ROLE OF H PYLORI OUTER MEMBRANE PROTEINS IN COLONIZATION AND HOST RESPONSE

幽门螺杆菌外膜蛋白在定植和宿主反应中的作用

• 批准号: 8357312
• 负责人: JAY V. SOLNICK
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357312
• 关键词: ABO blood group system; Address; Affinity; Bacterial Adhesins; Binding; Blood Group Antigens; California; Chronic; Clinical; Code; Dinucleoside Phosphates; Disease; Epithelium; Event; Family; Funding; Gastritis; Gene Conversion; Genes; Genome; Grant; Health; Helicobacter Infections; Helicobacter pylori; Human; Immune response; Immunity; Individual; Infection; Inflammation; Macaca; Macaca mulatta; Mediating; Membrane Proteins; Modification; Mus; National Center for Research Resources; Patients; Peptic Ulcer; Play; Primates; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Role; Source; Stomach; Surface; Translational Research; United States National Institutes of Health; Variant; adaptive immunity; clinically relevant; cost; malignant stomach neoplasm; pathogen; protein expression; protein profiling; vaccine candidate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Helicobacter pylori commonly infects the stomach, where it causes inflammation (gastritis) in all individuals and peptic ulcer disease or gastric cancer in some. H. pylori attachment to the gastric epithelium is mediated by a large family of outer membrane proteins (OMPs), the best studied of which is BabA, the Lewis b (Leb)/ABO blood group binding adhesin. BabA is clinically relevant because patients infected with strains that express it are more likely to develop peptic ulcer or gastric cancer. A closely related protein, BabB, shows extensive homology with BabA, but its function is unknown. We recently showed that H. pylori strains recovered from experimentally infected macaques had lost expression of BabA. In some cases the babA gene was replaced by babB (an apparent gene conversion event) and in other cases the babA gene was not expressed due to alteration in the number of dinucleotide CT repeats in the 5' coding region. Strains lacking BabA expression did not adhere to the Leb blood group antigen that is expressed on rhesus gastric epithelium. Analysis of human clinical strains showed that many patients are infected with variants of H. pylori whose OMP profile resembles that seen in macaques. Since BabA expression is also lost during experimental infection of both wild type and Rag-/- mice, evasion of adaptive immunity is probably not playing a role. We hypothesize that modifications in H. pylori OMP expression represents a remodeling of the bacterial surface so as to avoid innate host immunity and promote attachment to the gastric epithelium. Four Specific Aims are proposed to address this hypothesis. Aim 1 will determine the effect of BabA and BabB on host response and modulation of OMP expression during H. pylori infection of rhesus macaques. In Aim 2 we will determine the competitive effect of BabA and BabB on H. pylori colonization of rhesus macaques. Aim 3 will examine the role of affinity of BabA binding to Leb on the expression of BabA. In Aim 4 we will characterize the role of BabB in H. pylori attachment. These studies of BabA and BabB will contribute to ongoing translational research that seek to investigate the use of BabA and BabB as vaccine candidates, and also may have broad implications for the role of genome diversity in promoting chronic infection with H. pylori. PUBLIC HEALTH RELEVANCE: Helicobacter pylori is a bacterial pathogen that commonly infects the human stomach and sometimes causes peptic ulcers or gastric cancer. One factor that determines whether infection causes disease, or just asymptomatic colonization, is the particular profile of surface proteins that mediate attachment to the gastric epithelium. This project seeks to understand some of the factors that determine the expression of these surface proteins in H. pylori.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 幽门螺杆菌通常会感染胃，其中所有个体引起炎症（胃炎），有些人在某些人中会引起胃炎或消化性溃疡或胃癌。幽门螺杆菌附着胃上皮的附着是由大型外膜蛋白（OMP）介导的，其中最好的研究是Baba，Lewis B（Leb）/ABO血液组结合粘合剂。 BABA在临床上具有相关性，因为感染了表达菌株的患者更有可能患上消化性溃疡或胃癌。密切相关的蛋白质BABB与BABA表现出广泛的同源性，但其功能尚不清楚。我们最近表明，从实验感染的猕猴中回收的幽门螺杆菌菌株失去了BABA的表达。在某些情况下，BABA基因被BABB（一个明显的基因转换事件）取代，在其他情况下，由于5'编码区域中的二核苷酸CT重复序列的数量改变，BABA基因不会表达。缺乏BABA表达的菌株并未遵守在恒河猴上皮上表达的LEB血液组抗原。对人类临床菌株的分析表明，许多患者感染了幽门螺杆菌的变异，其OMP的特征类似于猕猴。由于在野生型和抹布 - / - 小鼠的实验感染期间，巴巴表达也丧失，因此逃避适应性免疫力可能不会发挥作用。我们假设幽门螺杆菌表达中的修饰代表了细菌表面的重塑，以避免先天宿主的免疫并促进对胃上皮的附着。提出了四个具体目标来解决这一假设。 AIM 1将确定BABA和BABB对恒河猕猴幽门螺杆菌感染期间OMP表达的宿主反应和调节的影响。在AIM 2中，我们将确定Baba和Babb对恒河猕猴的幽门螺杆菌定植的竞争作用。 AIM 3将研究Baba与LEB结合的亲和力对Baba表达的作用。在AIM 4中，我们将表征BABB在幽门螺杆菌附着中的作用。这些对BABA和BABB的研究将有助于持续的转化研究，这些研究旨在研究BABA和BABB作为候选疫苗的使用，并且可能对基因组多样性在促进幽门螺杆菌慢性感染中的作用具有广泛的影响。公共卫生相关性：幽门螺杆菌是一种细菌病原体，通常会感染人类胃，有时会引起消化性溃疡或胃癌。决定感染是导致疾病还是无症状的定植的一个因素是介导胃皮细胞附着的表面蛋白的特殊特征。该项目试图了解确定幽门螺杆菌中这些表面蛋白表达的一些因素。