The flagellated protozoan parasite Trypanosoma brucei is responsible for African trypanosomiasis, which is transmitted by the tsetse fly and 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, there is a pressing need for research to better understand these parasites and facilitate development of new therapeutic interventions. T. brucei depends on its flagellum for cell motility, coordination of signaling in response to the external environment, interaction with host tissues, and cell morphogenesis and division. Thus, the trypanosome flagellum is essential for parasite survival, transmission through the fly vector, and infection of the mammalian host. The long-term goal of our studies is to understand how motility and host-parasite interactions provided by the trypanosome flagellum contribute to infection and pathogenesis. Much is known about flagellum composition and structure, but important questions remain regarding the specific proteins and interactions that underlie trypanosome-specific motility and the role of motility during host infection. To address these knowledge gaps, we will employ motility mutants and mouse infection models to address the role of motility in avoidance of the host immune response and penetration of extravascular tissues, which both impact disease pathogenesis and transmission. We will also use cryoelectron tomography, together with mutational analysis, to build a three-dimensional molecular model of the flagellum and elucidate proteins that comprise trypanosome-specific flagellum structures and functions. 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

Trypanosomatids are motile protozoan parasites that cause devastating disease in humans and animals. The trypanosome flagellum is essential for motility and signaling functions that affect host-parasite interactions, with important consequences for host infection, parasite transmission, and treatment of disease. In the current project, we aim to elucidate trypanosome-specific features of motility and provide insight into aspects of parasite motility that impact disease outcome.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Mcgugan, Glen C
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Shimogawa, Michelle M; Ray, Sunayan S; Kisalu, Neville et al. (2018) Parasite motility is critical for virulence of African trypanosomes. Sci Rep 8:9122
Marti, Matthias; Hill, Kent L (2016) Sensing and signaling in parasitism. Mol Biochem Parasitol 208:1
Langousis, Gerasimos; Shimogawa, Michelle M; Saada, Edwin A et al. (2016) Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei. Proc Natl Acad Sci U S A 113:632-7
Oberholzer, Michael; Saada, Edwin A; Hill, Kent L (2015) Cyclic AMP Regulates Social Behavior in African Trypanosomes. MBio 6:e01954-14
Saada, Edwin A; DeMarco, Stephanie F; Shimogawa, Michelle M et al. (2015) ""With a Little Help from My Friends""-Social Motility in Trypanosoma brucei. PLoS Pathog 11:e1005272
Shimogawa, Michelle M; Saada, Edwin A; Vashisht, Ajay A et al. (2015) Cell Surface Proteomics Provides Insight into Stage-Specific Remodeling of the Host-Parasite Interface in Trypanosoma brucei. Mol Cell Proteomics 14:1977-88
Lopez, Miguel A; Saada, Edwin A; Hill, Kent L (2015) Insect stage-specific adenylate cyclases regulate social motility in African trypanosomes. Eukaryot Cell 14:104-12
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
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; 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

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