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: 10411966
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411966
• 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; 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.

细菌有多种形态，这可能会增强运动性，生物膜的形成，营养的吸收，和