Motility and more: The flagellum of Trypanosoma brucei

Nature Reviews Microbiology

Volumn 12, Issue 7, 2014, Pages 505-518

  Langousis, Gerasimos ^a   Hill, Kent L ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

VIRULENCE FACTOR;

AXONEME; CELL DIVISION; CELL FUNCTION; CELL MOTILITY; CELL STRUCTURE; DISEASE TRANSMISSION; EUKARYOTIC FLAGELLUM; HOST PARASITE INTERACTION; MORPHOGENESIS; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TRYPANOSOMA BRUCEI; CELL MATURATION; FLAGELLUM; KINETOPLASTIDA; LIFE CYCLE; PARASITE TRANSMISSION;

ANIMALS; CELL DIVISION; CELL MOVEMENT; FLAGELLA; HOST-PARASITE INTERACTIONS; HUMANS; INSECT VECTORS; TRYPANOSOMA BRUCEI BRUCEI; TRYPANOSOMIASIS, AFRICAN; TSETSE FLIES;

EID: 84902491737     PISSN: 17401526     EISSN: 17401534     Source Type: Journal    
DOI: 10.1038/nrmicro3274     Document Type: Review

References (162)

1. Simpson, A. G., Stevens, J. R. &Lukes, J. The evolution and diversity of kinetoplastid flagellates. Trends Parasitol. 22, 168-174 (2006).
2. Alvar, J. et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7, e35671 (2012).
3. Barrett, M. P. et al. The trypanosomiases. Lancet 362, 1469-1480 (2003).
4. Stuart, K. et al. Kinetoplastids: related protozoan pathogens, different diseases. J. Clin. Invest. 118, 1301-1310 (2008).
5. Kennedy, P. G. Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). Lancet Neurol. 12, 186-194 (2013).
6. Jamonneau, V. et al. Untreated human infections by Trypanosoma brucei gambiense are not 100% fatal. PLoS Negl. Trop. Dis. 6, e1691 (2012).
7. Simarro, P. P., Jannin, J. &Cattand, P. Eliminating human African trypanosomiasis: where do we stand and what comes next? PLoS Med. 5, e55 (2008).
8. Kohl, L., Robinson, D. &Bastin, P. Novel roles for the flagellum in cell morphogenesis and cytokinesis of trypanosomes. EMBO J. 22, 5336-5346 (2003).
9. Gruby, M. Recherches et observations sur une nouvelle espèce d'hématozoaire, Trypanosoma sanguinis. Comptes Rendus Hebdomadaire Séances l'Académie Sci. Paris 17, 1134-1136 (in French) (1843).
10. Valentin, G. G. Ueber ein Entozoon im Blute von Salmo fario. Arch. Anat. Phys. 435-436 (1841).
11. Ralston, K. S., Kabututu, Z. P., Melehani, J. H., Oberholzer, M. &Hill, K. L. The Trypanosoma brucei flagellum: moving parasites in new directions. Annu. Rev. Microbiol. 63, 335-362 (2009).
12. Gilula, N. B. &Satir, P. The ciliary necklace. A ciliary membrane specialization. J. Cell Biol. 53, 494-509 (1972).
13. Lacomble, S. et al. Three-dimensional cellular architecture of the flagellar pocket and associated cytoskeleton in trypanosomes revealed by electron microscope tomography. J. Cell Sci. 122, 1081-1090 (2009).
14. Vickerman, K. The mode of attachment of Trypanosoma vivax in the proboscis of the tsetse fly Glossina fuscipes: an ultrastructural study of the epimastigote stage of the trypanosome. J. Protozool. 20, 394-404 (1973).
15. Field, M. C. &Carrington, M. The trypanosome flagellar pocket. Nature Rev. Microbiol. 7, 775-786 (2009).
16. Benmerah, A. The ciliary pocket. Curr. Opin. Cell Biol. 25, 78-84 (2013).
17. Bonhivers, M., Nowacki, S., Landrein, N. &Robinson, D. R. Biogenesis of the trypanosome endo-exocytotic organelle is cytoskeleton mediated. PLoS Biol. 6, e105 (2008).
