Synergy of Host Defense Mechanisms in the Lung

 描述（由申请人提供）：本申请建议继续我们对人类致病真菌新型隐球菌的细胞内生活方式的研究，新型隐球菌是免疫抑制个体如AIDS患者、移植受体和免疫抑制治疗患者的主要病原体。C.新生菌是兼性细胞内病原体，其致病机制依赖于其在巨噬细胞中存活的能力。也许在C.新生菌是一种非溶解性胞吐现象，其中真菌细胞从巨噬细胞中释放而不溶解或对宿主细胞造成明显损伤。非溶解性吞噬作用涉及真菌和宿主细胞的贡献，并且它必须是一个非常精心设计的过程，其中吞噬体膜与细胞膜融合以将吞噬体内容物吐出到细胞外空间中而没有宿主细胞溶解。非溶解性胞吐现象现已在哺乳动物、昆虫、黏菌和原生动物细胞中被证实，表明对不同宿主具有显著的特异性，这一事实表明它利用高度保守的真核细胞机制或包括冗余机制。初步研究表明，C.来自巨噬细胞的新型非溶解性胞吐：自噬和膜联蛋白。此外，在非溶解性胞吐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的：1.建立巨噬细胞损伤与CN非溶解性胞吐的关系;建立宿主膜联蛋白参与CN非溶解性胞吐的机制; 3.鉴定促进非溶解性胞吐作用的真菌成分。

 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.