PLATELETS AND HOST DEFENSES AGAINST ASPERGILLOSIS

血小板和宿主对曲霉病的防御

• 批准号: 2518555
• 负责人: RICHARD D DIAMOND
• 金额: $ 35.68万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518555
• 关键词: Aspergillus; aspergillosis; cell adhesion; cell membrane; cellular immunity; confocal scanning microscopy; cytotoxicity; enzyme linked immunosorbent assay; granule; human tissue; immunoelectron microscopy; in situ hybridization; leukocyte activation /transformation; microorganism immunology; monocyte; neutrophil; northern blottings; oxidizing agents; phagocytes; phagocytosis; platelet activation; platelets; polymerase chain reaction; vascular endothelium; western blottings

Invasive aspergillosis is an increasingly common, usually fatal infection affecting growing numbers of immunocompromised patients. Predisposition to progressive invasive aspergillosis has been associated with specific factors. These include neutropenia, most often related to antineoplastic chemotherapy, or abnormalities in the host inflammatory response due to extended, high dose corticosteroid therapy, post-transplantation immunosuppression, or the acquired immunodeficiency syndrome (AIDS). Neutrophils (PAN) and macrophages are major host effector cells responsible for clearing the various forms of Aspergillus organisms from host tissues. However, recent data suggest key roles for other cell types besides phagocytes in the types of intravascular inflammatory responses that must prevent or contain progressive aspergillosis. The pathogenesis of invasive aspergillosis is marked by dramatic invasion of blood vessel walls, with thrombosis and hemorrhagic infarction. Platelets directly mediate pivotal components of intravascular inflammation and also are critical modulators of phagocytic and vascular endothelial cell function. Prolonged neutropenia is cited as a dominant associated risk factor for invasive aspergillosis, but almost all such patients have concomitant thrombocytopenia. Recent reports by others note avid platelet adherence to Candida albicans as well as candidacidal activity of a platelet granule-associated cationic peptide. Our data further show that Aspergillus fumigatus hyphae and resting or swollen conidia adhere to and activate human platelets. Platelets alone predominantly induce significant but reversible damage to functional cell walls. Some fungicidal activity occurs in the process, but is limited in the absence of other inflammatory cells. However, PAN and platelets combined have enhance fungicidal effects. Therefore, we plan to define: (a) the platelet and fungal surface constituents mediating adherence and platelet activation; (b) the specific mechanisms and consequences of fungal damage by platelets; and (c) the interactive effects of human platelets, PAN, monocytes, and/or endothelial cells on killing of A. fumigatus hyphae and conidia. Our prior data show that human vascular endothelial cells endocytose but do not kill A. fumigatus hyphae or conidia, so we will also study the interactive effects of platelets, phagocytes, and endothelium on fungal cell survival as well as inflammatory host cell damage related to platelet and leukocyte activation. The long-term objective is to increase understanding of the normally potent host defenses that prevent or contain invasive aspergillosis in the absence of immunosuppression. Ultimately, this may improve measures to prevent and/or treat this now too often lethal infection.

侵入性曲霉菌病是一种日益普遍的，通常是致命的感染 影响越来越多的免疫功能低下的患者。倾向 进行性侵袭性曲霉病与特定有关 因素。其中包括中性粒细胞减少，通常与抗肿瘤相关 宿主炎症反应的化学疗法或异常 扩展，高剂量皮质类固醇治疗，移植后 免疫抑制或获得的免疫缺陷综合征（AIDS）。 中性粒细胞（PAN）和巨噬细胞是主要的宿主效应细胞 负责清除各种形式的曲霉生物 宿主组织。但是，最近的数据提出了其他单元类型的关键作用 除了血管内炎症反应类型的吞噬细胞外 这必须防止或包含进行性曲霉病。发病机理 侵入性的曲霉菌病以血管的巨大入侵为标志 墙壁，血栓形成和出血性梗塞。血小板直接 介导血管内炎症的关键成分，也是 吞噬细胞和血管内皮细胞功能的关键调节剂。 长时间的中性粒细胞减少被认为是主要的相关风险因素 侵入性的曲霉菌病，但几乎所有此类患者均伴有 血小板减少症。其他人的最新报道记录了狂热的血小板依从性 对白色念珠菌以及血小板的念珠菌活性 颗粒相关的阳离子肽。我们的数据进一步表明 曲霉菌菌丝菌丝和休息或肿胀的分生孢子粘附在和 激活人血小板。仅血小板主要诱导 对功能细胞壁的巨大但可逆的损害。一些 杀真菌活动发生在此过程中，但在不存在的情况下受到限制 其他炎症细胞。但是，锅和血小板的总和 增强杀菌作用。因此，我们计划定义：（a） 血小板和真菌表面成分介导依从性和血小板 激活; （b）真菌损害的特定机制和后果 由血小板； （c）人血小板的互动效应，pan， 单核细胞和/或内皮细胞杀死烟曲霉和/或 分生孢子。我们先前的数据表明人血管内皮细胞 内吞但不杀死A. fumigatus菌丝或分生孢子，所以我们将 还研究血小板，吞噬细胞和 真菌细胞存活以及炎症宿主细胞的内皮 与血小板和白细胞激活有关的损伤。长期 目的是增加对正常有效宿主的理解 在缺席的情况下预防或含有侵入性曲霉病的防御措施 免疫抑制。最终，这可能会改善预防措施 和/或现在经常对此进行致命感染。