18. Maric, D., Epting, C. L. &Engman, D. M. Composition and sensory function of the trypanosome flagellar membrane. Curr. Opin. Microbiol. 13, 466-472 (2010).
19. Demmel L. et al. The endocytic activity of the flagellar pocket in Trypanosoma brucei is regulated by an adjacent phosphatidylinositol phosphate kinase. J. Cell Sci.127, 2351-2364 (2014).
20. Rotureau, B. et al. Flagellar adhesion in Trypanosoma brucei relies on interactions between different skeletal structures in the flagellum and cell body. J. Cell Sci. 127, 204-215 (2014).
21. Hoog, J. L., Bouchet-Marquis, C., McIntosh, J. R., Hoenger, A. &Gull, K. Cryo-electron tomography and 3D analysis of the intact flagellum in Trypanosoma brucei. J. Struct. Biol. 178, 189-198 (2012).
22. LaCount, D. J., Barrett, B. &Donelson, J. E. Trypanosoma brucei FLA1 is required for flagellum attachment and cytokinesis. J. Biol. Chem. 277, 17580-17588 (2002).
23. Sun, S. Y., Wang, C., Yuan, Y. A. &He, C. Y. An intracellular membrane junction consisting of flagellum adhesion glycoproteins links flagellum biogenesis to cell morphogenesis in Trypanosoma brucei. J. Cell Sci. 126, 520-531 (2013).
24. Vaughan, S., Kohl, L., Ngai, I., Wheeler, R. J. &Gull, K. A. Repetitive protein essential for the flagellum attachment zone filament structure and function in Trypanosoma brucei. Protist 159, 127-136 (2008).
25. Zhou, Q., Liu, B., Sun, Y. &He, C. Y. A coiled-coil-and C2-domain-containing protein is required for FAZ assembly and cell morphology in Trypanosoma brucei. J. Cell Sci. 124, 3848-3858 (2011).
26. Taylor, A. E. &Godfrey, D. G. A new organelle of bloodstream salivarian trypanosomes. J. Protozool. 16, 466-470 (1969).
27. Balber, A. E. The pellicle and the membrane of the flagellum, flagellar adhesion zone, and flagellar pocket: functionally discrete surface domains of the bloodstream form of African trypanosomes. Crit. Rev. Immunol. 10, 177-201 (1990).
28. Gadelha, C. et al. Membrane domains and flagellar pocket boundaries are influenced by the cytoskeleton in African trypanosomes. Proc. Natl Acad. Sci. USA 106, 17425-17430 (2009).
29. Satir, P. Landmarks in cilia research from Leeuwenhoek to us. Cell Motil. Cytoskeleton 32, 90-94 (1995).
30. Hughes, L. C., Ralston, K. S., Hill, K. L. &Zhou, Z. H. Three-dimensional structure of the trypanosome flagellum suggests that the paraflagellar rod functions as a biomechanical spring. PLoS ONE 7, e25700 (2012).
31. Gibbons, I. R. Studies on the protein components of cilia from Tetrahymena pyriformis. Proc. Natl Acad. Sci. USA 50, 1002-1010 (1963).
32. Heuser, T., Raytchev, M., Krell, J., Porter, M. E. &Nicastro, D. The dynein regulatory complex is the nexin link and a major regulatory node in cilia and flagella. J. Cell Biol. 187, 921-933 (2009).
33. Mitchell, D. R. Reconstruction of the projection periodicity and surface architecture of the flagellar central pair complex. Cell. Motil. Cytoskeleton 55, 188-199 (2003).
34. Branche, C. et al. Conserved and specific functions of axoneme components in trypanosome motility. J. Cell Sci. 119, 3443-3455 (2006).
35. Dawe, H. R., Shaw, M. K., Farr, H. &Gull, K. The hydrocephalus inducing gene product, Hydin, positions axonemal central pair microtubules. BMC Biol. 5, 33 (2007).
36. Ralston, K. S., Lerner, A. G., Diener, D. R. &Hill, K. L. Flagellar motility contributes to cytokinesis in Trypanosoma brucei and is modulated by an evolutionarily conserved dynein regulatory system. Eukaryot. Cell 5, 696-711 (2006).
