Innate and Adaptive Immunity in Experimental and Human Gonoccocal Infection

这一性传播感染合作研究中心(STI-CRC)题为“女性实验性和人类淋球菌感染中的先天免疫和获得性免疫”的主要目标旨在提供对与淋球菌感染相关的先天和获得性免疫机制的不同和全面的了解。我们将强调淋球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，长期目标是获得洞察力，以指导预防人类，特别是女性淋病感染的努力。我们将使用一个有前途的动物模型来检验这些机制，并分别采用一种普遍的翻译方法，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，然后在人源化的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)生物学中的一个基本和基本的问题，以了解LOS衍生的脂质A与其直接配体的结合，该配体是激活和允许Toll样受体(TLR)4信号的中间结构。在项目2(Robin Ingalls，MD，PL)中，我们将确定是否淋球菌LOS自然发生突变或TLR4适配器MAI的多态导致宿主对感染的炎症反应的差异。在项目3(Caroline A Genco，PhD，PL)中，我们将研究TLRs和胞质核苷酸寡聚域(NOD)蛋白受体(NOD样受体[NLRs])作为奈瑟菌配体的受体所起的作用。在项目4(Sanjay Ram，MD，PL)中，我们将研究替代补体途径(ACP)增强分子的新角色。备解素分别通过LOS和LOS阻断TLR4介导的信号转导，放大潜在保护性疫苗诱导的抗体功能。在项目5(Peter A.莱斯，医学博士)中，我们将在淋球菌感染的人源化小鼠模型中检验淋球菌LO的多肽模拟作为潜在的候选疫苗，同时也确定针对候选的天然抗体是否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个或5个项目提供支持。

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.