PDF(Pubmed)
Abstract：
Bacterial pathogens use protein secretion systems to transport virulence factors and regulate gene expression. Among pathogenic mycobacteria, including Mycobacterium tuberculosis and Mycobacterium marinum, the ESAT-6 system 1 (ESX-1) secretion is crucial for host interaction. Secretion of protein substrates by the ESX-1 secretion system disrupts phagosomes, allowing mycobacteria cytoplasmic access during macrophage infections. Deletion or mutation of the ESX-1 system attenuates mycobacterial pathogens. Pathogenic mycobacteria respond to the presence or absence of the ESX-1 system in the cytoplasmic membrane by altering transcription. Under laboratory conditions, the EspM repressor and WhiB6 activator control transcription of specific ESX-1-responsive genes, including the ESX-1 substrate genes. However, deleting the espM or whiB6 gene does not phenocopy the deletion of the ESX-1 substrate genes during macrophage infection by M. marinum. In this study, we identified EspN, a critical transcription factor whose activity is masked by the EspM repressor under laboratory conditions. In the absence of EspM, EspN activates transcription of whiB6 and ESX-1 genes during both laboratory growth and macrophage infection. EspN is also independently required for M. marinum growth within and cytolysis of macrophages, similar to the ESX-1 genes, and for disease burden in a zebrafish larval model of infection. These findings suggest that EspN and EspM coordinate to counterbalance the regulation of the ESX-1 system and support mycobacterial pathogenesis.IMPORTANCEPathogenic mycobacteria, which are responsible for tuberculosis and other long-term diseases, use the ESX-1 system to transport proteins that control the host response to infection and promote bacterial survival. In this study, we identify an undescribed transcription factor that controls the expression of ESX-1 genes and is required for both macrophage and animal infection. However, this transcription factor is not the primary regulator of ESX-1 genes under standard laboratory conditions. These findings identify a critical transcription factor that likely controls expression of a major virulence pathway during infection, but whose effect is not detectable with standard laboratory strains and growth conditions.
摘要：
细菌病原体使用蛋白质分泌系统来转运毒力因子并调节基因表达。在致病性分枝杆菌中，包括结核分枝杆菌和marinum分枝杆菌,ESAT-6系统1（ESX-1）的分泌对于宿主相互作用至关重要。ESX-1分泌系统分泌蛋白质底物会破坏吞噬体，在巨噬细胞感染期间允许分枝杆菌细胞质进入。ESX-1系统的缺失或突变减弱分枝杆菌病原体。致病性分枝杆菌通过改变转录来响应细胞质膜中ESX-1系统的存在或不存在。在实验室条件下,EspM阻遏物和WhiB6激活物控制特定ESX-1反应基因的转录，包括ESX-1底物基因。然而,删除espM或whiB6基因不会在巨噬细胞感染时表现出ESX-1底物基因的缺失。在这项研究中,我们确认了EspN,一种关键转录因子，其活性在实验室条件下被EspM阻遏物掩盖。在没有EspM的情况下,EspN在实验室生长和巨噬细胞感染期间激活whiB6和ESX-1基因的转录。EspN也是巨噬细胞内的M.marinum生长和细胞溶解所独立需要的，类似于ESX-1基因，以及斑马鱼幼虫感染模型中的疾病负担。这些发现表明EspN和EspM协调以抵消ESX-1系统的调节并支持分枝杆菌发病机理。重要致病性分枝杆菌,导致结核病和其他长期疾病的原因，使用ESX-1系统来运输控制宿主对感染的反应并促进细菌存活的蛋白质。在这项研究中,我们确定了一种未描述的转录因子,它控制ESX-1基因的表达,是巨噬细胞和动物感染所必需的.然而,在标准实验室条件下,该转录因子不是ESX-1基因的主要调节因子.这些发现确定了一个关键的转录因子，可能控制感染期间主要毒力途径的表达，但其效果在标准实验室菌株和生长条件下无法检测到。
