Cutaneous Immune Response in Early Syphilis

描述（申请人摘要）：性病梅毒是一种慢性炎症， 由于梅毒螺旋体的持续存在而引起的疾病。 本提案中的研究基于以下前提：当地（即， 基于组织的）对T.苍白球有两个不同的，然而， 相互关联，对梅毒发病机制具有根本重要性的后果。 它们导致组织损伤，最终引起临床 他们主要负责清除 细菌，病变消退的先决条件。人体皮肤是主要的焦点 我们努力阐明这些过程，因为（a）它是主要目标 早期梅毒感染的器官，（B）它在体内容易接近 实验，以及（c）存在丰富的试剂和信息 它的免疫功能。在上一次融资期间，我们 在表征细胞浸润方面取得了相当大的进展， 二期梅毒病变和描绘个体发育的皮肤 梅毒螺旋体引起的反应。这部作品的一个统一主题 已经获得了大量的证据，结合使用在 体外和体内方法，以支持我们的主要假设， 密螺旋体脂蛋白的促炎特性是主要的触发因素 先天免疫机制的早期梅毒。最近，我们发现 通过募集富含抗原呈递细胞的细胞浸润物， 特别是树突状细胞和记忆/效应T细胞，先天免疫 由这些脂质修饰的多肽诱导的过程为 自适应（即，特异性）对细菌的免疫反应。一个重要 这些发现的结果是认识到， 调查涉及一期梅毒和二期梅毒。在这 竞争性续期申请，我们将扩展这一概念框架， 进一步表征对密螺旋体的体内生物学应答， 脂蛋白/脂肽（Aim One）;通过进一步表征皮肤 二期梅毒皮损对梅毒螺旋体的免疫应答（目的二）：应用 体外/离体方法检测树突状细胞和T细胞对T细胞的应答 苍白球和密螺旋体蛋白（目的三）;并通过检验我们的假设 密螺旋体脂蛋白在摄取后激活巨噬细胞， 在巨噬细胞的吞噬体空泡内的降解（目的四）。这项工作 将导致对局部细胞反应的作用的更好理解 在梅毒发病机制，并将提供必要的基础， 最终研制出安全有效的梅毒疫苗。

DESCRIPTION (Applicant's Abstract): Venereal syphilis is a chronic inflammatory disorder driven by the persistence of its etiologic agent Treponema pallidum. Research in this proposal is based on the premise that the local (i.e., tissue-based) cellular immune responses to T. pallidum have two distinct, yet interrelated, consequences of fundamental importance to syphilis pathogenesis. They cause the tissue damage which ultimately gives rise to clinical manifestations, and they are primarily responsible for the clearance of bacteria, a prerequisite for lesion resolution. Human skin is the primary focus of our efforts to elucidate these processes because (a) it is the major target organ of early syphilitic infection, (b) it is easily accessible to in vivo experimentation, and (c) there exists a wealth of reagents and information concerning its immune-related functions. During the prior funding interval, we have made considerable progress in characterizing the cellular infiltrates in secondary syphilis lesions and in delineating the ontogeny of the cutaneous response engendered by the syphilis spirochete. A unifying theme of this work has been the acquisition of considerable evidence, using a combination of in vitro and in vivo approaches, to support our primary hypothesis that the proinflammatory properties of treponemal lipoproteins are the primary triggers of innate immune mechanisms in early syphilis. More recently, we have shown that by recruiting a cellular infiltrate rich in antigen presenting cells, particularly dendritic cells, and memory/effector T cells, the innate immune processes induced by these lipid-modified polypeptides set the stage for the adaptive (i.e., specific) immune responses to the bacterium. One important outcome of these findings is the recognition that the cutaneous responses under investigation relate to primary as well as to secondary syphilis. In this competitive renewal application, we will extend this conceptual framework by further characterizing the in vivo biological responses to treponemal lipoproteins/lipopeptides (Aim One); by further characterizing the cutaneous immune response to T pallidum in secondary syphilis lesions (Aim Two); by using in vitro/ex vivo approaches to examine dendritic and T cell responses to T pallidum and treponemal proteins (Aim Three); and by examining our hypothesis that treponemal lipoproteins activate macrophages following uptake and degradation within the phagosomal vacuoles of macrophages (Aim Four). This work will result in an enhanced appreciation of the role of local cellular responses in syphilis pathogenesis and will provide a necessary underpinning for the eventual development of a safe and effective syphilis vaccine.