Department of Infectious Disease, Imperial College London, London, United Kingdom
Department of Infectious Disease, Imperial College London, London, United Kingdom.
mSphere. 2019 Oct 9;4(5):e00665-19. doi: 10.1128/mSphere.00665-19.
Nonmenstrual toxic shock syndrome (nmTSS), linked to TSST-1-producing CC30 , is the leading manifestation of toxic shock syndrome (TSS). Due to case rarity and a lack of tractable animal models, TSS pathogenesis is poorly understood. We developed an abscess model in HLA class II transgenic mice to investigate pathogenesis and treatment. TSST-1 sensitivity was established using murine spleen cell proliferation assays and cytokine assays following TSST-1 injection HLA-DQ8 mice were infected subcutaneously with a -positive CC30 methicillin-sensitive clinical TSS-associated isolate. Mice received intraperitoneal flucloxacillin, clindamycin, flucloxacillin and clindamycin, or a control reagent. Abscess size, bacterial counts, TSST-1 expression, and TSST-1 bioactivity were measured in tissues. Antibiotic effects were compared with the effects of control reagent. Purified TSST-1 expanded HLA-DQ8 T-cell Vβ subsets 3 and 13 and instigated cytokine release , confirming TSST-1 sensitivity. TSST-1 was detected in abscesses (0 to 8.0 μg/ml) and draining lymph nodes (0 to 0.2 μg/ml) of infected mice. Interleukin 6 (IL-6), gamma interferon (IFN-γ), KC (CXCL1), and MCP-1 were consistent markers of inflammation during infection. Clindamycin-containing antibiotic regimens reduced abscess size and TSST-1 production. Infection led to detectable TSST-1 in soft tissues, and TSST-1 was detected in draining lymph nodes, events which may be pivotal to TSS pathogenesis. The reduction in TSST-1 production and lesion size after a single dose of clindamycin underscores a potential role for adjunctive clindamycin at the start of treatment of patients suspected of having TSS to alter disease progression. Staphylococcal toxic shock syndrome (TSS) is a life-threatening illness causing fever, rash, and shock, attributed to toxins produced by the bacterium , mainly toxic shock syndrome toxin 1 (TSST-1). TSS was in the past commonly linked with menstruation and high-absorbency tampons; now, TSS is more frequently triggered by other staphylococcal infections, particularly of skin and soft tissue. Investigating the progress and treatment of TSS in patients is challenging, as TSS is rare; animal models do not mimic TSS adequately, as toxins interact best with human immune cells. We developed a new model of staphylococcal soft tissue infection in mice producing human immune cell proteins, rendering them TSST-1 sensitive, to investigate TSS. The significance of our research was that TSST-1 was found in soft tissues and immune organs of mice and that early treatment of mice with the antibiotic clindamycin altered TSST-1 production. Therefore, the early treatment of patients suspected of having TSS with clindamycin may influence their response to treatment.
非经期中毒性休克综合征（nmTSS）与产生 TSST-1 的 CC30 有关，是中毒性休克综合征（TSS）的主要表现形式。由于病例罕见且缺乏可操作的动物模型，TSS 的发病机制尚不清楚。我们在 HLA 类 II 转基因小鼠中开发了脓肿模型，以研究发病机制和治疗方法。使用小鼠脾细胞增殖试验和细胞因子试验在 TSST-1 注射后建立 TSST-1 敏感性 HLA-DQ8 小鼠经皮下感染阳性 CC30 甲氧西林敏感的临床 TSS 相关分离株。小鼠接受腹腔氟氯西林、克林霉素、氟氯西林和克林霉素或对照试剂治疗。在组织中测量脓肿大小、细菌计数、TSST-1 表达和 TSST-1 生物活性。将抗生素作用与对照试剂的作用进行比较。纯化的 TSST-1 扩增了 HLA-DQ8 T 细胞 Vβ 亚群 3 和 13，并引发细胞因子释放，证实了 TSST-1 的敏感性。在感染小鼠的脓肿（0 至 8.0μg/ml）和引流淋巴结（0 至 0.2μg/ml）中检测到 TSST-1。白细胞介素 6（IL-6）、γ干扰素（IFN-γ）、KC（CXCL1）和 MCP-1 是感染过程中炎症的一致标志物。包含克林霉素的抗生素方案可减少脓肿大小和 TSST-1 的产生。感染导致软组织中可检测到 TSST-1，并且在引流淋巴结中检测到 TSST-1，这些事件可能是 TSS 发病机制的关键。在疑似 TSS 患者开始治疗时，单次使用克林霉素可减少 TSST-1 的产生和病变大小，这突出了辅助使用克林霉素改变疾病进展的潜在作用。葡萄球菌性中毒性休克综合征（TSS）是一种危及生命的疾病，可引起发热、皮疹和休克，归因于细菌产生的毒素，主要是毒性休克综合征毒素 1（TSST-1）。过去，TSS 通常与月经和高吸收性卫生巾有关；现在，TSS 更常由其他葡萄球菌感染引起，特别是皮肤和软组织感染。由于 TSS 很少见，因此研究 TSS 患者的进展和治疗具有挑战性；动物模型不能充分模拟 TSS，因为毒素与人类免疫细胞的相互作用最佳。我们开发了一种新的小鼠葡萄球菌软组织感染模型，该模型产生人类免疫细胞蛋白，使它们对 TSST-1 敏感，以研究 TSS。我们的研究意义在于在小鼠的软组织和免疫器官中发现了 TSST-1，并且早期用抗生素克林霉素治疗小鼠改变了 TSST-1 的产生。因此，早期用克林霉素治疗疑似 TSS 的患者可能会影响他们对治疗的反应。
