Innate and Adaptive Immunity in Experimental and Human Gonoccocal Infection

性传播感染合作研究中心的主要目标是“妇女实验性和人类淋球菌感染的先天和适应性免疫”，旨在提供对与淋球菌感染相关的先天和适应性免疫机制的全面了解。我们将强调淋球菌感染的基本宿主反应和先天免疫机制，其直接目的是提高对淋球菌免疫学和发病机制的认识，长期目标是获得有助于预防人类（特别是女性）淋球菌感染的见解。我们将使用一个有前途的动物模型来研究这些机制，并单独采用一种广义的翻译方法，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，然后将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（道格拉斯T Golenbock，MD，PL）中，我们将解决脂多糖（LPS，在N.淋病）生物学以理解LOS衍生的脂质A与其直接配体的结合，所述直接配体充当中间结构以激活并允许Toll样受体（TLR）4的信号传导。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TLR4衔接子Mai中的多态性是否导致宿主对感染的炎症反应差异。在项目3（Caroline A Genco，PhD，PL）中，我们将研究TLR和胞质核苷酸寡聚化结构域（NOD）蛋白受体（NOD样受体[NLR]）作为奈瑟氏菌配体受体的作用。在项目4（Sanjay Ram，MD，PL）中，我们将研究替代补体途径（ACP）增强分子的新作用。备解素在阻断LOS介导的TLR4信号传导中的作用，以及在增强疫苗诱导的潜在保护性抗体功能中的作用。在项目5（彼得A. Rice，MD），我们将在淋球菌感染的人源化小鼠模型中检查淋球菌LOS的肽模拟物作为潜在的疫苗候选物，同时还确定针对候选物的天然抗体是否保护暴露的妇女免受淋球菌感染。中心将有5个核心（临床、实验室、动物统计和管理），为5个项目中的4个或5个提供支持。

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.