The flagellated protozoan parasite Trypanosoma brucei is responsible for African trypanosomiasis, which causes widespread mortality and morbidity of humans and livestock in sub-Saharan Africa. Sleeping sickness is fatal if untreated, yet no vaccine exists and current treatments are old, toxic and difficult to administer. Thus, ther is a pressing need for research to better understand these parasites and facilitate development of new therapeutic interventions. Trypanosomes are also an important experimental system for studying biology of flagella and cilia, which are critical to normal human health. T. brucei depends on its flagellum for movement within host tissues and for directing cell development and division. Extensive work in a wide range of eukaryotes demonstrates that in addition to the flagellum's canonical role in motility, it functions as a signaling center to perceive and respond o external cues in the environment. Recent work indicates that the trypanosome flagellum likewise functions in motility and signaling capacity. The long term goal of the proposed work is to determine the role of motility in pathogenesis, define mechanisms that regulate trypanosome motility and test the hypothesis that the flagellum directs signaling systems important for virulence. To do this, we will employ motility mutants, mouse infection models to test signaling and motility functions for a contribution to infection. We will also employ systems biology approaches to define signaling systems in the flagellum and identify genes controlled by these signaling systems. Finally, we will use cryoelectron tomography, together with mutational analysis to build a three-dimensional molecular model of the flagellum in an effort to understand structural foundations of unique flagellum functions in trypanosomes. Our focus is on the flagellum of T. brucei. However, flagella are important for many other pathogenic protozoa as well as for normal human development and health. Therefore, we expect our results to be of wide interest for the community studying pathogenesis of parasitic protozoa, human development and physiology, and fundamental biology of eukaryotes.

Public Health Relevance

African trypanosomes are devastating human and animal pathogens that cause significant human mortality and limit economic development. The trypanosome flagellum is an essential organelle that is receiving increased attention as a drug target. The current proposal aims to understand aspects of flagellum biology that are important for disease transmission and pathogenesis. The studies will also provide insights into fundamental aspects of flagellum biology that are relevant for a broad spectrum of infectious and inherited diseases in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI052348-11A1
Application #
8696535
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2002-06-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
11
Fiscal Year
2014
Total Cost
$335,977
Indirect Cost
$110,977
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Freire, Eden R; Malvezzi, Amaranta M; Vashisht, Ajay A et al. (2014) Trypanosoma brucei translation initiation factor homolog EIF4E6 forms a tripartite cytosolic complex with EIF4G5 and a capping enzyme homolog. Eukaryot Cell 13:896-908
Saada, Edwin A; Kabututu, Z Pius; Lopez, Miguel et al. (2014) Insect stage-specific receptor adenylate cyclases are localized to distinct subdomains of the Trypanosoma brucei Flagellar membrane. Eukaryot Cell 13:1064-76
Freire, Eden R; Vashisht, Ajay A; Malvezzi, Amaranta M et al. (2014) eIF4F-like complexes formed by cap-binding homolog TbEIF4E5 with TbEIF4G1 or TbEIF4G2 are implicated in post-transcriptional regulation in Trypanosoma brucei. RNA 20:1272-86
Kisalu, Neville K; Langousis, Gerasimos; Bentolila, Laurent A et al. (2014) Mouse infection and pathogenesis by Trypanosoma brucei motility mutants. Cell Microbiol 16:912-24
Nguyen, HoangKim T; Sandhu, Jaspreet; Langousis, Gerasimos et al. (2013) CMF22 is a broadly conserved axonemal protein and is required for propulsive motility in Trypanosoma brucei. Eukaryot Cell 12:1202-13
Freund, Jonathan B; Goetz, Jacky G; Hill, Kent L et al. (2012) Fluid flows and forces in development: functions, features and biophysical principles. Development 139:1229-45
Merveille, Anne-Christine; Davis, Erica E; Becker-Heck, Anita et al. (2011) CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet 43:72-8
Ralston, Katherine S; Kisalu, Neville K; Hill, Kent L (2011) Structure-function analysis of dynein light chain 1 identifies viable motility mutants in bloodstream-form Trypanosoma brucei. Eukaryot Cell 10:884-94
Oberholzer, Michael; Langousis, Gerasimos; Nguyen, HoangKim T et al. (2011) Independent analysis of the flagellum surface and matrix proteomes provides insight into flagellum signaling in mammalian-infectious Trypanosoma brucei. Mol Cell Proteomics 10:M111.010538
Hill, Kent L (2010) Parasites in motion: flagellum-driven cell motility in African trypanosomes. Curr Opin Microbiol 13:459-65

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