Role of African Trypanosome Extracellular Vesicles in Infection and Pathogenesis

非洲锥虫胞外囊泡在感染和发病机制中的作用

基本信息

批准号：
9311314
负责人：
STEPHEN L HAJDUK
金额：
$ 37.5万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311314
关键词：
Address Adenylate Cyclase Africa South of the Sahara African African Trypanosomiasis Anemia Animal Diseases Binding Biochemical Biological Blood Circulation Cattle Diseases Cell Communication Cells Chronic Communication Complex Data Defense Mechanisms Development Differentiation and Growth Disease Progression Drug Metabolic Detoxication Effector Cell Endosomes Erythrocytes Erythrophagocytosis Glycosylphosphatidylinositols Growth Human Immune Immune Evasion Immune System Diseases Immune response Immunity Infection Lecithin Lipids Liposomes Liver Lytic Mammals Mediating Membrane Molecular Morphology Mus Myeloid Cells Nanotubes Natural Immunity Organ Outcome Parasites Pathogenesis Pathology Pathway interactions Phagocytosis Pharmaceutical Preparations Phospholipase C Platelet Factor 4 Population Predisposition Primates Process Production Proteins Proteomics Publications Resistance Risk Role Serum Specificity TNF gene Testing Toxic effect Trypanosoma Trypanosoma brucei brucei Trypanosoma brucei gambiense Trypanosoma brucei rhodesiense Vaccines Virulence Virulence Factors Wasting Syndrome adaptive immunity biophysical analysis calreticulin cell type combat cytokine extracellular vesicles fluidity human disease in vivo intercellular communication killings macrophage microbial monocyte nagana neutrophil novel diagnostics novel strategies novel therapeutic intervention pathogen physical property quorum sensing resistance factors response screening tool trafficking vesicular release

项目摘要

Intercellular communication between parasites and with host cells provides mechanisms for parasite development, immune evasion and disease pathology. Bloodstream African trypanosomes produce membranous nanotubes (NTs) that originate from the flagellar membrane and disassociate into free extracellular vesicles (EVs). Trypanosome EVs contain several flagellar proteins that contribute to virulence in the mammalian host including calflagin, adenylate cyclase (GRESAG4), glycosylphosphatidylinositol phospholipase C (GPI-PLC), calreticulin and metacaspase 4. In addition, the human sleeping sickness parasite Trypanosoma brucei rhodesiense produces EVs that contain the serum resistance associated protein (SRA) a virulence factor necessary for human infectivity. We have shown that T. b. rhodesiense EVs transfer SRA to non-human infectious trypanosomes allowing evasion of human innate immunity. Morphological and biophysical studies have shown that trypanosome EVs can also fuse with phosphatidylcholine liposomes, the trypanosome flagellar pocket and mammalian erythrocytes. Trypanosome EV fusion with erythrocytes alters the physical properties of erythrocytes increasing membrane rigidity resulting in rapid erythrocyte clearance and anemia. The proposed studies will extend these initial findings and address several fundamental questions about the function of membrane NTs and EVs. 1) Are EVs produced during trypanosome infection and if so what is the rate of production and does EV cargo change during the course of infection? 2) Do EVs deliver quorum-sensing molecules that trigger differentiation of BF trypanosomes? 3) Does the NT/EV pathway provide an efflux mechanism to rid human sleeping sickness parasites of trypanosome lytic factors (TLF)? 4) Do EVs deliver trypanosome effector molecules that modulate production of the cytokine, tumor necrosis factor-α, in myeloid cells? 5) Does the fusion of trypanosome EVs with host erythrocytes result in erythrophagocytosis and anemia? 6) What trypanosome proteins are necessary for EVs fusion to membranes? Together the proposed studies will result in a better understanding of the role of trypanosome EVs in cell-cell communication and pathogenesis associated by African trypanosomiasis. We anticipate these studies will lead to the development of new diagnostic tools and offer novel strategies to combat anemia in human sleeping sickness and Nagana.

寄生虫之间以及与宿主细胞之间的细胞间通讯为寄生虫提供了机制非洲锥虫的发育、免疫逃避和疾病病理学。膜纳米管（NT）源自鞭毛膜并解离成游离的细胞外囊泡 (EV) 含有多种鞭毛蛋白，有助于对哺乳动物宿主的毒力包括calflagin、腺苷酸环化酶（GRESAG4）、糖基磷脂酰肌醇磷脂酶 C (GPI-PLC)、钙网蛋白和元半胱天冬酶 4。此外，人类昏睡病寄生虫罗得西亚布氏锥虫产生的 EVs 含有血清耐药相关蛋白（SRA）是人类感染性所必需的毒力因子。已经表明，罗得西亚锥虫 EVs 将 SRA 转移到非人类传染性锥虫上，从而使形态学和生物物理学研究表明，逃避人类先天免疫。锥虫 EV 还可以与磷脂酰胆碱脂质体（锥虫鞭毛口袋）融合和哺乳动物红细胞的锥虫EV与红细胞的融合改变了物理特性。红细胞膜刚性增加，导致红细胞快速清除和贫血。拟议的研究将扩展这些初步发现并解决有关的几个基本问题膜 NT 和 EV 的功能 1) EV 是否在锥虫感染过程中产生？ 2) 做电动汽车传递引发 BF 锥虫分化的群体感应分子 3) NT/EV 是否有效？途径提供了一种外排机制，可以消除人类昏睡病寄生虫中的锥虫裂解物因素 (TLF)？ 4) EV 是否传递调节锥虫效应分子的产生骨髓细胞中的细胞因子、肿瘤坏死因子-α？ 5) 锥虫 EV 与宿主融合吗？ 6) 哪些锥虫蛋白是必需的拟议的研究将有助于更好地理解电动汽车与膜的融合？锥虫 EV 在细胞间通讯和非洲相关发病机制中的作用我们预计这些研究将导致新的诊断工具的开发和提供了对抗人类昏睡病和 Nagana 贫血的新策略。