权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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）：炭疽芽孢杆菌是蜡样芽孢杆菌群的成员，包括蜡样芽孢杆菌和苏云金芽孢杆菌。三种细菌在核苷酸水平上有90%的基因组相同，但它们因宿主特异性和/或疾病表现而有所区别。苏云金芽孢杆菌主要是一种昆虫病原体，蜡样芽孢杆菌对人类造成非致命性食物中毒，而炭疽芽孢杆菌感染对哺乳动物极为致命。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。这些毒力质粒在典型的蜡样芽孢杆菌和苏云金芽孢杆菌分离株中不存在。然而，同样明显的是，毒力基因表达的调控机制在炭疽芽孢杆菌中是不同的。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，但在炭疽芽孢杆菌中由于PlcR的无意义突变而不起作用。PlcR与PapR构成了一个基于肽的群体感应系统，PapR作为前肽产生，分泌和加工成活性形式的PapR。当达到足够的细胞外浓度时，活性的PapR被导入细胞，在细胞中结合并激活PlcR，随后控制目标毒力基因的表达。迄今为止，在炭疽杆菌中是否存在基于肽的群体感应系统是完全未知的。我们的初步研究结果强烈表明，炭疽芽胞杆菌具有一个尚未被鉴定的基于肽的群体感应系统，命名为AqsR和AqsP（炭疽群体感应调节器和肽），与PlcR-PapR不同。在小鼠肺炭疽模型中，AqsR-AqsP失活可使炭疽杆菌减毒，提示AqsR-AqsP系统调控炭疽杆菌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群体感应系统的遗传成分，并鉴定和表征AqsR/ aqsp调控的毒力基因。这些目标的实现将确立AqsR-AqsP群体感应作为炭疽芽胞杆菌毒力调控的新机制，促进我们对炭疽芽胞杆菌病理生理的认识，并有助于制定更好的抗炭疽策略。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，因此本研究获得的知识也将适用于蜡样芽孢杆菌群的生理。