Cutaneous Immune Response in Early Syphilis

描述(申请人摘要)：性病是一种慢性炎症性疾病 梅毒螺旋体引起的疾病。 该建议中的研究基于这样的前提：本地(即， 以组织为基础的)对梅毒螺旋体的细胞免疫反应有两种截然不同的 在梅毒发病机制中具有根本重要性的相互关联的后果。 它们会导致组织损伤，最终导致临床 表现，他们主要负责清除 细菌，是病变解决的先决条件。人的皮肤是主要的焦点 我们为阐明这些过程所作的努力，因为(A)它是主要目标 早期梅毒感染的器官，(B)在体内很容易接触到 实验，以及(C)存在丰富的试剂和信息 关于它的免疫相关功能。在之前的融资期间，我们 在表征细胞浸润物方面取得了相当大的进展 二期梅毒损害与皮肤个体发育的关系 梅毒螺旋体引起的反应。这部作品的统一主题 已经获得了相当多的证据，使用了 体外和体内的方法，以支持我们的主要假设 梅毒螺旋体脂蛋白的致炎特性是主要的触发因素 早期梅毒的先天免疫机制。最近，我们展示了 通过招募富含抗原提呈细胞的细胞浸润物， 特别是树突状细胞和记忆/效应器T细胞，这是先天免疫 这些脂质修饰的多肽诱导的过程为 对细菌的适应性(即特异性)免疫反应。一个重要的问题 这些发现的结果是认识到皮肤反应在 调查涉及一期梅毒和二期梅毒。在这 竞争性续订申请，我们将通过以下方式扩展此概念框架 进一步表征对梅毒螺旋体的体内生物学反应 脂蛋白/脂肽(目标一)；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(目标二)； 检测树突状细胞和T细胞对T细胞反应的体外/体外方法 梅毒和梅毒螺旋体蛋白(目标三)；通过检验我们的假设 梅毒螺旋体脂蛋白在摄取后激活巨噬细胞 巨噬细胞吞噬体空泡内的降解(目标四)。这部作品 将加强对局部细胞反应的作用的认识 在梅毒发病机制中的作用，并将为 最终开发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.