Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
mBio. 2019 Mar 19;10(2):e00214-19. doi: 10.1128/mBio.00214-19.
Mucosal and skin tissues form barriers to infection by most bacterial pathogens. causes diseases across these barriers in part dependent on the proinflammatory properties of superantigens. We showed, through use of a CRISPR-Cas9 CD40 knockout, that the superantigens toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins (SEs) B and C stimulated chemokine production from human vaginal epithelial cells (HVECs) through human CD40. This response was enhanced by addition of antibodies against CD40 through an unknown mechanism. TSST-1 was better able to stimulate chemokine (IL-8 and MIP-3α) production by HVECs than SEB and SEC, suggesting this is the reason for TSST-1's exclusive association with menstrual TSS. A mutant of TSST-1, K121A, caused TSS in a rabbit model when administered vaginally but not intravenously, emphasizing the importance of the local vaginal environment. Collectively, our data suggested that superantigens facilitate infections by disruption of mucosal barriers through their binding to CD40, with subsequent expression of chemokines. The chemokines facilitate TSS and possibly other epithelial conditions after attraction of the adaptive immune system to the local environment. Menstrual toxic shock syndrome (TSS) is a serious infectious disease associated with vaginal colonization by producing the exotoxin TSS toxin 1 (TSST-1). We show that menstrual TSS occurs after TSST-1 interaction with an immune costimulatory molecule called CD40 on the surface of vaginal epithelial cells. Other related toxins, where the entire family is called the superantigen family, bind to CD40, but not with a high-enough apparent affinity to cause TSS; thus, TSST-1 is the only exotoxin superantigen associated. Once the epithelial cells become activated by TSST-1, they produce soluble molecules referred to as chemokines, which in turn facilitate TSST-1 activation of T lymphocytes and macrophages to cause the symptoms of TSS. Identification of small-molecule inhibitors of the interaction of TSST-1 with CD40 may be useful so that they may serve as additives to medical devices, such as tampons and menstrual cups, to reduce the incidence of menstrual TSS.
黏膜和皮肤组织形成了抵御大多数细菌病原体感染的屏障。 某些细菌病原体能够突破这些屏障引发疾病，部分原因是它们具有超抗原的促炎特性。我们通过使用 CRISPR-Cas9 CD40 敲除技术发现，超抗原中毒性休克综合征毒素 1（TSST-1）和葡萄球菌肠毒素（SE）B 和 C 通过人 CD40 刺激人阴道上皮细胞（HVEC）产生趋化因子。通过未知机制，添加针对 CD40 的抗体可增强这种反应。与 SEB 和 SEC 相比，TSST-1 能够更好地刺激 HVEC 产生趋化因子（IL-8 和 MIP-3α），这表明这是 TSST-1 与月经 TSS 唯一相关的原因。TSST-1 的突变体 K121A，经阴道给药可在兔模型中引起 TSS，但静脉内给药则不能，这强调了局部阴道环境的重要性。总之，我们的数据表明，超抗原通过与 CD40 结合破坏黏膜屏障，从而促进感染，随后表达趋化因子。趋化因子通过吸引适应性免疫系统进入局部环境，促进 TSS 和其他上皮疾病的发生。月经性中毒性休克综合征（TSS）是一种严重的传染病，与 产生的外毒素 TSS 毒素 1（TSST-1）阴道定植有关。我们表明，月经 TSS 发生在 TSST-1 与阴道上皮细胞表面的免疫共刺激分子 CD40 相互作用之后。其他相关毒素，整个家族被称为超抗原家族，与 CD40 结合，但结合亲和力不足以引起 TSS；因此，TSST-1 是唯一与外毒素超抗原相关的毒素。一旦上皮细胞被 TSST-1 激活，它们就会产生可溶性分子，称为趋化因子，反过来又促进 TSST-1 激活 T 淋巴细胞和巨噬细胞，从而引起 TSS 的症状。识别 TSST-1 与 CD40 相互作用的小分子抑制剂可能有用，因此它们可以作为医疗设备（如卫生棉条和月经杯）的添加剂，以降低月经 TSS 的发病率。
