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，可以增强运动性、生物膜形成、营养吸收和 发病。然而，形状的这些功能后果尚未得到充分研究，部分原因是 缺乏操纵细菌细胞形状的工具。探究形态（细胞形状）如何驱动功能（辐射到 不同的利基），我们首先必须了解形状是如何生成的。细菌形状各异，从球形到 从杆到螺旋都源自相同的细胞壁聚合物：肽聚糖（PG）。 PG 壁包围细胞 含有膨胀压力。该领域的主要假设认为，不同的形状源于不同的模式 PG合成。事实上，大肠杆菌是直杆，而新月柄杆菌和霍乱弧菌是弯曲的 视杆细胞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， 存在于多种细菌谱系中，但尚未得到阐明。 幽门螺杆菌已成为研究螺旋形状的主要模型。这种细菌一直在 定植于人类胃部，引起慢性炎症和消化性溃疡等临床病理 胃癌是2012年世界第三大癌症死亡原因[2]。我们分离出稳定的突变体 非螺旋形状，我们的工作展示了它们在胃定植中的缺陷，这是第一个 细胞形状和细菌感染性之间联系的实验证据现已扩展到其他领域 细菌（弧菌、弯曲杆菌）[3-5]。然而，我们对它的重要性只有粗略的了解。 最初感染时的形状，但不了解改变的形状如何影响长期定植、生态位 获得性或宿主免疫反应。 此外，幽门螺杆菌维持螺旋形状的策略与迄今为止研究的细菌显着不同。 我们的五个形状突变体映射到已确认的 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/螺旋的，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]。 指导该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，允许非螺旋细菌和底层细菌在不同的生态位中定殖 持续感染。我们收集的非螺旋突变体提供了独特的机会来探索 细菌螺旋细胞形状生成和维持的机制以及细胞的功能作用 利基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 幽门螺杆菌和其他弯曲和螺旋病原体的新治疗靶点，因此将进一步推动 NIAID 的使命是了解和治疗传染病。