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.

寄生物与寄主细胞之间的细胞间通讯提供了寄生物生存的机制

项目成果

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