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

性状（由申请方提供）：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，估计每年在全世界造成110万人死亡。此外，志贺氏菌已被列为生物恐怖主义的B型因子。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，并随后侵入相邻细胞。志贺氏菌外膜蛋白，IcsA是志贺氏菌致病所必需的，因为这是唯一的细菌蛋白质所需的招募肌动蛋白丝。ICSA在所有志贺菌属物种中发现的大的220-β-内酰胺酶毒力质粒上表达。此外，IcsA的独特之处在于它靶向并限制于细菌的旧极。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运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、靶向芽孢杆菌的旧极、分泌和维持在该极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面调节icsA表达的染色体基因，以及鉴定定义ICsA的推定极性受体的蛋白质。 公共卫生相关性：该提案中所述的目标是鉴定和分析染色体基因，这些基因在全球范围内调节icsA的表达，并定义IcsA蛋白的推定极性受体。上述目标的成功完成将有助于更好地理解志贺氏菌如何响应环境以激活毒力因子，以及IcsA如何靶向单个细菌中的位置，以便细菌可以最有效地从一个结肠上皮细胞扩散到相邻细胞。这种理解应该导致治疗药物或疫苗的开发，可以破坏这些过程。

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.