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

描述（由申请人提供）：志贺氏菌属是志贺氏菌病（细菌性痢疾的一种形式）的专性细胞内病原体和病原体，每年导致全球约110万人死亡。此外，志贺氏菌被认为是生物恐怖主义的B型病原体。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，它们复制并招募肌动蛋白丝，以便在这些细胞内定向运动，并随后侵入邻近细胞。志贺氏菌外膜蛋白IcsA对志贺氏菌的发病机制至关重要，因为它是肌动蛋白丝募集所需的唯一细菌蛋白。IcsA在一个220千碱基的毒力质粒上表达，存在于所有志贺氏菌中。此外，IcsA的独特之处在于它的目标和限制在细菌的旧极。初步研究表明，IcsA的不对称分布与志贺菌在结肠上皮细胞内的定向运动及其向未感染细胞的有效传播直接相关。因此，了解IcsA的表达机制，针对杆菌的老极点，在极点分泌和维持，对于解决志贺氏菌的致病性质是重要的。本应用程序中提出的实验包括鉴定和分析一个全局调节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。

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.