37. Nicastro, D. et al. The molecular architecture of axonemes revealed by cryoelectron tomography. Science 313, 944-948 (2006).
38. Pigino, G. et al. Comparative structural analysis of eukaryotic flagella and cilia from Chlamydomonas, Tetrahymena, and sea urchins. J. Struct. Biol. 178, 199-206 (2012).
39. Gadelha, C., Wickstead, B., McKean, P. G. &Gull, K. Basal body and flagellum mutants reveal a rotational constraint of the central pair microtubules in the axonemes of trypanosomes. J. Cell Sci. 119, 2405-2413 (2006).
40. Satir, P. Studies on cilia. 3. Further studies on the cilium tip and a "sliding filament" model of ciliary motility. J. Cell Biol. 39, 77-94 (1968).
41. Heuser, T., Dymek, E. E., Lin, J., Smith, E. F. &Nicastro, D. The CSC connects three major axonemal complexes involved in dynein regulation. Mol. Biol. Cell 23, 3143-3155 (2012).
42. Yamamoto, R. et al. The MIA complex is a conserved and novel dynein regulator essential for normal ciliary motility. J. Cell Biol. 201, 263-278 (2013).
43. Bower, R. et al. The N-DRC forms a conserved biochemical complex that maintains outer doublet alignment and limits microtubule sliding in motile axonemes. Mol. Biol. Cell 24, 1134-1152 (2013).
44. Kabututu, Z. P., Thayer, M., Melehani, J. H. &Hill, K. L. CMF70 is a subunit of the dynein regulatory complex. J. Cell Sci. 123, 3587-3595 (2010).
45. Lin, J. et al. Building blocks of the nexin-dynein regulatory complex in Chlamydomonas flagella. J. Biol. Chem. 286, 29175-29191 (2011).
46. Wirschell, M. et al. The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. Nature Genet. 45, 262-268 (2013).
47. Nguyen, H. K., Sandhu, J. S., Langousis, G. &Hill, K. CMF22 is a broadly conserved axonemal protein and is required for propulsive motility in Trypanosoma brucei. Eukaryot. Cell 12, 1202-1213 (2013).
48. Huang, B., Ramanis, Z. &Luck, D. J. Suppressor mutations in Chlamydomonas reveal a regulatory mechanism for flagellar function. Cell 28, 115-124 (1982).
49. Cachon, J., Cachon, M., Cosson, M.-P. &Cosson, J.C. The paraflagellar rod: a structure in search of a function. Biol. Cell 63, 169-181 (1988).
50. Bastin, P., Sherwin, T. &Gull, K. Paraflagellar rod is vital for trypanosome motility. Nature 391, 548 (1998).
51. Koyfman, A. Y. et al. Structure of Trypanosoma brucei flagellum accounts for its bihelical motion. Proc. Natl Acad. Sci. USA 108, 11105-11108 (2011).
52. Portman, N. &Gull, K. The paraflagellar rod of kinetoplastid parasites: from structure to components and function. Int. J. Parasitol. 40, 135-148 (2010).
53. Oberholzer, M. et al. The Trypanosoma brucei cAMP phosphodiesterases TbrPDEB1 and TbrPDEB2: flagellar enzymes that are essential for parasite virulence. FASEB J. 21, 720-731 (2007).
54. Portman, N., Lacomble, S., Thomas, B., McKean, P. G. &Gull, K. Combining RNA interference mutants and comparative proteomics to identify protein components and dependences in a eukaryotic flagellum. J. Biol. Chem. 284, 5610-5619 (2009).
55. Salathe, M. Regulation of mammalian ciliary beating. Annu. Rev. Physiol. 69, 401-422 (2007).
56. Satir, P. &Christensen, S. T. Overview of structure and function of mammalian cilia. Annu. Rev. Physiol. 69, 377-400 (2007).
57. Sugrue, P., Hirons, M. R., Adam, J. U. &Holwill, M. E. Flagellar wave reversal in the kinetoplastid flagellate Crithidia oncopelti. Biol. Cell 63, 127-131 (1988).
