Jiang Xiaowu, Yang Yunkai, Zhou Jingjing, Zhu Lexin, Gu Yuanxing, Zhang Xiaoyan, Li Xiaoliang, Fang Weihuan
Zhejiang University Institute of Preventive Veterinary Medicine, and Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine Zhejiang, China.
Front Cell Infect Microbiol. 2016 Dec 2;6:172. doi: 10.3389/fcimb.2016.00172. eCollection 2016.
type 2 (SS2) is a zoonotic pathogen causing septic infection, meningitis and pneumonia in pigs and humans. SS2 may cause streptococcal toxic shock syndrome (STSS) probably due to excessive release of inflammatory cytokines. A previous study indicated that the gene in the putative type IV-like secretion system (T4SS) within the 89K pathogenicity island specific for recent epidemic strains contributed to the development of STSS. However, the functional basis of VirD4 in STSS remains unclear. Here we show that deletion of led to reduced virulence as shown by about 65% higher LD, lower bacterial load in liver and brain, and lower level of expression of inflammatory cytokines in mice and cell lines than its parent strain. The ΔVirD4 mutant was more easily phagocytosed, suggesting its role as an anti-phagocytic factor. Oxidative stress that mimic bacterial exposure to respiratory burst of phagocytes upregulated expression of . Proteomic analysis identified 10 secreted proteins of significant differences between the parent and mutant strains under oxidative stress, including PrsA, a peptidyl-prolyl isomerase. The SS2 PrsA expressed in caused a dose-dependent cell death and increased expression of proinflammatory IL-1β, IL-6 and TNF-α in murine macrophage cells. Our data provide novel insights into the contribution of the VirD4 factor to STSS pathogenesis, possibly via its anti-phagocytic activity, upregulation of its expression upon oxidative stress and its involvement in increased secretion of PrsA as a cell death inducer and proinflammatory effector.
2型（SS2）是一种人畜共患病原体，可在猪和人类中引起败血症感染、脑膜炎和肺炎。SS2可能由于炎性细胞因子的过度释放而导致链球菌中毒性休克综合征（STSS）。先前的一项研究表明，近期流行菌株特有的89K致病岛内假定的IV型分泌系统（T4SS）中的基因促成了STSS的发展。然而，VirD4在STSS中的功能基础仍不清楚。在此我们表明，与亲本菌株相比，缺失导致毒力降低，表现为半数致死剂量（LD）高约65%、肝脏和大脑中的细菌载量降低以及小鼠和细胞系中炎性细胞因子的表达水平降低。ΔVirD4突变体更容易被吞噬，表明其作为抗吞噬因子的作用。模拟细菌暴露于吞噬细胞呼吸爆发的氧化应激上调了的表达。蛋白质组学分析确定了亲本菌株和突变体菌株在氧化应激下10种分泌蛋白存在显著差异，包括肽基脯氨酰异构酶PrsA。在中表达的SS2 PrsA在鼠巨噬细胞中引起剂量依赖性细胞死亡并增加促炎细胞因子IL-1β、IL-6和TNF-α的表达。我们的数据为VirD4因子对STSS发病机制的贡献提供了新的见解，可能是通过其抗吞噬活性、氧化应激时其表达的上调以及其参与作为细胞死亡诱导剂和促炎效应物的PrsA分泌增加。
