ROLE OF MACROPHAGES IN CRYPTOCOCCAL INFECTIONS

巨噬细胞在隐球菌感染中的作用

• 批准号: 3139384
• 负责人: Stuart Michael Levitz
• 金额: $ 5.61万
• 依托单位: BOSTON UNIVERSITY MEDICAL CENTER HOSP
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1990-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3139384
• 关键词: AIDS; Cryptococcus neoformans; acidity /alkalinity; antibody dependent killer cell; antifungal agents; calcium transporting ATPase; cell capsule; cell free system; cell population study; cellular pathology; cryptococcosis; cytokine; helper T lymphocyte; histocompatibility antigens; host organism interaction; human tissue; immunosuppression; interferons; interleukin 1; interleukin 2; laboratory mouse; macrophage; macrophage activating factor; melanins; membrane potentials; monocyte; monophenol monooxygenase; mutant; opportunistic infections; opsonin; oxidizing agents; phagocytosis; polysaccharides; tissue /cell culture; tumor necrosis factor alpha; virulence

Cryptococcosis occurs disproportionately in patients with impaired cell-mediated immunity (CMI), especially those with AIDS. Although development of an effective CMI response is essential in combating this fungus, the role that specific cellular and soluble components of CMI play is incompletely understood. Two virulence factors of C. neoformans have been identified experimentally, its capsule and its ability to produce maelanin, yet it remains unclear how these help the organism elude host defenses. This proposal focuses on the central role of the macrophage (MP) as an effector and affector cell in CMI, in order to define the derangements occurring in the setting of impaired CMI that may allow C. neoformans to elude host defenses. The effector cell role will be probed by exploring why unactivated MP fail to kill C. neoformans, and the requirements to activate MP to kill. MP mediated killing will be determining following treatment with cytokines including gamma interferon and TNF and with the addition of purified non-MP cell populations. MP killing mechanisms will be studied (i) using inhibitors and stimulators of specific MP functions (ii) by determining opsonic and other condition necessary for adherance and internalization of the organisms, (iii) by quantitating generation of microbicidal substances such as oxidants by C. neoformans stimulated MP, (iv) by measuring early cellular events, such as calcium ion transients, which are presumed to relate to the generation of these microbicidal substances and, (v) in cell-free systems containing putative leukocyte fungicidal products. MP antigen presentation will be studied by determining expression of Ia glycoproteins and interleukin-1 during cryptococcal infections. The above studies will compare virulent cryptococcal strain with capsule and melanin deficient strains. Strains will be unopsonized or specifically opsonized with IgG, C3, or both. Completion of these studies should contribute important new information to our basic understanding of cryptococcal infections, and may provide a rational basis for studies in AIDS and other patients with cryptococcal infections.

隐球菌病在以下患者中发生率不成比例 细胞介导的免疫（CMI）受损，尤其是那些患有 艾滋病。 尽管制定有效的 CMI 应对措施是 对于对抗这种真菌至关重要，特定细胞的作用 CMI 发挥的可溶性成分尚不完全清楚。 已鉴定出新型隐球菌的两个毒力因子 实验上，它的胶囊及其产生黑色素的能力， 但目前尚不清楚这些如何帮助生物体逃避宿主 防御。 该提案重点强调了 巨噬细胞 (MP) 作为 CMI 中的效应细胞和影响细胞，按顺序排列 定义在受损环境中发生的混乱 CMI 可能允许新型隐球菌逃避宿主防御。 这 效应细胞的作用将通过探索 MP 未激活的原因来探究 未能杀死新型隐球菌，并且需要激活MP才能 杀。 MP 介导的杀伤将在治疗后确定 与包括γ干扰素和TNF在内的细胞因子以及与 添加纯化的非 MP 细胞群。 议员杀戮 将研究机制（i）使用抑制剂和刺激剂 (ii) 通过确定调理和其他特定 MP 功能 坚持和内化的必要条件 生物体，（iii）通过定量杀微生物剂的产生 新型隐球菌刺激 MP 产生的氧化剂等物质，(iv) 通过测量早期细胞事件，例如钙离子瞬变， 据推测与这些的产生有关 杀微生物物质，以及，(v) 在含有的无细胞系统中 假定的白细胞杀真菌产品。 MP抗原呈递 将通过测定 Ia 糖蛋白的表达来研究 隐球菌感染期间的白介素-1。 上述研究 将比较强毒力的隐球菌菌株与胶囊和 黑色素缺陷菌株。 菌株将不受调理或 与 IgG、C3 或两者特异性调理。 完成这些 研究应该为我们的基础研究提供重要的新信息 了解隐球菌感染，并可能提供 艾滋病和其他患有艾滋病的患者的研究的合理基础 隐球菌感染。