58. Walker, P. J. Organization of function in trypanosome flagella. Nature 189, 1017-1018 (1961).
59. Baron, D. M., Kabututu, Z. P. &Hill, K. L. Stuck in reverse: loss of LC1 in Trypanosoma brucei disrupts outer dynein arms and leads to reverse flagellar beat and backward movement. J. Cell Sci. 120, 1513-1520 (2007).
60. Heddergott, N. et al. Trypanosome motion represents an adaptation to the crowded environment of the vertebrate bloodstream. PLoS Pathog. 8, e1003023 (2012).
61. Jahn, T. L. &Bovee, E. C. in Infectious Blood Diseases of Man and Animals (eds Weinman, D. &Ristic, M.) 393-436 (Academic Press, 1968).
62. Uppaluri, S. et al. Impact of microscopic motility on the swimming behavior of parasites: straighter trypanosomes are more directional. PLoS Comput. Biol. 7, e1002058 (2011).
63. Rodriguez, J. A. et al. Propulsion of African trypanosomes is driven by bihelical waves with alternating chirality separated by kinks. Proc. Natl Acad. Sci. USA 106, 19322-19327 (2009).
64. Votta, J. J., Jahn, T. L., Griffith, D. L. &Fonseca, J. R. Nature of the flagellar beat in Trachelomonas volvocina, Rhabdomonas spiralis, Menoidium cultellus, and Chilomonas paramecium. Trans. Am. Microsc. Soc. 90, 404-412 (1971).
65. Wilson, L. G., Carter, L. M. &Reece, S. E. High-speed holographic microscopy of malaria parasites reveals ambidextrous flagellar waveforms. Proc. Natl Acad. Sci. USA 110, 18769-18774 (2013).
66. Shaevitz, J. W., Lee, J. Y. &Fletcher, D. A. Spiroplasma swim by a processive change in body helicity. Cell 122, 941-945 (2005).
67. Oberholzer, M., Lopez, M. A., McLelland, B. T. &Hill, K. L. Social motility in African trypanosomes. PLoS Pathog. 6, e1000739 (2010).
68. Harshey, R. M. Bacterial motility on a surface: many ways to a common goal. Annu. Rev. Microbiol. 57, 249-273 (2003).
69. Vickerman, K. Developmental cycles and biology of pathogenic trypanosomes. Br. Med. Bull. 41, 105-114. (1985).
70. Rotureau, B., Ooi, C. P., Huet, D., Perrot, S. &Bastin, P. Forward motility is essential for trypanosome infection in the tsetse fly. Cell. Microbiol. 16, 425-433 (2013).
71. Hill, K. L. Mechanism and biology of trypanosome cell motility. Eukaryot. Cell 2, 200-208 (2003).
72. Jennings, F. W., Whitelaw, D. D., Holmes, P. H., Chizyuka, H. G. &Urquhart, G. M. The brain as a source of relapsing Trypanosoma brucei infection in mice after chemotherapy. Int. J. Parasitol. 9, 381-384 (1979).
73. Mulenga, C., Mhlanga, J. D., Kristensson, K. &Robertson, B. Trypanosoma brucei brucei crosses the blood-brain barrier while tight junction proteins are preserved in a rat chronic disease model. Neuropathol. Appl. Neurobiol. 27, 77-85 (2001).
74. Wolburg, H. et al. Late stage infection in sleeping sickness. PLoS ONE 7, e34304 (2012).
75. Frevert, U. et al. Early invasion of brain parenchyma by African trypanosomes. PLoS ONE 7, e43913 (2012).
76. Engstler, M. et al. Hydrodynamic flow-mediated protein sorting on the cell surface of trypanosomes. Cell 131, 505-515 (2007).
77. Broadhead, R. et al. Flagellar motility is required for the viability of the bloodstream trypanosome. Nature 440, 224-227 (2006).
78. Ralston, K. S. &Hill, K. L. Trypanin, a component of the flagellar dynein regulatory complex, is essential in bloodstream form African trypanosomes. PLoS Pathog. 2, 873-882, e101 (2006).
