Peptide-Based Quorum Sensing Controlling Virulence in Bacillus anthracis

基于肽的群体感应控制炭疽杆菌的毒力

• 批准号: 8706771
• 负责人: Hyunwoo Lee
• 金额: $ 39.88万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706771
• 关键词: Amino Acids; Anthrax Vaccines; Anthrax disease; Antibiotic Therapy; Attenuated; Bacillus anthracis; Bacillus cereus; Bacteria; Binding; Blood; Blood Circulation; Breathing; Cells; Complement; D Glutamate; Development; Disease; Food Poisoning; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Genome; Goals; Growth; Human; Immunity; In Vitro; Infection; Insecta; Knowledge; Lung; Mammals; Modeling; Mus; Names; Nonsense Mutation; Nucleotides; Open Reading Frames; Operon; Pathogenesis; Pattern; Peptides; Physiology; Plasmids; Prevention; Process; RNA Sequences; Regulatory Pathway; Reproduction spores; Research; Resistance; Role; Serum; Specificity; Staging; Structural Genes; System; Systemic infection; Time; Virulence; anthrax toxin; antimicrobial peptide; base; capsule; extracellular; insight; macrophage; member; mortality; mouse model; neutrophil; novel; pathogen; quorum sensing; trait

DESCRIPTION (provided by applicant): Bacillus anthracis is a member of the B. cereus group that includes B. cereus and B. thuringiensis. Three bacterial species share >90% identical genomes at the nucleotide level, but they are differentiated by host specificity and/or disease manifestation. Whereas B. thuringiensis is mainly an insect pathogen and B. cereus causes a nonlethal food poisoning in humans, B. anthracis infections (anthrax) are extremely lethal in mammals. The virulence of B. anthracis has been primarily attributed to its two plasmids pXO1 and pXO2, which carry the structural genes encoding the anthrax toxins and genes involved in the synthesis of the poly-D- glutamate capsule. These virulence plasmids are absent in typical isolates of B. cereus and B. thuringiensis. However, it is also evident that regulatory mechanisms for virulence gene expression are distinct in B. anthracis. PlcR, for example, has been known to be a master virulence regulator in B. cereus and B. thuringiensis, but is nonfunctional in B. anthracis due to a nonsense mutation in plcR. PlcR constitutes a peptide-based quorum sensing system with PapR, which is produced as a pre-propeptide, secreted and processed proteolytically into an active form of PapR. Upon reaching a sufficient extracellular concentration, the active PapR is imported into the cell, in which it binds and activates PlcR, subsequently controlling expression of target virulence genes. To date, whether a peptide-based quorum sensing system exists in B. anthracis is completely unknown. Results from our preliminary study strongly indicate that B. anthracis possesses an as-yet-uncharacterized peptide-based quorum sensing system, named AqsR and AqsP for Anthrax quorum sensing Regulator and Peptide, which appears to be distinct from PlcR-PapR. Inactivation of AqsR-AqsP renders B. anthracis attenuated in a murine model of pulmonary anthrax, suggesting that the AqsR-AqsP system regulates expression of virulence-related genes in B. anthracis. In proposed studies, we will identify genetic components constituting and controlling the AqsR-AqsP quorum sensing system, and identify and characterize AqsR/AqsP-regulated virulence genes. An accomplishment of these goals will establish the AqsR-AqsP quorum sensing as a new virulence regulatory mechanism in B. anthracis, advance our knowledge about the pathophysiology of B. anthracis, and help the development of better anti-anthrax strategies. Moreover, because an intact AqsR-AqsP appears to be conserved in both B. cereus and B. thuringiensis, knowledge obtained in this study will also be applicable to the physiology of the B. cereus group of bacteria.

描述(申请人提供)：炭疽芽孢杆菌是蜡状芽孢杆菌属的成员，包括蜡状芽孢杆菌和苏云金芽孢杆菌。三种细菌在核苷酸水平上拥有90%相同的基因组，但它们因宿主特异性和/或疾病表现而有所区别。苏云金芽胞杆菌主要是一种昆虫病原体，蜡状芽胞杆菌对人类造成非致命性食物中毒，而炭疽杆菌感染(炭疽)对哺乳动物是极其致命的。炭疽杆菌的毒力主要归因于其两个质粒pXO1和pXO2，这两个质粒携带编码炭疽毒素的结构基因和参与合成聚-D-谷氨酸胶囊的基因。在蜡状芽孢杆菌和苏云金芽孢杆菌的典型分离株中不存在这些毒力质粒。然而，同样明显的是，在炭疽杆菌中对毒力基因表达的调控机制是不同的。例如，已知plcR在蜡样芽孢杆菌和苏云金芽孢杆菌中是主要的毒力调节因子，但在炭疽杆菌中由于plcR的无义突变而不起作用。PlcR与PAPR一起构成了一个基于多肽的群体感应系统，PAPR以前体肽的形式产生，分泌并加工成PAPR的活性形式。当达到足够的胞外浓度时，活性PAPR被输入细胞内，在细胞内它结合并激活PlcR，随后控制目标毒力基因的表达。到目前为止，炭疽杆菌中是否存在基于多肽的群体感应系统是完全未知的。我们的初步研究结果有力地表明，炭疽杆菌具有一个基于多肽的群体感应系统，命名为AqsR和AqsP，分别代表炭疽群体感应调节和多肽，这似乎与PlcR-PAPR有所不同。在小鼠肺炭疽模型中，AqsR-AqsP的失活使炭疽杆菌减弱，这表明AqsR-AqsP系统调节了炭疽杆菌毒力相关基因的表达。在拟议的研究中，我们将鉴定组成和控制AqsR-AqsP群体感应系统的遗传成分，并鉴定和鉴定AqsR/AqsP调节的毒力基因。这些目标的实现将建立AqsR-AqsP群体感应作为炭疽菌一种新的毒力调节机制，促进我们对炭疽菌病理生理的了解，并有助于开发更好的抗炭疽病策略。此外，由于完整的AqsR-AqsP似乎在蜡样芽孢杆菌和苏云金芽孢杆菌中都是保守的，本研究获得的知识也将适用于蜡样芽孢杆菌菌群的生理学。