title: Mouse infection and pathogenesis by Trypanosoma brucei motility mutants.
abstract: The flagellum of Trypanosoma brucei is an essential and multifunctional organelle that drives parasite motility and is receiving increased attention as a potential drug target. In the mammalian host, parasite motility is suspected to contribute to infection and disease pathogenesis. However, it has not been possible to test this hypothesis owing to lack of motility mutants that are viable in the bloodstream life cycle stage that infects the mammalian host. We recently identified a bloodstream-form motility mutant in 427-derived T. brucei in which point mutations in the LC1 dynein subunit disrupt propulsive motility but do not affect viability. These mutants have an actively beating flagellum, but cannot translocate. Here we demonstrate that the LC1 point mutant fails to show enhanced cell motility upon increasing viscosity of the surrounding medium, which is a hallmark of wild type T. brucei, thus indicating that motility of the mutant is fundamentally altered compared with wild type cells. We next used the LC1 point mutant to assess the influence of trypanosome motility on infection in mice. Wesurprisingly found that disrupting parasite motility has no discernible effect on T. brucei bloodstream infection. Infection time-course, maximum parasitaemia, number of waves of parasitaemia, clinical features and disease outcome are indistinguishable between motility mutant and control parasites. Our studies provide an important step toward understanding the contribution of parasite motility to infection and a foundation for future investigations of T. brucei interaction with the mammalian host.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Neville K
authors.initials: NK
authors.lastname: Kisalu
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Langousis
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Bentolila
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Ralston
authors.forename: Kent L
authors.initials: KL
authors.lastname: Hill
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008124:Locomotion; D051379:Mice; D018512:Parasitemia; D016019:Survival Analysis; D013997:Time Factors; D014346:Trypanosoma brucei brucei / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D014353:Trypanosomiasis, African / Q000469:parasitology* / Q000473:pathology*; D014774:Virulence