PATHOGENESIS AND THERAPY OF EXPERIMENTAL NEUROSYPHILIS

实验性神经梅毒的发病机制和治疗

• 批准号: 3084668
• 负责人: Christina M Marra
• 金额: $ 8.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3084668
• 关键词: HIV infections; T lymphocyte; bacterial antigens; central nervous system; disease /disorder model; immunodeficiency; laboratory rabbit; macrophage; nonhuman therapy evaluation; opsonin; pathologic process; penicillins; syphilis

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.

虽然T.中央苍白球感染 几个世纪以来，神经系统一直受到重视，其发病机制和 对中枢神经系统梅毒宿主反应了解很少。 梅毒螺旋体 在感染的第一周侵入中枢神经系统（CNS）， 如CSF细胞增多、蛋白质升高、反应性CSF-VDRL或 识别有机体。 虽然大多数人解决他们的CSF 随着时间的推移，大约25%的人无法做到这一点， 临床神经梅毒的发展。 有关的问题 中枢神经系统梅毒的发病机制和治疗已被重新强调， 近年来，由于两个原因：1）在美国， States. 1990年，传染性梅毒的报告病例数为 比之前40年的任何一年都要高，估计有150万人 这个国家的人都感染了梅毒。 2)近期病例报告 这表明与艾滋病毒合并感染可能会增加 神经梅毒的发展，即使在早期的标准治疗后， 感染 我们最近建立了一个早期神经梅毒的兔子模型。 这 模型与人类脑池内早期CNS梅毒相似， 受感染的兔子持续地发展出单核CSF细胞增多症， 可以证明T。脑脊液和脑组织苍白球;梅毒性葡萄膜炎 在兔子中的出现频率与早期梅毒患者相同。 我们建议使用该模型来1）定义病理和临床 CNS T的后果苍白球感染; 2）研究苍白球感染的机制 中枢神经系统梅毒的发病机制与抗原特异性有关，如果 CSF中的浸润细胞，CSF的产生和特异性 抗体和炎症介质; 3）检查特异性， 抗体和T淋巴细胞在机体清除中的作用 从CNS; 4）确定疾病进展和宿主 免疫抑制兔的免疫反应;和5）评估 早期梅毒和神经梅毒的推荐治疗方法的疗效 免疫活性和免疫缺陷兔。 的 从拟议研究中获得的信息将直接适用于 关于CNS的发病机制、免疫应答和治疗的问题 人类梅毒，以及梅毒感染与 艾滋病。