Synergy of Host Defense Mechanisms in the Lung

肺部宿主防御机制的协同作用

• 批准号: 9123661
• 负责人: Arturo Casadevall
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123661
• 关键词: Acquired Immunodeficiency Syndrome; Actins; Amoeba genus; Annexins; Area; Autophagocytosis; Back; Cell Communication; Cell membrane; Cells; Cellular biology; Cryptococcus neoformans; Cytochalasins; Cytolysis; Disease; Distant; Employee Strikes; Etiology; Eukaryotic Cell; Event; Exocytosis; Extracellular Space; Fungal Components; Health; Host Defense Mechanism; Human; Immune system; Individual; Insecta; Knowledge; Laboratories; Lead; Life Style; Lung; Lytic; Mammals; Membrane; Membrane Fusion; Modification; Mus; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Permeability; Phagocytes; Phagocytosis; Phagolysosome; Phagosomes; Physarum polycephalum; Process; Property; Protozoa; Reporting; Research; Robin bird; Role; Specificity; Structure; Sum; Surface Tension; System; Therapeutic immunosuppression; Time; Transplant Recipients; Vomiting; Water; Work; capsule; cell injury; cell killing; cinematography; cytokine; design; fascinate; fungus; immunosuppressed; in vivo; inhibitor/antagonist; interest; killings; macrophage; novel therapeutics; novel vaccines; pathogen

 DESCRIPTION (provided by applicant): This application proposes to continue our studies on the intracellular lifestyle of the human pathogenic fungus Cryptococcus neoformans, which is a major pathogen of immunosuppressed individuals such as patients with AIDS, transplant recipients, and those on immunosuppressive therapy. C. neoformans is a facultative intracellular pathogen and is dependent on its ability to survive in macrophages for its pathogenic mechanisms. Perhaps the most dramatic effect observed with C. neoformans is the phenomenon of non-lytic exocytosis whereby fungal cells are released from macrophages without lysis or apparent damage to the host cells. Non-lytic phagocytosis involves contributions from both the fungus and host cells and it must be a remarkably well choreographed process whereby the phagosomal membrane fuses with the cell membrane to disgorge the phagosomal contents into the extracellular space without host cell lysis. The phenomenon of non-lytic exocytosis has now been documented in mammalian, insect, slime mold and protozoal cells indicating remarkable specificity for different hosts, a fact suggesting that it either exploits hihly conserved eukaryotic cellular mechanisms or includes redundant mechanisms. Preliminary studies indicate that two highly conserved eukaryotic cellular systems are involved in C. neoformans non-lytic exocytosis from macrophages: autophagy and annexins. Furthermore, the requirement for fungal viability in non-lytic exocytosis events implies active modification of the cryptococcal phagosome by the fungus. Consequently, this application proposes the following three specific aims: 1. To establish the relationship between macrophage damage and CN non-lytic exocytosis; 2. To establish the mechanism by which host annexins contribute to CN non-lytic exocytosis; 3. To identify the fungal components that facilitates non-lytic exocytosis.

 描述（由申请人提供）：本申请拟继续研究人类致病真菌新型隐球菌的细胞内生活方式，该真菌是免疫抑制个体（例如艾滋病患者、移植受者和接受免疫抑制治疗的患者）的主要病原体。新型隐球菌是一种兼性细胞内病原体，其致病机制依赖于其在巨噬细胞中的存活能力。也许在新型隐球菌中观察到的最显着的效果是非裂解性胞吐作用现象，即真菌细胞从巨噬细胞中释放出来，而不会裂解或对宿主细胞造成明显损害。非裂解性吞噬作用涉及真菌和宿主细胞的贡献，并且它必须是一个精心设计的过程，吞噬体膜与细胞膜融合，将吞噬体内容物释放到细胞外空间而不裂解宿主细胞。非裂解性胞吐现象现已在哺乳动物、昆虫、粘菌和原生动物细胞中得到记录，表明其对不同宿主具有显着的特异性，这一事实表明它要么利用高度保守的真核细胞机制，要么包括冗余机制。初步研究表明，两种高度保守的真核细胞系统参与了新型隐球菌巨噬细胞的非裂解性胞吐作用：自噬和膜联蛋白。此外，非裂解性胞吐作用事件中对真菌活力的要求意味着真菌对隐球菌吞噬体的主动修饰。因此，本申请提出以下三个具体目标： 1. 建立巨噬细胞损伤与CN非裂解性胞吐作用之间的关系； 2. 建立宿主膜联蛋白促进CN非裂解性胞吐作用的机制； 3. 鉴定促进非裂解性胞吐作用的真菌成分。