Cell-cell signaling, gene expression, and horizontal gene transfer in Bacillus

描述(申请人提供)：细胞-细胞信号控制着生物世界中的许多过程，包括发育、发病、生长、转化和交配。信号传递过程通常是由一些细胞产生并被另一些细胞感知的扩散因子(如激素、信息素、神经递质)介导的。除了可扩散的信号分子外，细胞间交流的最亲密形式之一涉及接合和水平基因转移。微生物的交配反应通常是由多肽信息素介导的。该项目的长期目标是了解细胞如何调节基因表达和水平基因转移以响应环境条件，重点是细胞-细胞信号和控制枯草杆菌中可移动遗传元件的调节机制。可移动的遗传元件包括噬菌体、接合质粒和接合转座子，也称为整合和接合元件(ICE)。可移动的遗传元件在进化、基因组可塑性、共生、发病机制和抗生素耐药性的传播等方面发挥着重要作用。尽管它们很重要，但人们对革兰氏阳性生物中冰的调节机制知之甚少。可移动遗传元件ICEBs1是枯草芽孢杆菌中的一个整合和结合元件。它存在于枯草芽孢杆菌的染色体上，并与宿主染色体一起稳定繁殖。ICEBs1基因的表达、切除、复制和交配由细胞-细胞信号反应调节，并在DNA损伤时诱导(SOS反应)。本项目将侧重于ICEBs1调节和功能的机制，这些机制似乎是广泛保守的，而且在革兰氏阳性中并不被很好地理解。该项目包括：阐明保守的反抑制因子和抑制因子介导的诱导机制及其DNA损伤和细胞间信号的调节；确定切除后供体细胞中ICEBs1的复制机制和功能，以及复制如何有助于水平基因转移和ICEBs1的稳定；确定保守的细胞-细胞信号模块在控制其他可移动元件的水平基因转移中的作用。枯草杆菌是一种相对简单、可通过实验获得的微生物，我们对其细胞间信号、基因表达和水平基因转移的研究应该会为许多生物使用的一般机制提供见解。公共卫生相关性：可移动的遗传因素和微生物中的水平基因转移极大地促进了致病机制和抗生素耐药性的传播。这个项目研究了一种常见的可移动遗传元素，这种基因存在于许多不同的生物体中，特别是革兰氏阳性细菌，如金黄色葡萄球菌、肺炎链球菌、粪肠球菌和炭疽杆菌，它们会导致严重的人类疾病。

DESCRIPTION (provided by applicant): Cell-cell signaling controls many processes in the biological world, including development, pathogenesis, growth, transformation, and mating. Signaling processes are often mediated by diffusible factors (e.g., hormones, pheromones, neurotransmitters) that are produced by some cells and sensed by others. In addition to diffusible signaling molecules, one of the most intimate forms of cell-cell communication involves conjugation and horizontal gene transfer. Mating responses in microbes are often mediated by peptide pheromones. The long term goal of this project is to understand how cells modulate gene expression and horizontal gene transfer in response to environmental conditions, with emphasis on cell-cell signaling and the regulatory mechanisms controlling a mobile genetic element in the bacterium Bacillus subtilis. Mobile genetic elements include phages, conjugative plasmids, and conjugative transposons, also known as integrative and conjugative elements (ICEs). Mobile genetic elements play significant roles in evolution, genome plasticity, symbiosis, pathogenesis, and the spread of antibiotic resistance. Despite their importance, relatively little is known about the mechanisms regulating ICEs in Gram-positive organisms. The mobile genetic element ICEBs1 is an integrative and conjugative element in Bacillus subtilis. It resides in the B. subtilis chromosome and is stably propagated with the host chromosome. ICEBs1 gene expression, excision, replication, and mating are regulated by a cell-cell signaling response and induced upon DNA damage (the SOS response). This project will focus on mechanisms of ICEBs1 regulation and function that appear to be broadly conserved and that are not well-understood in Gram-positives. The project includes: elucidation of the mechanisms of induction mediated by a conserved anti-repressor and repressor and their regulation by DNA damage and cell-cell signaling; determination of the mechanisms and functions of replication of ICEBs1 in donor cells after excision and how replication contributes to horizontal gene transfer and stability of ICEBs1; determination of roles of conserved cell-cell signaling modules in the control of horizontal gene transfer in other mobile elements. Our studies on cell-cell signaling, gene expression, and horizontal gene transfer in B. subtilis, a relatively simple, experimentally accessible microbe, should provide insights into general mechanisms used in many organisms. PUBLIC HEALTH RELEVANCE: Mobile genetic elements and horizontal gene transfer in microbes contribute significantly to pathogenesis and the spread of antibiotic resistances. This project investigates a common type of mobile genetic element that is found in many different organisms, especially Gram-positive bacteria exemplified by Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and Bacillus anthracis, that cause serious human disease.