79. Ralston, K. S., Kisalu, N. K. &Hill, K. L. Structure-function analysis of dynein light chain 1 identifies viable motility mutants in bloodstream-form Trypanosoma brucei. Eukaryot. Cell 10, 884-894 (2011).
80. Kisalu, N. K., Langousis, G., Bentolila, L. A., Ralston, K. S. &Hill, K. L. Mouse infection and pathogenesis by Trypanosoma brucei motility mutants. Cell. Microbiol. 16, 912-924 (2014).
81. MacGregor, P., Rojas, F., Dean, S. &Matthews, K. R. Stable transformation of pleomorphic bloodstream form Trypanosoma brucei. Mol. Biochem. Parasitol.190, 60-62 (2013).
82. Rotureau, B., Subota, I., Buisson, J. &Bastin, P. A new asymmetric division contributes to the continuous production of infective trypanosomes in the tsetse fly. Development 139, 1842-1850 (2012).
83. Sharma, R. et al. Asymmetric cell division as a route to reduction in cell length and change in cell morphology in trypanosomes. Protist 159, 137-151 (2008).
84. Robinson, D. R., Sherwin, T., Ploubidou, A., Byard, E. H. &Gull, K. Microtubule polarity and dynamics in the control of organelle positioning, segregation, and cytokinesis in the trypanosome cell cycle. J. Cell Biol. 128, 1163-1172 (1995).
85. Vaughan, S. Assembly of the flagellum and its role in cell morphogenesis in Trypanosoma brucei. Curr. Opin. Microbiol. 13, 453-458 (2010).
86. Moreira-Leite, F. F., Sherwin, T., Kohl, L. &Gull, K. A trypanosome structure involved in transmitting cytoplasmic information during cell division. Science 294, 610-621 (2001).
87. Briggs, L. J. et al. The flagella connector of Trypanosoma brucei: an unusual mobile transmembrane junction. J. Cell Sci. 117, 1641-1651 (2004).
88. Hughes, L., Towers, K., Starborg, T., Gull, K. &Vaughan, S. A cell body groove housing the new flagellum tip suggests an adaptation of cellular morphogenesis for parasitism in bloodstream form Trypanosoma brucei. J. Cell Sci. 126, 5748-5757 (2013).
89. Sonneborn, T. M. The determinants and evolution of life. Proc. Natl Acad. Sci. USA 51, 915-929 (1964).
90. Woods, K., Nic a'Bhaird, N., Dooley, C., Perez-Morga, D. &Nolan, D. P. Identification and characterization of a stage specific membrane protein involved in flagellar attachment in Trypanosoma brucei. PLoS ONE 8, e52846 (2013).
91. Hammarton, T. C., Kramer, S., Tetley, L., Boshart, M. &Mottram, J. C. Trypanosoma brucei Polo-like kinase is essential for basal body duplication, kDNA segregation and cytokinesis. Mol. Microbiol. 65, 1229-1248 (2007).
92. Ikeda, K. N. &de Graffenried, C. L. Polo-like kinase is necessary for flagellum inheritance in Trypanosoma brucei. J. Cell Sci. 125, 3173-3184 (2012).
93. Li, Z., Umeyama, T. &Wang, C. C. The Aurora kinase in Trypanosoma brucei plays distinctive roles in metaphase-anaphase transition and cytokinetic initiation. PLoS Pathog. 5, e1000575 (2009).
94. Li, Z. et al. Identification of a novel chromosomal passenger complex and its unique localization during cytokinesis in Trypanosoma brucei. PLoS ONE 3, e2354 (2008).
95. Ginger, M. L. et al. Calmodulin is required for paraflagellar rod assembly and flagellum-cell body attachment in trypanosomes. Protist 164, 528-540 (2013).
96. Ogbadoyi, E. O., Robinson, D. R. &Gull, K. A high-order trans-membrane structural linkage is responsible for mitochondrial genome positioning and segregation by flagellar basal bodies in trypanosomes. Mol. Biol. Cell 14, 1769-1779 (2003).
97. Robinson, D. R. &Gull, K. Basal body movements as a mechanism for mitochondrial genome segregation in the trypanosome cell cycle. Nature 352, 731-733 (1991).
