p38-mediated defense pathway against pore-forming toxins

描述(申请人提供)：成孔毒素(PFT)是已知的最大一类细菌蛋白毒素，被许多致病细菌(如金黄色葡萄球菌和化脓性链球菌)用来致病。这些毒素在细胞膜上打洞，扰乱正常的细胞功能。尽管它们很重要，但PFT是如何工作的，宿主细胞如何对它们做出反应，以及动物细胞是否对这种形式的攻击具有防御能力，人们对此知之甚少。最近，线虫秀丽线虫已经成为研究PFTs的一个很好的系统。利用线虫，已经证明p38 MAP激酶通路被PFT激活，并且p38通路为动物提供了一种固有的防御PFTs攻击的能力。此外，p38途径随后被证明也保护哺乳动物细胞免受PFTs的攻击，这表明这种防御在线虫和哺乳动物之间是保守的，并扩大了这一关键途径的已知免疫学功能。本基金建议跟进这些结果，并利用线虫强大的基因组和遗传学工具，在全球范围内剖析需要哪些宿主基因来激活p38 MAPK途径以响应PFT，揭示执行防御程序的p38 MAPK途径的下游靶标，研究这些线虫p38防御途径基因在哺乳动物细胞防御PFT中的作用，并研究p38途径防御动物细胞对抗PFT的生理机制。了解p38通路如何控制对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.