p38-mediated defense pathway against pore-forming toxins

描述（由申请人提供）：成孔毒素（pft）是已知最大的一类细菌蛋白毒素，被许多致病菌（如金黄色葡萄球菌和化脓性链球菌）利用来致病。这些毒素会在细胞膜上打洞，破坏正常的细胞功能。尽管它们很重要，但pft是如何工作的，宿主细胞是如何对它们做出反应的，以及动物细胞是否对这种形式的攻击有防御能力，人们知之甚少。最近，秀丽隐杆线虫已经成为研究pft的一个很好的系统。在秀丽隐杆线虫中，p38 MAP激酶途径被PFT激活，p38途径为动物抵抗PFT的攻击提供了先天防御。此外，p38通路随后被证明也能保护哺乳动物细胞免受pft的侵害，这表明这种防御在秀丽隐杆线虫和哺乳动物之间是保守的，并扩展了这一关键通路的已知免疫功能。本基金拟继续研究这些结果，利用线虫强大的基因组和遗传工具，全面剖析在PFT反应中激活p38 MAPK通路所需的宿主基因，揭示p38 MAPK通路执行防御程序的下游靶点，研究这些线虫p38防御通路基因在哺乳动物细胞防御PFT中的作用。并研究p38通路保护动物细胞免受PFT侵袭的生理机制。了解p38途径如何控制对PFTs的防御可能会为处理一系列使用PFTs作为关键毒力因子的重要细菌病原体提供新的治疗策略。

DESCRIPTION (provided by applicant): Pore-forming toxins (PFTs) are the single largest class of bacterial protein toxins known and are employed by many pathogenic bacteria (e.g., Staphylococcus aureus and Streptococcus pyogenes) to cause disease. These toxins punch holes in cell membranes and disrupt normal cell functions. Despite their importance, how PFTs work, how host cells respond to them, and whether or not animal cells have a defense against this form of attack are poorly understood. Recently, the nematode Caenorhabditis elegans has emerged as an excellent system for studying PFTs. Using C. elegans, it has been demonstrated that the p38 MAP kinase pathway is activated by PFT and that the p38 pathway provides an innate defense for the animal against attack by PFTs. Furthermore, the p38 pathway was subsequently shown to also protect mammalian cells against PFTs, suggesting this defense is conserved between C. elegans and mammals and expanding the known immunological functions of this key pathway. This grant proposes to follow up these results and utilize the powerful genomic and genetic tools of C. elegans to globally dissect what host genes are needed to activate the p38 MAPK pathway in response to PFT, to uncover the downstream targets of the p38 MAPK pathway that execute the defensive program, to study the role of these C. elegans p38 defense pathway genes in the defense of mammalian cells against PFT, and to study the physiological mechanisms by which the p38 pathway defends animal cells against PFT. Understanding how the p38 pathway controls defense against PFTs is likely to suggest new therapeutic strategies for dealing with a range of important bacterial pathogens that use PFTs as key virulence factors.