Characterizing the function and regulation of a conserved virulence-associated genetic pathway of pathogenic Alphaproteobacteria

致病性α变形菌保守毒力相关遗传途径的功能和调控特征

• 批准号: 10630575
• 负责人: Jason Eugene Heindl
• 金额: $ 3.15万
• 依托单位: SAINT JOSEPH'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630575
• 关键词: Characterizing; function; regulation; conserved; virulence

PROJECT SUMMARY Pathogenic bacteria employ myriad processes to cause human disease, and these processes include biofilm formation, chemotaxis and motility, and the implementation of secretion systems, all of which ultimately aid in establishing intimate associations between the bacterium and the host. Several medically important bacteria, including some human pathogenic Alphaproteobateria, are extremely difficult to grow, handle, and/or manipulate, and thus, many of the basic virulence mechanisms related to the processes mentioned above are poorly defined in these organisms. Therefore, there are many benefits, including novel therapeutic and vaccine development that may be gleaned from defining broadly conserved bacterial virulence mechanisms. Considering members of the Alphaproteobacteria, the plant pathogen Agrobacterium tumefaciens serves as an exemplary model for studying basic virulence mechanisms that are highly conserved among the Alphaproteobacteria, including those causing human disease. A. tumefaciens is a free-living soil bacterium that senses and responds to signals released from wounded plants, resulting in bacterial chemotaxis toward the wounded plant. A. tumefaciens subsequently employs a type IV secretion system to transfer a T- DNA complex into the cells of the plant. This conjugation event leads to the formation of crown gall tumors, which are severely detrimental to the plant. Preliminary results indicate a LysR-type transcriptional regulator, VtlR (for virulence-associated transcriptional LysR-family regulator) is required for efficient A. tumefaciens-mediated tumor formation. Preliminary data demonstrate that an A. tumefaciens vtlR deletion strain produces fewer and less robust tumors in potatoes compared to the parental strain, and moreover, the vtlR deletion strain exhibits significant defects in biofilm formation. Transcriptomic analyses revealed that VtlR controls the expression of a small regulatory RNA (sRNA) called AbcR1, as well as a multitude of other genes related to conjugation systems, nutrient uptake, and virulence. The VtlR orthologue in the closely related alphaproteobacterium Brucella abortus is required for virulence in an animal model of infection, and thus, VtlR-family regulators are highly conserved and appear to be required for host-bacteria interactions in the Alphaproteobacteria. Therefore, the systematic characterization of VtlR in A. tumefaciens will significantly illuminate the mechanism by which this transcriptional regulator is linked to virulence in Alphaproteobacteria.

项目摘要 病原菌利用无数过程来引起人类疾病，这些过程包括生物膜形成、趋化性和运动性以及分泌系统的实现，所有这些过程都是生物膜形成、趋化性和运动性的结果。 最终有助于在细菌和宿主之间建立密切的联系。几个医学 重要的细菌，包括一些人类致病的α蛋白细菌，极难生长， 处理和/或操纵，因此，许多基本的毒力机制有关的过程 上面提到的在这些生物体中的定义很差。因此，有很多好处，包括新颖 治疗和疫苗的发展，可以收集从定义广泛保守的细菌毒力机制。 考虑到阿尔法变形菌门的成员，植物病原体根癌农杆菌 作为研究基本毒力机制的示范模型， α变形菌，包括那些引起人类疾病的。A.根癌农杆菌是一种自由生活的土壤细菌，它能感知并响应受伤植物释放的信号，从而产生细菌的趋化性 受伤的植物。A.根癌农杆菌随后使用IV型分泌系统将T- DNA复合体进入植物细胞。这种接合事件导致冠瘿瘤的形成， 这对植物非常有害。 初步结果表明，一个LysR型转录调控因子，VtlR（毒力相关转录LysR家族调控因子）是高效A. tumefaciens介导的肿瘤形成。初步数据表明，A.根癌农杆菌vtlR缺失菌株在大肠杆菌中产生更少和更不健壮的肿瘤。 与亲本菌株相比，马铃薯中vtlR缺失菌株表现出显着缺陷 在生物膜形成中。转录组学分析显示，VtlR控制称为AbcR 1的小调控RNA（sRNA）的表达，以及与接合系统、营养吸收和毒力相关的许多其他基因。密切相关的α蛋白杆菌流产布氏杆菌中的VtlR直系同源物 是感染动物模型中毒力所需的，因此，VtlR家族调节因子是高度保守的，并且似乎是α变形菌中宿主-细菌相互作用所需的。因此 对A.根瘤菌将显著阐明 这种转录调节因子与α变形菌中的毒力有关。