p38-mediated defense pathway against pore-forming toxins

描述（由申请人提供）：成孔毒素（PFT）是已知的最大一类细菌蛋白毒素，被许多病原菌（例如，金黄色葡萄球菌和化脓性链球菌）引起疾病。这些毒素在细胞膜上穿孔，破坏正常的细胞功能。尽管PFT很重要，但它们如何工作，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有防御能力，这些都知之甚少。最近，线虫秀丽隐杆线虫已成为一个很好的系统，用于研究PFT。利用C.在线虫中，已经证明p38 MAP激酶途径被PFT激活，并且p38途径为动物提供了抵抗PFT攻击的先天防御。此外，p38通路随后被证明也保护哺乳动物细胞免受PFT的侵害，这表明这种防御在C.并扩展了这一关键途径的已知免疫功能。该基金建议跟进这些结果，并利用强大的基因组和遗传工具的C。p38 MAPK信号通路的下游靶点，研究这些靶点在PFT应答中的作用。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PFT的防御可能会提出新的治疗策略，用于处理一系列使用PFT作为关键毒力因子的重要细菌病原体。

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.