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

• 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
• 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

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.

寄生虫与宿主细胞之间的细胞间通讯提供了寄生虫 发育、免疫逃避和疾病病理学。非洲锥虫的血液 膜纳米管（NT），其起源于鞭毛膜并解离成游离的 细胞外囊泡（EV）。锥虫EV含有几种鞭毛蛋白， 在哺乳动物宿主中的毒力，包括calflagin，腺苷酸环化酶（GRESAG4）， 糖基磷脂酰肌醇磷脂酶C（GPI-PLC）、钙网蛋白和后半胱天冬酶4。此外，本发明还提供了一种方法， 人类昏睡病寄生虫布氏罗得西亚锥虫产生的EV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。我们 表明T. B.罗得西亚EV将SRA转移到非人感染性锥虫， 逃避人类的先天免疫形态学和生物物理学研究表明， 锥虫EV也可以与磷脂酰胆碱脂质体融合，锥虫鞭毛口袋 和哺乳动物红细胞。锥虫EV与红细胞融合改变了其物理性质 红细胞增加膜硬度导致红细胞快速清除和贫血。的 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)在锥虫感染期间是否产生EV，如果是， 在感染过程中，EV的生产率和货物是否发生变化？2)做电动汽车 传递群体感应分子，触发BF锥虫的分化？3)NT/EV是否 途径提供了一种外排机制，以清除人类昏睡病寄生虫的锥虫溶解 因素（TLF）？4)EV是否递送调节分泌的锥虫效应分子？ 细胞因子，肿瘤坏死因子-α，在骨髓细胞中？5)锥虫EV与宿主的融合 红细胞导致红细胞吞噬作用和贫血？6)哪些锥虫蛋白是必需的 用于电动汽车与膜的融合这些拟议的研究将有助于更好地了解 锥虫EV在细胞间通讯中作用和非洲人相关的发病机制 锥虫我们预计这些研究将导致新的诊断工具的开发， 提供了新的战略，以打击贫血症在人类昏睡病和Nagana。