Innate and Adaptive Immunity in Experimental and Human Gonoccocal Infection

实验性和人类淋球菌感染中的先天性和适应性免疫

• 批准号: 8318899
• 负责人: Peter A. Rice
• 金额: $ 276.85万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318899
• 关键词: Accounting; Address; Alternative Complement Pathway; Animal Model; Antibodies; Binding; Biology; Clinical; Development; Doctor of Philosophy; Genetic Polymorphism; Goals; Gonorrhea; HIV Infections; Human; Immune; Immune response; Immunobiology; Immunology; Infection; Infertility; Inflammatory Response; Laboratory Animals; Lead; Ligands; Link; Lipid A; Lipopolysaccharides; Mediating; Mutation; Natural Immunity; Neisseria; Neisseria gonorrhoeae; Nucleotides; Pathogenesis; Pelvic Inflammatory Disease; Peptides; Play; Prevention; Properdin; Research; Research Project Grants; Rice; Robin bird; Role; Services; Sexually Transmitted Diseases; Signal Transduction; Structure; Symptoms; TLR4 gene; Tertiary Protein Structure; Vaccines; Woman; adaptive immunity; clinical epidemiology; improved; insight; lipooligosaccharide; mouse model; novel; nucleotide receptor; pathogen; receptor; therapy development; toll-like receptor 4; translational approach; vaccine candidate

The major objectives of this Sexually Transmitted Infections Co-operative Research Center (STI-CRC) entitled "Innate and Adaptive Immunity in Experimental and Human Gonococcal Infection in Women" are directed to providing a diverse and comprehensive understanding of the innate and adaptive immune mechanisms associated with gonococcal infection. We will emphasize basic host responses and innate immune mechanisms in infection with Neisseria gonorrhoeae with the immediate aim of improving understanding of gonococcal immunology and pathogenesis and a longer term goal to gain insights that will direct efforts to facilitate the prevention of gonococcal infections in humans, particularly women. We will use a promising animal model to examine these mechanisms and separately employ a generalized translational approach that will emphasize the links between immunobiology and clinical epidemiology to assess the potential of vaccine candidates in humans, which will then be investigated in the context of the humanized mouse model of infection. Five research projects and four service cores are proposed. In the first project (Douglas T Golenbock, MD, PL), we will address a basic and fundamental question in lipopolysaccharide (LPS, called lipooligosaccharide [LOS] in the case of N. gonorrhoeae) biology to understand the binding of LOS derived lipid A with its direct ligand that serves as an intermediary structure to activate and permit signaling of toll-like receptor (TLR)4. In Project 2 (Robin Ingalls, MD, PL), we will determine if naturally occurring mutations in gonococcal LOS or polymorphisms in the TLR4 adaptor Mai, account for differences in the host inflammatory response to infection. In Project 3 (Caroline A Genco, PhD, PL), we will examine the role that TLRs and cytosolic nucleotide oligomerization domain (NOD) protein receptors (NOD-like receptors [NLRs]) play as receptors for Neisseria ligands. In Project 4 (Sanjay Ram, MD, PL), we will examine novel roles for the alternative complement pathway (ACP) enhancing molecule. Properdin, in blocking TLR4 mediated signaling by LOS and separately, in amplifying potentially protective vaccine induced antibody function. In Project 5 (Peter A. Rice, MD), we will examine peptide mimics of gonococcal LOS as potential vaccine candidates in a humanized mouse model of gonococcal infection while also determining if natural antibodies against the candidates protect exposed women from gonococcal infection. The Center will have five Cores (Clinical, Laboratory, Animal Statistical, and administrative) providing support to 4 or 5 of the 5 Projects.

这种性传播感染合作研究中心（STI-CRC）的主要目标是“女性实验性和人类淋球菌感染中的先天和适应性免疫”，旨在提供对先天性的多样化和全面的理解，并适应与聚球菌感染相关的免疫机制。我们将强调淋病奈瑟氏菌感染中基本的宿主反应和先天免疫机制，其目的是提高对淋球菌免疫学和发病机理的理解，以及一个长期目标，以实现洞察力，以实现努力，以促进预防人类的淋球菌感染，尤其是女性。我们将使用有前途的动物模型来检查这些机制，并分别采用一种广义的翻译方法，该方法将强调免疫生物学和临床流行病学之间的联系，以评估人类候选疫苗的潜力，然后将在人文化的感染小鼠模型的背景下进行研究。提出了五个研究项目和四个服务核心。在第一个项目（MD，MD，PL）的第一个项目中，我们将在脂多糖（LPS，称为Lipooligosacachide [los]）中讨论一个基本的，基本的问题，在N. gonorrhoeae n. gonorrhoeae）的情况下，以了解LOS导致的脂质结构的结合，以允许其与los的结合，以允许其与ligiDy的结合，以使ligiDy and toctions to and iNtermiary actiaction to toction and in Intermy to toction and in Intermed to andirate in Intermed to andirate in Intermed to an （TLR）4。在项目2（Robin Ingalls，MD，PL）中，我们将确定TLR4适配器MAI中的淋球菌LOS或多态性中自然发生的突变是宿主对感染炎症反应的差异。在项目3（Caroline A Genco，PhD，PL）中，我们将研究TLR和胞质核苷酸寡聚结构域（NOD）蛋白受体（NOD样受体[NLRS]）的作用，作为Neisseria Girigands的受体。在项目4（医学博士Sanjay Ram）中，我们将研究替代补体途径（ACP）增强分子的新作用。在阻止LOS和分别介导的信号传导的过程中，在扩增潜在的保护性疫苗诱导的抗体功能时。在项目5（医学博士Peter A. Rice）中，我们将研究淋球菌LOS的肽模拟物作为淋球菌感染的人源化小鼠模型中的潜在疫苗候选，同时还确定针对候选者的天然抗体是否保护暴露的妇女免受淋球菌感染的侵害。该中心将有五个核心（临床，实验室，动物统计和行政）为5个项目中的4或5个提供支持。