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.

该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性和适应性免疫”，旨在提供对与淋球菌感染相关的先天性和适应性免疫机制的多样化和全面的了解。我们将强调淋病奈瑟菌感染的基本宿主反应和先天免疫机制，近期目标是提高对淋球菌免疫学和发病机制的了解，长期目标是获得见解，从而指导促进预防人类（特别是女性）淋球菌感染的努力。我们将使用一种有前途的动物模型来检查这些机制，并分别采用一种通用的转化方法，该方法将强调免疫生物学和临床流行病学之间的联系，以评估候选疫苗在人类中的潜力，然后在人源化小鼠感染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（Douglas T Golenbock，MD，PL）中，我们将解决脂多糖（LPS，在淋病奈瑟菌中称为脂寡糖 [LOS]）生物学中的一个基本问题，以了解 LOS 衍生的脂质 A 与其直接配体的结合，该配体作为中间结构来激活并允许 Toll 样受体的信号传导 （TLR）4。在项目 2（Robin Ingalls，MD，PL）中，我们将确定淋球菌 LOS 中自然发生的突变或多态性 TLR4 接头 Mai 是否可以解释宿主对感染的炎症反应的差异。在项目 3（Caroline A Genco，博士，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 [NLR]）作为奈瑟菌配体受体的作用。在项目 4（Sanjay Ram，医学博士、PL）中，我们将研究替代补体途径 (ACP) 增强分子的新作用。备解素可阻断 LOS 介导的 TLR4 信号传导，并分别放大潜在的保护性疫苗诱导抗体功能。在项目 5（Peter A. Rice，医学博士）中，我们将在淋球菌感染人源化小鼠模型中检查淋球菌 LOS 的肽模拟物作为潜在的候选疫苗，同时确定针对候选物的天然抗体是否可以保护暴露的女性免受淋球菌感染。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。