REGULATORY MECHANISMS DETERMINING FUNGICIDAL RESPONSES

决定杀菌反应的调节机制

• 批准号: 3091999
• 负责人: RICHARD D DIAMOND
• 金额: $ 66.03万
• 依托单位: BOSTON UNIVERSITY MEDICAL CENTER HOSP
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-01 至 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3091999
• 关键词: Candida albicans; blastomycosis; candidiasis; cellular immunity; cryptococcosis; leukocyte activation /transformation; microorganism immunology; neutrophil

This Program aims to define the range of critical responses by which major types of leukocyte effector cells combat distinct, serious mycoses, facilitating collaborative insights into comparative mechanisms of effector response patterns to disparate target fungi with differing susceptibilities to varying leukocyte products. The major objective of Project # 1 (R.D. Diamond and F.R. Sullivan, co-investigators) is to determine the bases for preliminary results indicating disparate effects of human cytokines on killing of Candida albicans hyphae by neutrophils (PMN), even though three cytokines (interferon-gamma, tumor necrosis factor-alpha and granulocyte- macrophage colony stimulating factor) all enhance the PMN respiratory burst primarily required for killing these organisms. Project # 2 (E.H. Smail) aims to characterize biochemically and functionally a product of C. albicans hyphae which inhibits PMN superoxide release and degranulation but not chemotaxis induced by a wide range of agonists, without altering responses to phorbol myristate acetate. Project # 3 (S.M. Levitz) addresses the unique interactions with macrophages of Cryptococcus neoformans yeasts and the role of its capsular polysaccharide in its interactions with both host serum opsonins and phagocytic cells, particularly effects on killing and on specific cellular signal transduction response patterns to stimulation, which will be determined in single cells and cell populations upon activation via single or multiple defined macrophage membrane receptors. Project # 4 (A.M. Sugar) addresses the process by which macrophages act as major effector mediating defenses controlling blastomycosis, aiming to define receptor activation mechanisms, signal transduction pathways, and ultimate responses which determine divergent fungicidal responses against conidia and yeasts, as well as the mechanisms by which cytokines augment inefficient killing by unstimulated macrophages. Project # 5 (W.E. Hauser) focuses on defining the receptor- mediated signal transduction pathways responsible for triggering and controlling direct inhibition and/or killing of C. neoformans and indirect release of mediators by NK cells to augment neutrophil candidacidal effects. Three Core units are designed to provide coordinated facilities for all projects in analysis of individual cell responses, surface receptor and lipid metabolic changes related to signal transduction, and coordination of leukocyte supplies from normal and immunodeficient donors.

该计划旨在定义主要响应的范围 白细胞效应细胞的类型对抗明显，严重的mycose， 促进对效应器比较机制的协作见解 具有不同敏感性的不同目标真菌的响应模式 变化的白细胞产品。 项目＃1的主要目标（R.D. 钻石和F.R. Sullivan，共同研究器）是确定 初步结果表明人类细胞因子对 尽管三个 细胞因子（干扰素 - γ，肿瘤坏死因子-Alpha和粒细胞 - 巨噬细胞菌落刺激因子）均增强了PMN呼吸爆发 杀死这些生物的主要需要。 项目＃2（E.H. Smail） 旨在以生物化学和功能为C的产物。 白色的菌丝抑制PMN超氧化物释放和脱粒，但 不是多种激动剂诱导的趋化性，而不会改变 对佛罗宝纳肉豆蔻酸酯的反应。 项目＃3（S.M. Levitz） 解决与隐球菌巨噬细胞的独特相互作用 Neoformans酵母及其囊多糖在其中的作用 与宿主血清反素和吞噬细胞的相互作用， 特别对杀戮和特定的蜂窝信号的影响 刺激的转导反应模式将在 通过单个或多个激活后，单细胞和细胞种群 定义的巨噬细胞膜受体。 项目＃4（A.M. Sugar）地址 巨噬细胞充当主要效应子介导的防御的过程 控制爆术，旨在定义受体激活机制， 信号转导途径和确定的最终响应 针对分生孢子和酵母的杀真菌反应分歧，以及 细胞因子通过未刺激增强无效杀死的机制 巨噬细胞。 项目＃5（W.E。Hauser）着重于定义受体 介导的信号转导途径负责触发和 控制直接抑制和/或杀死新梭菌和间接 NK细胞释放介体以增强嗜中性粒细胞念珠菌 效果。 三个核心单元旨在提供协调的设施 对于分析单个细胞反应的所有项目，表面受体 和脂质代谢变化与信号转导相关，以及 来自正常和免疫缺陷供体的白细胞供应的协调。