytolysin α-toxin are known to contribute to staphylococcal pneumonia. Immunization of rabbits against these secreted toxins provided complete protection from highly lethal challenge with a USA200 S. aureus strain producing all three exotoxins; USA200 strains are common causes of staphylococcal infections. The same three exotoxins plus the cytolysins β-toxin and γ-toxin contribute to infective endocarditis and sepsis caused by USA200 strains. Immunization against these five exotoxins protected rabbits from infective endocarditis and lethal sepsis. These data suggest that immunization against toxoid proteins of S. aureus exotoxins protects from serious illnesses, and concurrently superantigen toxoid mutants provide endogenous adjuvant activity.
金黄色葡萄球菌在全球范围内引起多种严重疾病，包括中毒性休克综合征（TSS）、肺炎和感染性心内膜炎。金黄色葡萄球菌产生的分泌性毒力因子是导致这些疾病的主要因素，包括超抗原和细胞毒素。本研究探讨了将超抗原和细胞毒素作为金黄色葡萄球菌疫苗候选物的用途。重要的是，我们 TSS 模型中 20%的人类和 50%的兔子不能对天然超抗原产生抗体反应。我们生成了三个 TSST-1 突变体；G31S/S32P、H135A 和 Q136A。所有接受这些 TSST-1 类毒素的兔子都产生了强烈的抗体反应（滴度>10,000），可中和 TSS 模型中天然 TSST-1 的毒性，无论是在体外还是体内。这些 TSST-1 突变体没有检测到残留毒性。此外，TSST-1 突变体具有内在的佐剂活性，可增强对第二种金黄色葡萄球菌抗原（β-毒素）的抗体反应。这种效应可能是由于 TSST-1 突变体与免疫协同刺激分子 CD40 结合。超抗原 TSST-1 和 SEC 以及细胞毒素 α-毒素已知会导致金黄色葡萄球菌肺炎。用这些分泌毒素免疫兔子可完全预防携带三种外毒素的 USA200 金黄色葡萄球菌株的高度致死性攻击；USA200 株是金黄色葡萄球菌感染的常见原因。同样的三种外毒素加上细胞毒素 β-毒素和 γ-毒素会导致 USA200 株引起的感染性心内膜炎和败血症。针对这五种外毒素的免疫可保护兔子免受感染性心内膜炎和致命性败血症的侵害。这些数据表明，针对金黄色葡萄球菌外毒素的类毒素蛋白进行免疫可预防严重疾病，同时超抗原类毒素突变体提供内源性佐剂活性。
