Host genes required for P. aeruginosa pathogenesis

这项研究的目的是确定在假单胞菌感染过程中发挥作用的哺乳动物宿主的基因和途径。具体地说，将研究由铜绿假单胞菌产生的一类蛋白质的作用机制，铜绿假单胞菌是免疫低下患者的一种机会病原体。这些蛋白质在宿主细胞中通过不同的细胞内机制发挥作用，但共享共同的递送机制。大多数铜绿假单胞菌临床分离株都能产生四种外酶S、Y、T和U(exOS、T、Y和U)，它们通过一种接触依赖的机制被运送到哺乳动物细胞中，这种机制被称为II型分泌途径。一旦进入宿主，这些外源酶就会操纵宿主信号转导通路，最终导致宿主细胞的细胞毒性或凋亡。参与这些毒素传递和激活的宿主因素尚未得到很好的描述。这项建议旨在结合新开发的哺乳动物体细胞遗传学工具和哺乳动物基因组的可用性，以确定有助于EXOS、T、Y和U功能的宿主因子，从它们通过细菌III型分泌机制输出到它们在哺乳动物细胞细胞质中的最终活性部位开始。

The goal of this research is to identify genes and pathways of mammalian host that play a role during Pseudomonas infections. Specifically, the mechanism of action of a class of proteins produced by Pseudomonas aeruginosa, an opportunistic pathogen of immuno- compromised patients, will be studied. These proteins act by distinct intracellular mechanisms in the host cell, but share a common delivery mechanism. Four proteins, exoenzymes S, Y, T and U (ExoS, T, Y and U) are produced by most clinical isolates of P. aeruginosa and are delivered into mammalian cells by a contact-dependent mechanism, called the Type II secretion pathway. Once in the host, these exoenzymes manipulate host signal transduction pathways eventually leading to either host cell cytotoxicity or apoptosis. The host factors that are involved in the delivery and activation of these toxins are not well characterized. This proposal aims to combine the newly developed tools of mammalian somatic cell genetics and the availability of the mammalian genomes to identify host factors that contribute to the function of ExoS, T, Y and U, starting with their export by the bacterial type III secretion machinery to their final site of activity in the mammalian cell cytoplasm.