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: 10088373
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088373
• 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; PF4 Gene; Parasites; Pathogenesis; Pathology; Pathway interactions; Phagocytosis; Pharmaceutical Preparations; Phospholipase C; 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; macrophage; microbial; monocyte; nagana; neutrophil; novel diagnostics; novel strategies; novel therapeutic intervention; pathogen; physical property; quorum sensing; 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.

寄生虫和宿主细胞之间的细胞间通信提供了寄生虫的机制 发育，免疫进化和疾病病理学。血液非洲锥虫的生产 源自鞭毛膜并分离为自由的膜纳米管（NTS） 细胞外蔬菜（EV）。锥虫电动汽车包含几种有助于的鞭毛蛋白 哺乳动物宿主的病毒，包括钙蛋白酶，腺苷酸环化酶（Gresag4）， 糖基磷脂酰肌醇磷脂酶C（GPI-PLC），钙网蛋白和肠胃菜酶4。此外， 人类睡眠疾病寄生虫锥虫brucei Rhodesiense产生的电动汽车包含 血清抗性相关蛋白（SRA）是人类感染所必需的病毒因子。我们 已经表明T. b。 Rhodesiense EVS将SRA转移到非人类感染性锥虫中，允许 逃避人类先天免疫。形态学和生物物理研究表明 锥虫电动汽车还可以与磷脂酰胆碱脂质体（锥虫鞭毛袋）融合 和哺乳动物红细胞。与红细胞的锥虫eV融合改变了物理特性 红细胞增加膜刚度，导致红细胞清除和贫血。 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NTS和EV的功能。 1）是锥虫感染期间产生的电动汽车等等 在感染过程中，EV货物的生产率是多少？ 2）做电动汽车 提供触发BF锥虫分化的群体感应分子？ 3）nt/ev 途径提供了一种流出机制，可以消除锥虫裂解的人类睡病寄生虫 因素（TLF）？ 4）DO EV提供了调节产生的锥虫效应分子 细胞因子，髓样细胞中的肿瘤坏死因子-α？ 5）锥形电动汽车与主机的融合 红细胞会导致红细胞增多和贫血？ 6）需要什么锥体蛋白 对于电动汽车融合到膜？拟议的研究一起将使人们更好地理解 锥虫电动汽车在非洲相关的细胞传播和发病机理中的作用 锥虫病。我们预计这些研究将导致新的诊断工具的开发 提供新颖的策略来打击人类睡眠和长纳纳的贫血。

项目成果

Lexis and Grammar of Mitochondrial RNA Processing in Trypanosomes

• DOI: 10.1016/j.pt.2020.01.006
• 发表时间: 2020-04-01
• 期刊: TRENDS IN PARASITOLOGY
• 影响因子: 9.6
• 作者: Aphasizheva, Inna;Alfonzo, Juan;Aphasizhev, Ruslan
• 通讯作者: Aphasizhev, Ruslan

Hypothesis-generating proteome perturbation to identify NEU-4438 and acoziborole modes of action in the African Trypanosome.

• DOI: 10.1016/j.isci.2022.105302
• 发表时间: 2022-11-18
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Sharma, Amrita;Cipriano, Michael;Ferrins, Lori;Hajduk, Stephen L.;Mensa-Wilmot, Kojo
• 通讯作者: Mensa-Wilmot, Kojo