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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 幽门螺杆菌通常会感染胃，在所有人中都会引起炎症(胃炎)，一些人还会患上消化性溃疡或胃癌。幽门螺杆菌与胃上皮细胞的黏附是由一大类外膜蛋白(OMP)介导的，其中研究最多的是BABA，即结合粘附素的Lewis b(Leb)/ABO血型。BABA具有临床意义，因为感染了表达BABA的菌株的患者更有可能发展为消化性溃疡或胃癌。一种与BABA密切相关的蛋白质BABB与BABA有广泛的同源性，但其功能尚不清楚。我们最近发现，从实验感染的猕猴中恢复的幽门螺杆菌菌株已经失去了BABA的表达。在某些情况下，BABA基因被BABB(一种明显的基因转换事件)取代，而在另一些情况下，由于5‘编码区二核苷酸CT重复数的改变，BABA基因没有表达。缺乏BABA表达的菌株不附着于表达在恒河猴胃上皮细胞上的LEB血型抗原。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种，其OMP图谱与猕猴的相似。由于BABA的表达在野生型和RAG-/-小鼠的实验感染过程中也会丢失，因此逃避适应性免疫可能不起作用。我们推测，幽门螺杆菌OMP表达的改变代表了细菌表面的重塑，从而避免了天然宿主免疫，促进了与胃上皮细胞的附着。针对这一假设，本文提出了四个具体目标。目的1研究BABA和BABB在Hp感染恒河猴过程中对宿主反应和OMP表达的影响。在目标2中，我们将确定BABA和BABB对幽门螺杆菌在恒河猴定植中的竞争作用。目的3研究BABA与Leb的亲和力对BABA表达的影响。在目标4中，我们将描述BABB在幽门螺杆菌附着中的作用。这些对Baba和Babb的研究将有助于正在进行的翻译研究，寻求调查Baba和Babb作为候选疫苗的使用，并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产生广泛的影响。公共卫生相关性：幽门螺杆菌是一种细菌病原体，通常感染人类的胃，有时会导致消化性溃疡或胃癌。决定感染是导致疾病还是仅仅是无症状的定植的一个因素是，介导与胃上皮附着的表面蛋白的特殊轮廓。该项目试图了解决定这些表面蛋白在幽门螺杆菌中表达的一些因素。