Host genes required for P. aeruginosa pathogenesis

本研究的目标是确定哺乳动物宿主在假单胞菌感染期间发挥作用的基因和途径。具体而言，将研究由铜绿假单胞菌（免疫受损患者的机会致病菌）产生的一类蛋白质的作用机制。 这些蛋白质在宿主细胞中通过不同的细胞内机制起作用，但具有共同的递送机制。 四种蛋白质，外切酶S、Y、T和U（ExoS、T、Y和U）由铜绿假单胞菌的大多数临床分离株产生，并通过称为II型分泌途径的接触依赖性机制递送到哺乳动物细胞中。 一旦进入宿主，这些胞外酶操纵宿主信号转导途径，最终导致宿主细胞的细胞毒性或凋亡。 参与这些毒素的传递和活化的宿主因素尚未得到很好的表征。 该提议旨在将新开发的哺乳动物体细胞遗传学工具联合收割机与哺乳动物基因组的可用性相结合，以鉴定有助于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质中的最终活性位点开始。

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.