Engineering a soluble high-affinity receptor domain that neutralizes staphylococcal enterotoxin C in rabbit models of disease
Engineering a soluble high-affinity receptor domain that neutralizes staphylococcal enterotoxin C in rabbit models of disease
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DOI：
10.1093/protein/gzs094
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发表时间：
2013-02-01
影响因子：
2.4
通讯作者：
Kranz, D. M.
中科院分区：
文献类型：
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作者：
Mattis, D. M.;Spaulding, A. R.;Kranz, D. M.
超抗原(SAG)是一类免疫刺激性外毒素，能激活大量的T细胞，导致细胞因子的过度产生以及随后的炎症反应和全身毒性。金黄色葡萄球菌肠毒素C(Sec)是金黄色葡萄球菌分泌的一种SAG，与非经期中毒性休克综合征(TSS)和坏死性肺炎等多种疾病有关。SEC已被证明可导致兔的TSS疾病，该毒素可导致与耐甲氧西林金黄色葡萄球菌(MRSA)相关的致死性，导致兔肺炎模型。为了减少SEC的发病率和死亡率，通过酵母展示定向进化，获得了SEC T细胞受体β链胞外可变区的高亲和力变体(约14 kDa)。该蛋白的生化特征表明，它与同源(65个相同)的SAG葡萄球菌肠毒素B(SEB)发生交叉反应。可溶的高亲和力T细胞受体蛋白在体外中和SEC和SEB，并在感染性心内膜炎模型中显著降低SEC阳性MRSA菌株(USA400 MW2)的细菌负担。在坏死性肺炎兔模型中，中和剂还防止了MW2的致死性。这些研究表征了一种针对SEC的可溶性高亲和力中和剂，它与SEB具有交叉反应，并有可能与抗生素一起静脉使用，以治疗涉及这些SAG的葡萄球菌疾病。
Superantigens (SAgs) are a class of immunostimulatory exotoxins that activate large numbers of T cells, leading to overproduction of cytokines and subsequent inflammatory reactions and systemic toxicity. Staphylococcal enterotoxin C (SEC), a SAg secreted by Staphylococcus aureus, has been implicated in various illnesses including non-menstrual toxic shock syndrome (TSS) and necrotizing pneumonia. SEC has been shown to cause TSS illness in rabbits and the toxin contributes to lethality associated with methicillin-resistant S.aureus (MRSA) in a rabbit model of pneumonia. With the goal of reducing morbidity and mortality associated with SEC, a high-affinity variant of the extracellular variable domain of the T-cell receptor beta-chain for SEC (approximate to 14 kDa) was generated by directed evolution using yeast display. This protein was characterized biochemically and shown to cross-react with the homologous (65 identical) SAg staphylococcal enterotoxin B (SEB). The soluble, high-affinity T-cell receptor protein neutralized SEC and SEB in vitro and also significantly reduced the bacterial burden of an SEC-positive strain of MRSA (USA400 MW2) in an infective endocarditis model. The neutralizing agent also prevented lethality due to MW2 in a necrotizing pneumonia rabbit model. These studies characterize a soluble high-affinity neutralizing agent against SEC, which is cross-reactive with SEB, and that has potential to be used intravenously with antibiotics to manage staphylococcal diseases that involve these SAgs.