Role of LOS and Opa in gonococcal host interactions

描述（由申请人提供）：淋病奈瑟菌每年在美国造成约60万新感染，每年的医疗费用接近20亿美元。伴随的淋球菌感染似乎促进了艾滋病毒的传播，这一事实加剧了成本和人类痛苦。淋球菌优先感染人类泌尿生殖道，其进入并通过粘膜表面的能力是盆腔炎、输卵管性不孕症、异位妊娠和慢性盆腔疼痛的主要原因。各种表面成分，如低脂寡糖（LOS）和不透明蛋白（Opa）在介导这些疾病中起重要作用。大多数研究使用组织培养模型来研究单个表面成分在致病过程中的作用，尽管可能需要多种成分和/或能够协同作用。这种病原体操纵其外膜的事实表明，这种修饰在发病机制中很重要。对于表面分子之间可能的相互作用，我们一无所知，因为到目前为止，我们还缺乏具有不变的、明确的表面的细菌菌株。这使我们无法对淋球菌病的发病机制有一个全面的了解。本提案的目的是了解Opa和LOS在疾病中的作用，并确定这两种抗原是否在致病过程中相互作用。提出的研究的中心假设是，这些表面抗原的不同变体对感染的不同阶段很重要。我们打算通过追求三个特定目标来验证我们的假设：我们将确定不同的表面结构如何促进对不同组织培养细胞的入侵，我们将确定这种相互作用激活的信号通路，我们将定义宿主细胞中由淋球菌粘附引发的细胞反应。我们的研究结果将使我们能够确定LOS和Opa变异如何促进疾病发病机制。预计对人类健康的影响将是重大的，因为新的知识可能使预防和治疗淋病的新方法成为可能。

DESCRIPTION (provided by applicant): Neisseria gonorrhoeae causes about 600,000 new infections each year in the United States, with health- care costs approaching 2 billion dollars/year. The costs and human suffering are amplified by the fact that concomitant gonococcal infections appear to facilitate HIV transmission. Gonococci preferentially infect the human urogenital tract, and its ability to enter and transcytose this mucosal surface is a chief cause of pelvic inflammatory disease, tubal infertility, ectopic pregnancy, and chronic pelvic pain. Various surface components, i.e. lipooligosaccharide (LOS) and opacity proteins (Opa) are important in mediating these diseases. Most studies have used tissue culture models to study the role of individual surface components in the pathogenic process, even though it is likely that multiple components are needed and/or are able to act synergistically. The fact that this pathogen manipulates its outer membrane suggests that such modifications are important in pathogenesis. Nothing is known about possible interactions between the surface molecules, because to date, we have lacked bacterial strains that have invariant, defined surfaces. This has prevented us from developing a comprehensive understanding of the pathogenesis of gonococcal disease. The objectives of this proposal are to understand how Opa and LOS function in disease, and determine if these two antigens interact in the pathogenic process. The central hypothesis of the proposed research is that different variants of these surface antigens are important for the various stages of infection. We intend to test our hypotheses by pursuing three specific aims: We will determine how various surface structures promote invasion into different tissue culture cells, we will identify the signaling pathways activated by this interaction, and we will define the cellular responses in host cells that are initiated by gonococcal adherence. The results of our study will allow us to define how LOS and Opa variation contribute to disease pathogenesis. The impact on human health is expected to be significant, because the new knowledge will likely make possible new approaches to the prevention and treatment of gonorrhea.