Anderson Mark, Ohr Ryan Jay, Aly Khaled A, Nocadello Salvatore, Kim Hwan K, Schneewind Chloe E, Schneewind Olaf, Missiakas Dominique
Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
Department of Microbiology, University of Chicago, Chicago, Illinois, USA
J Bacteriol. 2016 Dec 13;199(1). doi: 10.1128/JB.00527-16. Print 2017 Jan 1.
Staphylococcus aureus, an invasive pathogen of humans and animals, requires a specialized ESS pathway to secrete proteins (EsxA, EsxB, EsxC, and EsxD) during infection. Expression of ess genes is required for S. aureus establishment of persistent abscess lesions following bloodstream infection; however, the mechanisms whereby effectors of the ESS pathway implement their virulence strategies were heretofore not known. Here, we show that EssE forms a complex with other members of the ESS secretion pathway and its substrates, promoting the secretion of EsxA, EsxB, EsxC, EsxD, and EssD. During bloodstream infection of mice, the S. aureus essE mutant displays defects in host cytokine responses, specifically in the production of interleukin-12 (IL-12) (p40/p70) and the suppression of RANTES (CCL5), activators of T1 T cell responses and immune cell chemotaxis, respectively. Thus, essE-mediated secretion of protein effectors via the ESS pathway may enable S. aureus to manipulate host immune responses by modifying the production of cytokines.
Staphylococcus aureus and other firmicutes evolved a specialized ESS (EsxA/ESAT-6-like secretion system) pathway for the secretion of small subsets of proteins lacking canonical signal peptides. The molecular mechanisms for ESS-dependent secretion and their functional purpose are still unknown. We demonstrate here that S. aureus EssE functions as a membrane assembly platform for elements of the secretion machinery and their substrates. Furthermore, S. aureus EssE-mediated secretion contributes to the production or the suppression of specific cytokines during host infection, thereby modifying immune responses toward this pathogen.
金黄色葡萄球菌是人和动物的一种侵袭性病原体，在感染过程中需要一种特殊的ESS途径来分泌蛋白质（EsxA、EsxB、EsxC和EsxD）。在血流感染后，金黄色葡萄球菌建立持续性脓肿病变需要ess基因的表达；然而，ESS途径的效应器实施其毒力策略的机制此前尚不清楚。在这里，我们表明EssE与ESS分泌途径的其他成员及其底物形成复合物，促进EsxA、EsxB、EsxC、EsxD和EssD的分泌。在小鼠血流感染期间，金黄色葡萄球菌essE突变体在宿主细胞因子反应方面存在缺陷，特别是在白细胞介素-12（IL-12）（p40/p70）的产生以及RANTES（CCL5）的抑制方面，RANTES分别是T1 T细胞反应和免疫细胞趋化性的激活剂。因此，essE通过ESS途径介导的蛋白质效应器分泌可能使金黄色葡萄球菌通过改变细胞因子的产生来操纵宿主免疫反应。
金黄色葡萄球菌和其他厚壁菌进化出一种特殊的ESS（EsxA/ESAT-6样分泌系统）途径，用于分泌缺乏典型信号肽的一小部分蛋白质。ESS依赖性分泌的分子机制及其功能目的仍然未知。我们在此证明，金黄色葡萄球菌EssE作为分泌机制元件及其底物的膜组装平台发挥作用。此外，金黄色葡萄球菌EssE介导的分泌有助于在宿主感染期间产生或抑制特定细胞因子，从而改变对该病原体的免疫反应。
