Mechanisms and consequence of helical shape generation in Helicobacter pylori

幽门螺杆菌螺旋形状产生的机制和后果

• 批准号: 10593360
• 负责人: Nina Salama
• 金额: $ 47.57万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593360
• 关键词: Mechanisms; consequence; helical; shape; generation

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.

细菌有多种形状，这可能会增强运动性、生物膜形成、营养吸收和 发病机制然而，这些形状的功能后果尚未得到很好的研究，部分原因是 缺乏操纵细菌细胞形状的工具。为了探索形式（细胞形状）如何驱动功能（辐射）， 不同的壁龛），我们必须首先了解形状是如何产生的。细菌形状从球形到 从棒状体到螺旋体都来自于相同的细胞壁聚合物：肽聚糖（PG）。PG壁围绕细胞， 包含膨压。该领域的主要假设认为，不同的形状来自不同的模式 PG合成。事实上，大肠杆菌，直杆，新月柄杆菌和霍乱弧菌，弯曲 杆，需要细胞骨架蛋白来调节其PG合成模式。产生螺旋细胞的机制， 在多种细菌谱系中可见，尚未阐明。 幽门螺杆菌已成为研究螺旋形状的主要模型。这种细菌持续地 定植于人胃，引起慢性炎症和临床病理， 胃癌是2012年全球第三大癌症死亡原因[2]。我们分离出了具有稳定 非螺旋形状，我们的工作证明了它们在胃定植中的缺陷， 细胞形状和细菌感染性之间的联系的实验证据，现在已经扩展到其他 细菌（弧菌，弯曲杆菌）[3-5]。然而，我们对以下问题的重要性只有粗略的了解： 形状在初始感染，不了解如何改变形状影响长期殖民，生态位 获得或宿主免疫反应。 此外，H.幽门螺杆菌维持螺旋形状的策略与迄今为止研究的细菌有很大不同。 我们的五个形状突变体映射到确认的PG水解酶，表明螺旋形状出现的模型 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 可以在几个变形菌纲中找到，其中大多数是弯曲/螺旋状的，这表明其他细菌 也可以采用直接修改PG来实现曲率和扭曲[5，8，9]。 指导这一建议的主要假设是，空间定位的PG水解酶促进H。幽门 螺旋形状，这使得非螺旋细菌能够在不同的小生境中定植， 持续感染我们收集的非螺旋突变体提供了独特的机会，探索 细菌螺旋细胞形状产生和维持的机制以及细胞的功能作用 在生态位获取和持续殖民的形状。 更全面地了解螺旋细胞形状的原因和后果可以阐明 新的治疗靶点幽门螺杆菌和其他弯曲和螺旋状病原体，因此将进一步 NIAID的使命是了解和治疗传染病。