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

基本信息

批准号：
8899415
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899415
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 differential expression extracellular insight macrophage member mortality mouse model neutrophil novel pathogen quorum sensing trait transcriptome sequencing

项目摘要

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（由申请人提供）：炭疽芽孢杆菌是蜡状芽孢杆菌组的成员，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具有> 90％相同的基因组，但它们通过宿主特异性和/或疾病表现而区分。苏云金芽孢杆菌主要是一种昆虫病原体，蜡状芽孢杆菌在人类中引起非致命的食物中毒，而嗜血芽孢杆菌感染（炭疽）在哺乳动物中极具致命性。炭疽芽孢杆菌的毒力主要归因于其两个质粒PXO1和PXO2，这些质粒携带着炭疽毒素和基因涉及聚谷氨酸胶囊的结构基因。这些毒力质粒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。然而，很明显，毒力基因表达的调节机制在炭疽芽孢杆菌中是不同的。例如，众所周知，PLCR是蜡状芽孢杆菌和苏云金芽孢杆菌中的主要毒力调节剂，但由于PLCR中的胡说八道突变，在炭疽芽孢杆菌中是非功能的。 PLCR用PAPR构成基于肽的群体传感系统，PAPR是作为蛋白肽的前分泌和加工成活性PAPR的蛋白水解生产的。在达到足够的细胞外浓度后，将活性的PAPR导入到细胞中，在该细胞中结合并激活PLCR，随后控制靶毒力基因的表达。迄今为止，炭疽芽孢杆菌中是否存在基于肽的群体传感系统是完全未知的。我们的初步研究的结果强烈表明，炭疽芽孢杆菌具有基于肽的肽群体传感系统，称为AQSR和AQSP，用于炭疽群体群体传感调节剂和肽，这似乎与PLCR-PAPR不同。 AQSR-AQSP的灭活使植物b。炭疽病b。在肺炭疽的鼠模型中衰减的炭疽菌，这表明AQSR-AQSP系统调节炭疽杆菌中毒力相关基因的表达。在拟议的研究中，我们将确定构成和控制AQSR-AQSP Quorum传感系统的遗传成分，并识别和表征AQSR/AQSP调节的毒力基因。这些目标的实现将确定AQSR-AQSP法定人数在炭疽芽孢杆菌中作为一种新的毒力调节机制，促进我们对炭疽芽孢杆菌病理生理学的了解，并帮助发展更好的抗性策略。此外，由于完整的AQSR-AQSP似乎在蜡状芽孢杆菌和苏云金芽孢杆菌中都是保守的，因此在这项研究中获得的知识也适用于蜡链球菌细菌的生理学。