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: 10166763
• 负责人: Nina Salama
• 金额: --
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166763
• 关键词: 3-Dimensional; Antibodies; Bacteria; Binding; Biochemical; Biophysical Process; Campylobacter; Cancer Etiology; Caulobacter crescentus; Cell Shape; Cell Wall; Cell surface; Cells; Chemicals; Chronic; Clinical; Clinical Pathology; Collection; Communicable Diseases; Complex; Cytoskeletal Proteins; Cytosol; Data; Defect; Disease; Elasticity; Escherichia coli; Gastric Glands; Gastritis; Generations; Helicobacter pylori; Heterogeneity; Homologous Gene; Human; Hydrolase; Immune response; Infection; Inflammation; Label; Link; Maintenance; Maps; Measures; Membrane; Metabolic; Metabolism; Microbial Biofilms; Microscopy; Minor; Mission; Modeling; Modification; Movement; Mus; Mutation Analysis; N-Acetylmuramoyl-L-alanine Amidase; Names; National Institute of Allergy and Infectious Disease; Nutrient; Outcome; Pathogenesis; Pattern; Penetration; Peptic Ulcer; Peptidoglycan; Phenotype; Polymers; Proteins; Proteobacteria; Radiation; Recovery; Resolution; Rod; Role; Shapes; Signal Transduction; Stomach; Structure; Study models; Testing; Three-Dimensional Image; Vibrio; Vibrio cholerae; Work; cell motility; chronic infection; gene discovery; image reconstruction; inhibitor/antagonist; malignant stomach neoplasm; mortality; mutant; new therapeutic target; pathogen; periplasm; persistent bacteria; physical property; pressure; tool; uptake

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，可以增强运动能力，生物膜形成，营养摄取和 发病。但是，形状的这些功能后果尚未很好地研究，部分原因是 操纵细菌细胞形状的工具的稀少。探测如何形成（单元格）驱动功能（辐射到 潜水壁ni），我们必须首先了解形状的产生方式。细菌形状从球体到 螺旋螺旋的螺旋均来自相同的细胞壁聚合物：PepperyDoglycan（PG）。 PG墙周围环境 含有张力压力。该领域的主要假设认为，潜水员构成了不同的模式 PG合成。实际上，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， 在细菌的多个谱系中可见，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 殖民的胃殖民，导致慢性感染和临床病理范围从胡椒粉溃疡 胃癌是2012年癌症死亡率的第三大主要原因[2]。我们用稳定的突变体隔离 非螺旋形状，我们的工作证明了他们在摊位殖民中的缺陷，提出了第一个 实验证据表明细胞形状与细菌感染之间的联系已扩展到其他 细菌（Vibrio，弯曲杆菌）[3-5]。但是，我们只对 最初感染中的形状，不了解形状改变如何影响长期定植，利基 收购或托管免疫调查。 此外，幽门螺杆菌维持螺旋形状的策略与迄今为止的细菌显着区别。 我们的五个形状突变体映射到确认的PG水解酶，暗示了一个模型，螺旋形成了形状 来自PG的结构修饰，而不是PG合成的调节[5-7]。这些水解酶的同源物 可以在几个蛋白细菌类别中找到，其中大多数是弯曲/螺旋的，表明其他细菌 还可以采用PG的直接修饰来实现曲率和扭曲[5,8,9]。 指导该提议的主要假设是空间定位的pg水解促进了幽门螺杆菌 螺旋形状，可以从非螺旋细菌和基础定植不同的壁ni 持续感染。我们的非螺旋突变体集合为探索 细菌中螺旋细胞形状产生和维持的机制以及细胞的功能作用 利基习得和持续定殖的形状。 对螺旋细胞形状的原因和后果有更完整的了解可以阐明 幽门螺杆菌和其他弯曲和螺旋病原体中的新治疗靶标，因此将进一步 NIAID的使命理解和治疗传染病。