Elucidation of a bacterial cell shape generating program and pathogenic functions

阐明细菌细胞形状生成程序和致病功能

• 批准号: 8586518
• 负责人: Nina Salama
• 金额: $ 42.88万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586518
• 关键词: Bacteria; Behavior; Binding; Biochemical; Campylobacter jejuni; Cell Shape; Cell Wall; Cells; Clinical; Communicable Diseases; Complex; Cytoskeletal Proteins; Deposition; Disease; Epithelium; Fluorescence-Activated Cell Sorting; Gastric Mucin; Gastritis; Generations; Genes; Genetic Epistasis; Genetic Screening; Goals; Grant; Helicobacter pylori; Homologous Gene; Human; In Vitro; Infection; Learning; Libraries; Life; Membrane Proteins; Mission; Modeling; Modification; Molecular; Molecular Probes; Morphology; Mucous body substance; Names; National Institute of Allergy and Infectious Disease; Outcome; Pathogenesis; Pathway interactions; Penetration; Peptic Ulcer; Peptides; Peptidoglycan; Periplasmic Proteins; Phenotype; Polymers; Population; Proteins; Proteobacteria; Publishing; Resistance; Role; Shapes; Stomach; Swimming; Testing; Thick; Vibrio cholerae; Virulence; Visual; Work; antimicrobial; cell motility; crosslink; design; dimer; gene discovery; malignant stomach neoplasm; monomer; mutant; pathogen; programs; retinal rods; theories

DESCRIPTION (provided by applicant): Helicobacter pylori is a helical rod shaped bacterium that colonizes the human stomach causing clinical outcomes that range from mild gastritis to peptic ulcer and gastric cancers. Most descriptions of H. pylori virulence include the widely-accepted hypothesis that its helical cell shape enhances colonization of the stomach. We recently provided the first experimental support for this theory with the characterization of four cell shape determining genes (csd1, csd2, csd3, ccmA) that promote helical cell curvature and twist through changes in cell wall peptidoglycan (PG) crosslinking and are required for efficient stomach colonization. Alteration of peptide crosslinking within the PG sacculus defines a new mechanism for bacterial cell shape generation; previous studies delineated localized deposition and restriction of new PG deposition as drivers of straight rod and curved rod shapes. Though the mutants described above have lost helical twist, they retain some curvature. Thus much remains to be learned about the precise molecular mechanisms for generating helical shape in H. pylori. This grant builds on our published work with a goal of elucidating the H. pylori helical shape generating program and the contributions of this cell shape program to H. pylori pathogenesis. Aim 1 will identify and characterize additional genes involved in helical cell shape determination. Aim 2 will investigate how these genes work together to promote shape using biochemical studies of cell shape proteins and PG cell wall composition. Aim 3 will investigate possible mechanisms by which the helical cell shape generating program promotes stomach colonization including modulation of swimming behavior and niche utilization within the stomach. Bacteria manifest an impressive diversity of cell shapes that are highly conserved within species but the selective forces leading to conservation of specific shapes are poorly understood. We have established H. pylori as an excellent model to elucidate molecular determinants of helical cell shape and the selective role of shape during host colonization in the Proteobacteria; Csd proteins and CcmA homologues are well conserved among curved to helical Proteobacteria including several other pathogens such as Campylobacter jejuni and Vibrio cholerae. The elucidation of a helical shape generating program required for stomach colonization promises to illuminate new targets for antimicrobial design which are badly needed in H. pylori as current strains display increasing resistance to existing therapies and fits the mission of NIAID to understand and treat infectious diseases.

描述（由申请人提供）：幽门螺杆菌是一种螺旋杆状细菌，可在人类胃中定居，导致临床结局，从轻度胃炎到消化性溃疡和胃癌。幽门螺杆菌毒力的大多数描述包括广泛认可的假设，即其螺旋细胞形状增强了胃的定殖。最近，我们通过表征了四个细胞形状确定基因（CSD1，CSD2，CSD3，CCMA）的第一个实验支持，该基因（CSD1，CSD2，CSD3，CCMA）通过细胞壁肽聚糖（PG）交联的变化来促进螺旋细胞曲率并扭曲，并且需要进行有效的胃结构。 PG囊中肽交联的改变定义了一种新的细菌细胞形状产生机制；先前的研究将局部沉积和新PG沉积的限制描述为直杆和弯曲杆形状的驱动因素。尽管上述突变体失去了螺旋扭曲，但它们仍保留了一些曲率。因此，关于在幽门螺杆菌中产生螺旋形状的精确分子机制还有很多待了解。这项赠款以我们发表的工作为基础，目的是阐明幽门螺杆菌螺旋形生成程序以及该细胞形状程序对幽门螺杆菌发病机理的贡献。 AIM 1将识别并表征涉及螺旋细胞形状测定的其他基因。 AIM 2将研究这些基因如何使用细胞形状蛋白和PG细胞壁组成的生化研究一起促进形状。 AIM 3将研究可能的机制，通过这些机制，螺旋细胞形状产生程序促进胃定植，包括调节游泳行为和胃内的利基利用率。细菌表现出令人印象深刻的细胞形状多样性，这些细胞形状在物种中高度保守，但是导致保护特定形状的选择性能力很少。我们已经建立了幽门螺杆菌作为阐明螺旋细胞形状的分子决定因素的出色模型，并在蛋白杆菌中宿主定植期间形状的选择性作用。 CSD蛋白和CCMA同源物在弯曲至螺旋蛋白杆菌中得到了很好的保守，包括其他几种病原体，例如弯曲杆菌的空肠和弧菌霍乱。胃定植所需的螺旋形产生程序的阐明有望照亮幽门螺杆菌在幽门螺杆菌中迫切需要的新目标，因为当前菌株表现出对现有疗法的耐药性的增加，并适合NIAID的使命，以了解和治疗感染性疾病。