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

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 幽门螺杆菌通常会感染胃，导致所有个体出现炎症（胃炎），并导致某些个体出现消化性溃疡或胃癌。幽门螺杆菌与胃上皮的附着是由一大类外膜蛋白 (OMP) 介导的，其中研究最多的是 BabA，即 Lewis b (Leb)/ABO 血型结合粘附素。 BabA 具有临床意义，因为感染表达它的菌株的患者更有可能患上消化性溃疡或胃癌。一种密切相关的蛋白质 BabB 与 BabA 显示出广泛的同源性，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 取代（明显的基因转换事件），而在其他情况下，由于 5' 编码区中二核苷酸 CT 重复次数的改变，babA 基因不表达。缺乏 BabA 表达的菌株不粘附在恒河猴胃上皮上表达的 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变种，其 OMP 谱与猕猴中的相似。由于 BabA 表达在野生型和 Rag-/- 小鼠的实验感染过程中也会丢失，因此适应性免疫的逃避可能没有发挥作用。我们假设幽门螺杆菌 OMP 表达的改变代表细菌表面的重塑，以避免先天宿主免疫并促进与胃上皮的附着。提出了四个具体目标来解决这一假设。目标 1 将确定 BabA 和 BabB 在恒河猴感染幽门螺杆菌期间对宿主反应和 OMP 表达调节的影响。在目标 2 中，我们将确定 BabA 和 BabB 对恒河猴幽门螺杆菌定植的竞争效应。目标 3 将检查 BabA 与 Leb 结合的亲和力对 BabA 表达的作用。在目标 4 中，我们将描述 BabB 在幽门螺杆菌附着中的作用。 BabA 和 BabB 的这些研究将有助于正在进行的转化研究，旨在调查 BabA 和 BabB 作为候选疫苗的用途，并且还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，通常感染人类胃，有时会导致消化性溃疡或胃癌。决定感染是否引起疾病或只是无症状定植的因素之一是介导胃上皮附着的表面蛋白的特定特征。该项目旨在了解决定幽门螺杆菌中这些表面蛋白表达的一些因素。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.