Role of H. pylori Outer Membrane Proteins in Colonization and Host Response

描述（由申请人提供）：幽门螺杆菌通常感染胃，在所有个体中引起炎症（胃炎），在一些个体中引起消化性溃疡疾病或胃癌。H.幽门螺杆菌与胃上皮的附着是由一个大家族的外膜蛋白（OMP）介导的，其中研究得最好的是BabA，即刘易斯B（LeB）/ABO血型结合粘附素。BabA与临床相关，因为感染表达它的菌株的患者更有可能发展为消化性溃疡或胃癌。一个密切相关的蛋白质，BabB，显示出广泛的同源性与BabA，但其功能是未知的。我们最近发现H.从实验感染的猕猴中回收的pylori菌株失去了BabA的表达。在某些情况下，babA基因被babB取代（一种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重复序列数量的改变，babA基因不表达。缺乏BabA表达的菌株不粘附于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H. pylori，其OMP谱类似于在猕猴中看到的。由于BabA表达在野生型和Rag-/-小鼠的实验感染期间也丢失，因此逃避适应性免疫可能不起作用。我们假设，在H。幽门螺杆菌OMP表达代表了细菌表面的重塑，以避免先天性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。目的1研究BabA和BabB对宿主反应的影响及对宿主外膜蛋白表达的调节作用。恒河猴幽门螺杆菌感染。在目标2中，我们将确定BabA和BabB对H的竞争效应。恒河猴的幽门螺杆菌定殖。目的3研究BabA与Leb结合的亲和力对BabA表达的影响。在目标4中，我们将描述BabB在H中的作用。幽门附着这些对BabA和BabB的研究将有助于正在进行的转化研究，这些研究旨在研究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H.幽门。

DESCRIPTION (provided by applicant): 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.