Mechanisms and consequence of helical shape generation in Helicobacter pylori

细菌有多种形式，它们可以增强运动性、生物膜的形成、营养吸收和 发病机制。然而，形状的这些功能后果还没有得到很好的研究，部分原因是 缺乏操纵细菌细胞形状的工具。探索形态(细胞形状)如何驱动功能(辐射 不同的利基)，我们必须首先了解形状是如何产生的。细菌的形状从球状到 从杆状到螺旋状的所有物质都来自相同的细胞壁聚合物：肽聚糖(PG)。PG墙围绕着细胞以 包含充气压力。该领域的主要假说认为，不同的形状来自不同的图案 PG的合成。事实上，直杆的大肠杆菌和弯曲的新月弯杆菌和霍乱弧菌 杆状，需要细胞骨架蛋白来调节它们的PG合成模式。创造螺旋细胞的机制， 在细菌的多个谱系中都有发现，但尚未阐明。 幽门螺杆菌已经成为研究螺旋形状的主要模型。这种细菌顽强地 定植于人的胃部，引起慢性炎症和消化性溃疡等临床病理。 仅次于2012年世界第三大癌症死亡率--胃癌[2]。我们分离出了稳定的突变体 非螺旋形状，我们的工作证明了它们在胃定植中的缺陷，提出了第一个 细胞形状和细菌感染性之间存在联系的实验证据现已扩展到其他 细菌(弧菌、弯曲杆菌)[3-5]。然而，我们对……的重要性只有粗略的认识。 最初感染时的形状，不了解改变的形状如何影响长期定居，生态位 获得性，或宿主免疫反应。 此外，幽门螺杆菌保持螺旋形状的策略与迄今研究的细菌有很大不同。 我们的五个形状突变映射到确认的PG水解酶，这表明了一个螺旋形状产生的模型 来自PG的结构修饰，而不是PG合成的调节[5-7]。这些水解酶的同系物 可以在几个变形杆菌类中发现，其中大多数是弯曲/螺旋的，这表明其他细菌 也可以直接修改PG以实现曲率和扭曲[5，8，9]。 指导这一提议的主要假设是空间定位的PG水解酶促进幽门螺杆菌 螺旋形状，允许从非螺旋细菌和底层中分离出不同的生态位 持续性感染。我们收集的非螺旋突变体提供了探索 细菌中螺旋细胞形态产生和维持的机制以及细胞的功能作用(S) 形成了利基获取和持久的殖民。 对螺旋细胞形状的原因和后果的更完整的理解可以阐明 幽门螺杆菌和其他弯曲和螺旋病原体的新治疗靶点，从而将进一步 NIAID了解和治疗传染病的使命。

Bacteria come in many shapes, which may enhance motility, biofilm formation, nutrient uptake, and pathogenesis. However, these functional consequences of shape have not been well studied, owing in part to a paucity of tools to manipulate bacterial cell shape. To probe how form (cell shape) drives function (radiation to diverse niches), we must first understand how shape is generated. Bacterial shapes varying from spheres to rods to helices all arise from the same cell wall polymer: peptidoglycan (PG). The PG wall surrounds the cell to contain turgor pressure. The major hypothesis in the field holds that diverse shapes arise from different patterns of PG synthesis. Indeed Escherichia coli, a straight rod, and Caulobacter crescentus and Vibrio cholerae, curved rods, require cytoskeletal proteins to modulate their PG synthesis patterns. Mechanisms that create helical cells, seen in multiple lineages of bacteria, have not been elucidated. Helicobacter pylori has emerged as the leading model for the study of helical shape. This bacterium persistently colonizes the human stomach causing chronic inflammation and clinical pathologies ranging from peptic ulcers to gastric cancer, the world’s third leading cause of cancer mortality in 2012 [2]. We isolated mutants with stable non-helical shapes, and our work demonstrating their defects in stomach colonization presented the first experimental evidence for a link between cell shape and bacterial infectivity that has now been extended to other bacteria (Vibrio, Campylobacter) [3-5]. However, we only have a cursory understanding of the importance of shape in initial infection and do not understand how altered shape impacts long-term colonization, niche acquisition, or host immune responses. Furthermore, H. pylori’s strategy for maintaining helical shape differs significantly from bacteria studied thus far. Five of our shape mutants map to confirmed PG hydrolases suggesting a model whereby helical shape arises from structural modification of PG rather than modulation of PG synthesis [5-7]. Homologues of these hydrolases can be found in several Proteobacteria classes, most of which are curved/helical, indicating that other bacteria may also employ direct modification of the PG to achieve curvature and twist [5, 8, 9]. The main hypothesis that guides this proposal is that spatially localized PG hydrolases promote H. pylori helical shape, which allows colonization of distinct niches from non-helical bacteria and underlies persistent infection. Our collection of non-helical mutants provides unique opportunities to explore the mechanisms of helical cell shape generation and maintenance in bacteria as well as the functional role(s) of cell shape in niche acquisition and persistent colonization. A more complete understanding of the causes and consequences of helical cell shape could elucidate new therapeutic targets in H. pylori and other curved and helical pathogens, and will thus further the mission of NIAID to understand and treat infectious diseases.