PATHOGENESIS AND THERAPY OF EXPERIMENTAL NEUROSYPHILIS

尽管梅毒螺旋体感染对中枢神经系统的临床影响 神经系统几个世纪以来一直被认识到，其发病机制和 宿主对中枢神经系统梅毒的反应知之甚少。梅毒螺旋体 在感染的第一周入侵中枢神经系统(CNS)， 如脑脊液细胞增多症、蛋白升高、反应性脑脊液-VDRL或 生物体的识别。当大多数人解决他们的脑脊液时 随着时间的推移，大约25%的人无法做到这一点，并面临风险 用于临床神经梅毒的发展。关于以下方面的问题 中枢神经系统梅毒的发病机制和治疗在 最近几年有两个原因：1)梅毒在美国流行 各州。一九九零年，传染性梅毒的呈报个案数目为 比过去40年中的任何一年都要高，估计为150万 这个国家的人感染梅毒。2)最近的病例报告 提示与HIV混合感染可能会增加 神经梅毒的发展，即使在早期的标准治疗之后 感染。 我们最近开发了一种早期神经梅毒的兔模型。这 该模型在脑池内与人类早期中枢神经系统梅毒相似 感染的兔持续出现单核脑脊液细胞增多症，并 脑脊液和脑组织中有明显的梅毒螺旋体；梅毒葡萄膜炎 在兔身上出现的频率与早期梅毒患者相同。 我们建议使用这个模型来1)定义病理和临床 中枢神经系统梅毒螺旋体感染的后果；2)探讨梅毒螺旋体感染的机制 中枢神经系统梅毒的发病机制与抗原特异性 脑脊液中的浸润性细胞与脑脊液的产生和特异性 抗体和炎症介质；3)检查特异性和 抗体和T淋巴细胞在清除生物体中的作用 从CNS；4)确定疾病进展和宿主的变化 对药物免疫抑制兔的反应；以及5)评估 早期梅毒和神经梅毒推荐治疗方案的疗效 免疫活性和药理免疫缺陷兔。这个 从拟议研究中获得的资料将直接适用于 中枢神经系统的发病机制、免疫反应和治疗问题 梅毒在人类中的作用，以及梅毒感染和 爱滋病毒。

Although the clinical consequences of T. pallidum infection on the central nervous system have been appreciated for centuries, the pathogenesis and host response to CNS syphilis are poorly understood. Treponema pallidum invades the central nervous system (CNS) in the first weeks of infection, as demonstrated by CSF pleocytosis, elevated protein, reactive CSF-VDRL or identification of the organism. While most individuals resolve their CSF abnormalities over time, approximately 25% fail to do so and are at risk for development of clinical neurosyphilis. The issues regarding pathogenesis and treatment of CNS syphilis have been re-emphasized in recent years for two reasons: 1) Syphilis is epidemic in the United States. In 1990, the number of reported cases of infectious syphilis was higher than in any of the preceding 40 years, and an estimated 1.5 million persons in this country are infected with syphilis. 2) Recent case reports suggest that coinfection with HIV may increase the likelihood of development of neurosyphilis, even after standard therapy for early infection. We have recently developed a rabbit model of early neurosyphilis. This model parallels early CNS syphilis in humans in that intracisternally infected rabbits consistently develop a mononuclear CSF pleocytosis and have demonstrable T. pallidum in CSF and brain tissue; syphilitic uveitis is seen with same frequency in rabbits as in patients with early syphilis. We propose to use this model to 1) define the pathological and clinical consequences of CNS T. pallidum infection; 2) investigate the mechanisms of pathogenesis of CNS syphilis with respect to antigen specificity if infiltrating cells in the CSF, production and specificity of CSF antibodies, and inflammatory mediators; 3) examine the specificities and functions of antibodies and T lymphocytes in the clearance of organisms from the CNS; 4) determine the alterations in disease progression and host response in pharmacologically immunosuppressed rabbits; and 5) evaluate the efficacy of recommended therapies for early syphilis and neurosyphilis in immunocompetent and pharmacologically immunodeficient rabbits. The information gained from the proposed studies will be directly applicable to questions regarding the pathogenesis, immune response and treatment of CNS syphilis in humans, and to the interaction between syphilis infection and HIV.