Role of LOS and Opa in gonococcal host interactions

LOS 和 Opa 在淋球菌宿主相互作用中的作用

• 批准号: 7599119
• 负责人: DANIEL C STEIN
• 金额: $ 32.78万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7599119
• 关键词: Adherence; Antigens; Cell Communication; Cell Line; Cell surface; Cells; Cellular biology; Chemistry; Clinical; Cytoskeleton; Development; Disease; Ectopic Pregnancy; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Flow Cytometry; Genetic; Genitourinary system; Goals; Gonorrhea; HIV; Health; Health Care Costs; Human; Immune; Individual; Infection; Infertility; Invaded; Knowledge; Laboratories; Lead; Mediating; Membrane; Modeling; Modification; Neisseria gonorrhoeae; Organism; Outcome; Pathogenesis; Pathogenicity; Pelvic Inflammatory Disease; Play; Positioning Attribute; Prevention approach; Process; Research; Research Personnel; Role; Series; Signal Pathway; Signal Transduction; Staging; Structure; Surface; Surface Antigens; Technology; Testing; Tissues; United States; Variant; base; chemokine; chronic pelvic pain; cost; cytokine; human tissue; lipooligosaccharide; novel strategies; opacity protein (Neisseria gonorrhoeae); pathogen; prevent; programs; receptor; response; tissue culture; tissue/cell culture; tool; transcytosis; transmission process

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.

描述（由申请人提供）：淋病的奈瑟氏菌每年在美国引起约60万新的感染，卫生保健费用接近20亿美元。伴随淋球菌感染似乎有助于艾滋病毒传播，这一事实使成本和人类的痛苦得到了扩大。 Gonococci优先感染人类泌尿生殖道，并且其进入和透射的能力这种粘膜表面是骨盆炎性疾病，输卵管不育症，异位妊娠和慢性骨盆疼痛的主要原因。各种表面成分，即脂肪糖（LOS）和不透明度蛋白（OPA）在介导这些疾病中很重要。大多数研究都使用组织培养模型来研究各个表面成分在致病过程中的作用，即使可能需要多个组件和/或能够协同作用。这种病原体操纵其外膜的事实表明，这种修饰在发病机理中很重要。关于表面分子之间可能的相互作用，尚无任何了解，因为迄今为止，我们缺乏具有不变的，定义的表面的细菌菌株。这阻止了我们对淋球菌疾病的发病机理的全面理解。该提案的目标是了解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。拟议的研究的中心假设是，这些表面抗原的不同变异对于感染的各个阶段很重要。我们打算通过追求三个具体目标来检验我们的假设：我们将确定各种表面结构如何促进对不同组织培养细胞的侵袭，我们将确定这种相互作用激活的信号传导途径，我们将定义宿主细胞中细胞的细胞反应，这些细胞是由淋球菌依从性发起的。我们的研究结果将使我们能够定义LOS和OPA变异如何促进疾病发病机理。预计对人类健康的影响将是重要的，因为新知识可能会为预防和治疗淋病提供新的方法。