Nicotine & Immunopathogenesis of Cryptococcal meningitis

描述（由申请人提供）：中枢神经系统的机会性感染是获得性免疫缺陷综合征（艾滋病）患者常见的并发症。新型隐球菌（Cne）是一种包膜酵母菌，在7-30%的艾滋病患者中引起致命的隐球菌性脑膜脑炎（CM）。虽然高活性抗逆转录病毒疗法成功地降低了许多机会性感染的发生率，但它在降低晚期艾滋病患者机会性真菌感染的发生率方面效果较差。宿主对Cne的反应是先天免疫和适应性免疫之间复杂的相互作用。在动物模型中，无法增加脑促炎细胞因子水平或促进白细胞向脑迁移通常与致死性CM相关。因此，中枢神经系统需要“促炎”反应来控制Cne感染。流行病学研究表明，吸烟是隐球菌病和其他机会性真菌感染的重要危险因素，而艾滋病隐球菌病患者中有85%是吸烟者。然而，吸烟影响Cne发病的机制是完全未知的。我们已经证明香烟烟雾会抑制免疫系统，尼古丁（NT）是香烟烟雾中主要的免疫抑制成分，它会引起T细胞的能量并抑制炎症反应。我们的初步研究表明，慢性NT治疗抑制趋化/趋化和白细胞向炎症部位的迁移，降低脑il -1 β表达，以响应炎症刺激，如松节油和Cne，并促进Cne的生长和早期传播到大脑。因此，我们假设香烟烟雾/NT调节Cne的先天和适应性免疫反应，从而促进其传播到大脑和CM的发展。为了验证这一假设并确定NT促进Cne脑感染的机制，提出了以下研究：研究NT对Cne诱导的先天免疫的影响，包括脑内促炎细胞因子/趋化因子的表达和白细胞对受Cne影响的细胞因子/趋化因子的反应，建立Cne和白细胞向脑内迁移和CM发展的动力学，并研究NT对Cne诱导的发热反应的影响。2. 确定对适应性免疫反应的影响，包括抗Cne抗体的产生，对隐球菌抗原的增殖性和延迟型超敏反应，以及对Cne蛋白免疫优势表位的细胞毒性T细胞的产生，以及评估Cne感染后迁移到大脑的T细胞的保护功能。3. 探讨NT抑制白细胞向感染部位迁移的机制。我们相信，这些研究将描述吸烟/NT促进Cne传播以及其他真菌感染进入艾滋病患者大脑的机制，并确定CM治疗的潜在治疗靶点。

DESCRIPTION (provided by applicant): Opportunistic infections of the central nervous system are common complication in acquired immunodeficiency syndrome (AIDS) patients. Cryptococcus neoformans (Cne) is an encapsulated yeast that causes often fatal cryptococcal meningoencephalitis (CM) in 7-30% of AIDS patients. While highly active anti-retroviral therapy has successfully decreased the incidence of many opportunistic infections, it is less effective in decreasing the incidence of opportunistic fungal infections in advanced AIDS patients. The host's response to Cne is a complex interplay between the innate and adaptive immunities. In animal models, the inability to increase the brain levels of proinflammatory cytokines or promote leukocyte migration into the brain is typically associated with lethal CM. Thus, "proinflammatory" responses are required to contain Cne infection in the central nervous system. Epidemiological studies show that cigarette smoking is a significant risk factor in cryptococcosis and other opportunistic fungal infections, and >85% of AIDS patients with cryptococcosis are cigarette smokers. However, the mechanism by which smoking affects the pathogenesis of Cne is totally unknown. We have demonstrated that cigarette smoke suppresses the immune system, and nicotine (NT) is a major immunosuppressive component of cigarette smoke that causes T cell anergy and inhibits the inflammatory responses. Our preliminary studies suggest that chronic NT treatment inhibits chemokinesis/chemotaxis and the migration of leukocytes to the site of inflammation, decreases brain IL-1beta expression in response to an inflammatory stimuli such as turpentine and Cne, and promotes growth and early dissemination of Cne into the brain. Therefore, we hypothesize that cigarette smoke/NT modulates both the innate and adaptive immune responses to Cne, thus facilitating its dissemination to the brain and the development CM. To test this hypothesis and to identify mechanism(s) by which NT facilitates brain infection by Cne, the following studies are proposed: 1. To investigate the effects of NT on Cne-induced innate immunity, including the expression of proinflammatory cytokines/chemokines in the brain and the response of leukocytes to cytokines/chemokines that are affected by Cne, to establish the kinetics of Cne and leukocyte migration into the brain and the development of CM, and to examine the effects of NT on the Cne-induced fever response. 2. To ascertain the effects on the adaptive immune responses including generation of anti-Cne antibodies, proliferative and delayed-type hypersensitivity responses to cryptococcal antigens, and generation of cytotoxic T cells to immunodominant epitopes of Cne proteins, as well as to evaluate the protective function of T cells that migrate into the brain after Cne infection. 3. To investigate the mechanisms by which NT suppresses the migration of leukocytes toward the site of infection. These studies, we believe, will delineate the mechanism(s) by which smoking/NT encourages dissemination of Cne and, perhaps, other fungal infections into the brain of AIDS patients, and identify potential therapeutic targets for treatment of CM.