The molecular mechanisms for the unipolar surface expression of IcsA of Shigella

描述(申请人提供)：志贺氏菌属。是志贺氏菌病(细菌性痢疾的一种形式)的专有细胞内病原体和病原体，每年在全世界造成约110万人死亡。此外，志贺氏菌被认为是生物恐怖主义的B型毒剂。志贺氏菌的发病机制涉及结肠上皮细胞的侵袭。一旦细菌进入细胞，它们就会复制和招募肌动蛋白细丝，以便在这些细胞内定向移动，并随后入侵邻近的细胞。志贺氏菌外膜蛋白ICSA是志贺氏菌致病所必需的，因为它是肌动蛋白细丝募集所需的唯一细菌蛋白。ICSA在一个大的220kb的毒力质粒上表达，在所有种类的志贺氏菌中都存在。此外，ICSA的独特之处在于它的靶点和限制在细菌的老极点。初步研究表明，ICSA的不对称分布与志贺氏菌在结肠上皮细胞内的定向移动及其向未感染细胞的有效传播直接相关。因此，了解ICSA表达、针对旧杆状杆菌、在杆状杆菌分泌和维持的机制，对于解决志贺氏菌的致病性质是重要的。本申请中提出的实验涉及鉴定和分析全球调节ICSA表达的染色体基因，以及鉴定定义ICSA的假定极性受体的蛋白质。 与公共卫生相关：提案中陈述的目标是识别和分析染色体基因，这些基因在全球范围内调节ICSA的表达，并定义ICSA蛋白的假定极性受体。成功完成上述目标应有助于更好地了解志贺氏菌如何对环境做出反应以激活毒力因子，以及ICSA如何针对单个细菌的某个位置，从而使细菌能够最有效地从一个结肠上皮细胞传播到邻近细胞。这样的理解应该导致能够扰乱这些过程的治疗性药物或疫苗的开发。

DESCRIPTION (provided by applicant): Shigella spp. are obligate intracellular pathogens and causative agents of shigellosis (a form of bacillary dysentery) that causes an estimated 1.1 million deaths worldwide per annum. Furthermore, Shigella has been cited as a Type B agent of bioterrorism. The pathogenesis of Shigella involves the invasion of colonic epithelial cells. Once the bacteria have entered a cell they replicate and recruit actin filaments for directional movement within these cells and for subsequent invasion of adjacent cells. The Shigella outer membrane protein, IcsA is essential to Shigella pathogenesis in that this is the sole bacterial protein required for the recruitment of actin filaments. IcsA is expressed on a large 220- kilobase virulence plasmid found in all species of Shigella. Furthermore, IcsA is unique in that it is targeted and restricted to the old pole of the bacterium. Preliminary studies indicate that the asymmetrical distribution of IcsA is directly correlated with directional movement of Shigella within colonic epithelial cells and its efficient dissemination to uninfected cells. Therefore an understanding of the mechanisms by which IcsA is expressed, targeted to the old pole of the bacillus, secreted and maintained at the pole is important in addressing the pathogenic nature of Shigella. Experiments proposed in this application involve the identification and analysis of a chromosomal gene that globally regulates the expression of icsA and the identification of proteins that define a putative polar receptor for the IcsA. PUBLIC HEALTH RELEVANCE: The goals stated in the proposal are to identify and analyze chromosomal genes that globally regulate the expression of icsA and that define a putative polar receptor for the IcsA protein. Successful completion of the goals stated above should aid in better understanding how Shigella respond to the environment to activate virulence factors and how IcsA is targeted to a location in an individual bacterium such that the bacteria can most efficiently spread from one colonic epithelial cell to adjacent cells. Such understanding should lead to the development of therapeutic drugs or vaccines that can disrupt these processes.