The Staphylococcus aureus superantigen SElX is a bifunctional toxin that inhibits neutrophil function.
The Staphylococcus aureus superantigen SElX is a bifunctional toxin that inhibits neutrophil function.
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DOI：
10.1371/journal.ppat.1006461
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发表时间：
2017-09
期刊：
影响因子：
6.7
通讯作者：
Fitzgerald JR
中科院分区：
文献类型：
--
作者：
Tuffs SW;James DBA;Bestebroer J;Richards AC;Goncheva MI;O'Shea M;Wee BA;Seo KS;Schlievert PM;Lengeling A;van Strijp JA;Torres VJ;Fitzgerald JR
细菌超抗原 (SAgs) 会引起 Vβ 依赖性 T 细胞增殖，导致免疫失调，从而导致中毒性休克综合征和坏死性肺炎等危及生命的感染的发病机制。此前，我们证明来自金黄色葡萄球菌的葡萄球菌肠毒素样毒素 X (SElX) 是一种经典的超抗原，它以 Vβ 特异性方式表现出 T 细胞激活，并有助于坏死性肺炎的发病机制。在这里，我们发现SElX还可以与来自人类和其他哺乳动物物种的中性粒细胞结合并破坏IgG介导的吞噬作用。 SElX的保守唾液酸结合基序的定点诱变消除了中性粒细胞结合和吞噬杀伤，并揭示了用于SElX结合的多个糖基化中性粒细胞受体。此外，SElX的嗜中性粒细胞结合缺陷突变体保留了其T细胞激活的能力，这表明SElX对分别与获得性免疫和先天免疫相关的不同细胞群表现出机械独立的活性。最后，我们证明中性粒细胞结合活性而不是超抗原性是导致在坏死性肺炎兔感染模型中观察到的 SElX 依赖性毒力的原因。综上所述，我们报告了第一个 SAg 的例子，它可以在金黄色葡萄球菌发病过程中操纵人类免疫系统的先天性和适应性。金黄色葡萄球菌是一种细菌病原体，导致医疗保健和社区环境中的一系列疾病类型。这种病原体成功的关键之一是它能够破坏宿主的免疫系统。在这里，我们证明超级抗原（SAg）葡萄球菌肠毒素样毒素X（SElX）通过诱导不受调节的T细胞增殖和抑制中性粒细胞的吞噬作用而有助于免疫逃避。我们观察到，结合中性粒细胞的能力似乎是在兔坏死性肺炎感染模型中观察到的 SElX 依赖性毒性的核心。我们报告了第一个葡萄球菌 SAg 的例子，它具有作用于不同免疫细胞类型的两种独立的免疫调节功能。
Bacterial superantigens (SAgs) cause Vβ-dependent T-cell proliferation leading to immune dysregulation associated with the pathogenesis of life-threatening infections such as toxic shock syndrome, and necrotizing pneumonia. Previously, we demonstrated that staphylococcal enterotoxin-like toxin X (SElX) from Staphylococcus aureus is a classical superantigen that exhibits T-cell activation in a Vβ-specific manner, and contributes to the pathogenesis of necrotizing pneumonia. Here, we discovered that SElX can also bind to neutrophils from human and other mammalian species and disrupt IgG-mediated phagocytosis. Site-directed mutagenesis of the conserved sialic acid-binding motif of SElX abolished neutrophil binding and phagocytic killing, and revealed multiple glycosylated neutrophil receptors for SElX binding. Furthermore, the neutrophil binding-deficient mutant of SElX retained its capacity for T-cell activation demonstrating that SElX exhibits mechanistically independent activities on distinct cell populations associated with acquired and innate immunity, respectively. Finally, we demonstrated that the neutrophil-binding activity rather than superantigenicity is responsible for the SElX-dependent virulence observed in a necrotizing pneumonia rabbit model of infection. Taken together, we report the first example of a SAg, that can manipulate both the innate and adaptive arms of the human immune system during S. aureus pathogenesis. Staphylococcus aureus is a bacterial pathogen responsible for an array of disease types in healthcare and community settings. One of the keys to the success of this pathogen is its ability to subvert the immune system of the host. Here we demonstrate that the superantigen (SAg) staphylococcal enterotoxin-like toxin X (SElX) contributes to immune evasion by inducing unregulated T-cell proliferation, and by inhibition of phagocytosis by neutrophils. We observed that the capacity to bind neutrophils appears to be central to the SElX-dependent toxicity observed in a necrotising pneumonia infection model in rabbits. We report the first example of a staphylococcal SAg with two independent immunomodulatory functions acting on distinct immune cell types.
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29.7
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