Bacterial type III secretion systems: from structure to function

许多致病性革兰氏阴性菌具有微小的细胞表面局部注射装置，称为III型分泌系统（t3ss），专门将毒力介导蛋白输送到真核宿主的细胞中。通过注射针的末端，这些装置直接感知到与宿主细胞的物理接触，并激活细菌内部的分泌机制。我们希望了解这种最初的串扰是如何在机制和分子水平上发生的，它代表了两种非常不同类型的生物体之间令人着迷的复杂信号转导事件。我们的工作将直接帮助了解志贺菌、沙门氏菌、假单胞菌、衣原体和耶尔森氏菌等人类病原体是如何首先与宿主细胞相互作用的，这些细菌都携带t3ss。所涉及的一些蛋白质是唯一已知的针对这些生物体的保护性抗原，对它们的深入研究可能会为疫苗设计带来新的机会。精确地确定它们的分子作用也可能导致治疗药物的发展。抗生素耐药性不断增加，并在不同细菌种类之间迅速传播，而发现的化学新类型越来越少。新的抗微生物药物的合理设计可以从筛选化学文库开始，但这首先需要确定合适的生物学靶点。这只能通过增加特异性和保守的毒力因子如何运作的基本机制知识来实现。这正是我们打算做的。携带t3ss的细菌不仅是人类传染病的主要原因，也是动物和植物传染病的主要原因，甚至在发达国家也是如此。由于T3SS是如此广泛和保守，我们的发现可能适用于预防/治疗人类，动物和作物植物的许多疾病。

Many pathogenic Gram negative bacteria possess tiny cell surface-localised injection devices, called type III secretion systems (T3SSs), dedicated to the delivery of virulence- mediating proteins into the cells of their eukaryotic hosts. Through the distal tip of their injection needle, these devices directly sense physical contact with host cells and activate the secretion machinery within the bacterium. We wish to understand how this initial cross-talk, which represents a fascinatingly complex signal transduction event between two very different types of organism, occurs at the mechanistic and molecular level.Our work will directly help understand how bacteria such as Shigella, Salmonella, Pseudomonas, Chlamydia and Yersinia, human pathogens which all carry T3SSs, first interact with the cells of their host. Some of the proteins involved are the only known protective antigens against these organisms, and their in-depth study may generate new opportunities for vaccine design. Precisely defining their molecular roles may also lead to the development of therapeutic drugs. Antibiotic resistance is ever increasing and spreading rapidly between different bacterial species, while fewer and fewer chemically new types are being discovered. The rational design of new anti-microbial drugs can be initiated from screening chemical libraries but this first requires that appropriate biological targets are defined. This can only be achieved by increasing basic mechanistic knowledge of how specific and conserved virulence factors operate. This is precisely what we propose to do.T3SSs carrying-bacteria are a major cause of infectious diseases not only in humans, but also in animals and plants, even in the developed world. As T3SS are so wide-spread and conserved, what we find may be applicable to preventing/treating numerous diseases in humans, animals and crops plants.