PULMONARY AND SYSTEMIC KILLING OF OPPORTUNISTIC FUNGI

肺部和全身杀灭机会性真菌

• 批准号: 2060205
• 负责人: RICHARD D DIAMOND
• 金额: $ 36.06万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-09-01 至 1995-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2060205
• 关键词: Aspergillus; Candida albicans; antifungal antibody; biological signal transduction; disease /disorder proneness /risk; eicosanoid metabolism; fluorescent dye /probe; host organism interaction; human subject; laboratory mouse; laboratory rabbit; leukocyte oxidative burst; monoclonal antibody; monocyte; mycosis; neutrophil; opportunistic infections; phagocytosis; phosphorylation; receptor binding; respiratory infections; tissue /cell culture

DESCRIPTION: (Adapted from applicant's abstract) Opportunistic mycoses continue to increase in frequency and importance. In 3 of the most common of these, candidiasis, aspergillosis, and mucormycosis, hyphae must be cleared from lesions, primarily by neutrophils (PMN), to prevent progressive disseminated infections. These studies focus upon a stepwise analysis of interactions between fungal hyphae and PMN that ultimately result in killing of the organisms. Initially, experiments will concentrate on interactions os PMN with Candida albicans, with additional studies using Aspergillus fumigatus and Rhizopus oryzae for specific aspects likely to differ, if time permits. Opsonized and unopsonized hyphae elicit different patterns of early PMN responses leading to activation of the PMN respiratory burst that is required for hyphal killing. Previous data provide initial clues to the identity of apparently separate PMN binding and activation sites as well as interacting ligands on opsonized and unopsonized hyphae. These will be further pursued using specific MAbs combined with hyphae selectively opsonized with individual serum factors reactive with PMN receptors. Activation of specific receptors will be linked to initiation of early PMN ion fluxes and biochemical events to determine events and pathways necessary and sufficient for activation of the respiratory burst and degranulation. Recent data imply that both are required for fungicidal effects. Identification of pathways for initial PMN activation will continue, including studies of temporal involvement of specific phospholipases, phospholipids, and possible endogenous mediators derived from arachidonic acid-containing or other lipids. Hyphal killing by PMN is a relatively slow process, not attributable to the almost immediate lethal effects of cell-free oxidants. To define the mechanisms and loci of lethal hyphal damage by PMN, a combined approach will employ both intact PMN and granule-depleted cytoplast with added granule constituents separately or in combination (e.g., myeloperoxidase, defensins, cathepsin G, lactoferrin, lysozyme and elastase). In addition to processes initiating PMN responses to hyphae, we will begin to identify and study factors modulating the sustained PMN activation response required for killing. To define effects of PMN on the target organisms, temporal biochemical and visual changes in multiple localized fluorescent markers loaded into live hyphae will be correlated with localized biochemical indicators of damage, PMN oxidant and granule release, and their coincidence with the onset of killing.

描述：（改编自申请人的摘要）机会性mycoses 继续增加频率和重要性。 在最常见的三个 其中，念珠菌病，曲霉病和粘膜细胞增多，菌丝必须是 从病变中清除，主要是由中性粒细胞（PMN）清除 进行性传播感染。 这些研究集中于逐步 分析真菌菌丝和PMN之间的相互作用 导致杀死生物体。 最初，实验会 专注于与白色念珠菌的相互作用OS PMN，并附加 使用曲霉曲霉和根茎oryzae进行特定的研究 如果时间允许，方面可能会有所不同。 调整和未封闭 菌丝引起早期PMN反应的不同模式，导致 菌丝所需的PMN呼吸爆发的激活 杀人。 以前的数据为显然的身份提供了初始线索 单独的PMN结合和激活位点以及在 调子和未透明的菌丝。 这些将进一步追求 特定的mAb与菌丝结合选择性地与个体结合 血清因子与PMN受体反应。 特定的激活 受体将与早期PMN离子通量的启动有关 生化事件以确定必要的事件和途径， 足以激活呼吸爆发和脱粒。 最近的数据表明，两者都是杀真菌效应所必需的。 识别初始PMN激活的途径将继续， 包括研究特定磷脂酶的时间参与， 磷脂，以及可能衍生自蛛形子的内源介质 含酸或其他脂质。 PMN杀死菌丝是一个相对的 缓慢的过程，不是归因于几乎立即致死的影响 无细胞氧化剂。 定义致命菌丝的机制和基因座 PMN的损害，合并的方法将同时采用完整的PMN和 分别或分别添加的颗粒成分颗粒的细胞生成物质或 组合（例如髓过氧化物酶，防御蛋白，组织蛋白酶G，乳铁蛋白， 溶菌酶和弹性酶）。 除了启动PMN响应的过程 对于菌丝，我们将开始识别和研究调节的因素 杀死需要持续的PMN激活反应。 定义效果 目标生物上的PMN，时间生化和视觉变化 装入活菌丝中的多个局部荧光标记将是 与局部损伤，PMN氧化剂和 颗粒释放，以及它们与杀戮的发作的巧合。