Host genes required for P. aeruginosa pathogenesis

本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。具体而言，将研究一类由铜绿假单胞菌产生的蛋白质的作用机制，铜绿假单胞菌是免疫功能低下患者的机会致病菌。这些蛋白在宿主细胞中通过不同的细胞内机制起作用，但有一个共同的传递机制。大多数临床分离的铜绿假单胞菌产生四种蛋白，即外泌酶S， Y， T和U (ExoS， T， Y和U)，并通过一种称为II型分泌途径的接触依赖机制传递到哺乳动物细胞中。一旦进入宿主，这些外泌酶操纵宿主信号转导途径，最终导致宿主细胞毒性或凋亡。参与这些毒素的传递和激活的宿主因子还没有很好地表征。本研究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，从细菌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，鉴定有助于ExoS， T， Y和U功能的宿主因子。

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.