98. Davidge, J. A. et al. Trypanosome IFT mutants provide insight into the motor location for mobility of the flagella connector and flagellar membrane formation. J. Cell Sci. 119, 3935-3943 (2006).
99. Absalon, S. et al. Basal body positioning is controlled by flagellum formation in Trypanosoma brucei. PLoS ONE 2, e437 (2007).
100. Farr, H. &Gull, K. Cytokinesis in trypanosomes. Cytoskeleton (Hoboken) 69, 931-941 (2012).
101. Ludington, W. B., Wemmer, K. A., Lechtreck, K. F., Witman, G. B. &Marshall, W. F. Avalanche-like behavior in ciliary import. Proc. Natl Acad. Sci. USA 110, 3925-3930 (2013).
102. Rotureau, B., Subota, I. &Bastin, P. Molecular bases of cytoskeleton plasticity during the Trypanosoma brucei parasite cycle. Cell. Microbiol. 13, 705-716 (2011).
103. Sharma, R. et al. The heart of darkness: growth and form of Trypanosoma brucei in the tsetse fly. Trends Parasitol. 25, 517-524 (2009).
104. MacGregor, P., Szoor, B., Savill, N. J. &Matthews, K. R. Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act. Nature Rev. Microbiol. 10, 431-438 (2012).
105. Berbari, N. F., O'Connor, A. K., Haycraft, C. J. &Yoder, B. K. The primary cilium as a complex signaling center. Curr. Biol. 19, R526-R535 (2009).
106. Singla, V. &Reiter, J. F. The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 313, 629-633 (2006).
107. Bloodgood, R. A. Sensory reception is an attribute of both primary cilia and motile cilia. J. Cell Sci. 123, 505-509 (2010).
108. Rotureau, B., Morales, M. A., Bastin, P. &Spath, G. F. The flagellum-mitogen-activated protein kinase connection in Trypanosomatids: a key sensory role in parasite signalling and development? Cell. Microbiol. 11, 710-718 (2009).
109. Tetley, L. &Vickerman, K. Differentiation in Trypanosoma brucei: host-parasite cell junctions and their persistence during acquisition of the variable antigen coat. J. Cell Sci. 74, 1-19 (1985).
110. Hemphill, A. &Ross, C. A. Flagellum-mediated adhesion of Trypanosoma congolense to bovine aorta endothelial cells. Parasitol. Res. 81, 412-420 (1995).
111. Van Den Abbeele, J., Caljon, G., De Ridder, K., De Baetselier, P. &Coosemans, M. Trypanosoma brucei modifies the tsetse salivary composition, altering the fly feeding behavior that favors parasite transmission. PLoS Pathog. 6, e1000926 (2010).
112. Peacock, L. et al. Identification of the meiotic life cycle stage of Trypanosoma brucei in the tsetse fly. Proc. Natl Acad. Sci. USA 108, 3671-3676 (2011).
113. Kolev, N. G., Ramey-Butler, K., Cross, G. A., Ullu, E. &Tschudi, C. Developmental progression to infectivity in Trypanosoma brucei triggered by an RNA-binding protein. Science 338, 1352-1353 (2012).
114. Peacock, L., Bailey, M., Carrington, M. &Gibson, W. Meiosis and haploid gametes in the pathogen Trypanosoma brucei. Curr. Biol. 24, 181-186 (2013).
115. Goodenough, U. W. &Thorner, J. in Cell Interactions and Development (ed. Yamada, K.) 29-75 (Wiley Interscience, 1983).
116. Miyake, A. in Biochemistry and Physiology of Protozoa (eds Hunter, S.H. &Levandrowsky, M.) 126-198 (Academic Press, 1981).
117. Pan, J. &Snell, W. J. Signal transduction during fertilization in the unicellular green alga, Chlamydomonas. Curr. Opin. Microbiol. 3, 596-602 (2000).
118. Salmon, D. et al. A novel heterodimeric transferrin receptor encoded by a pair of VSG expression site-associated genes in T. brucei. Cell 78, 75-86 (1994).
119. Kieft, R. et al. Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor. Proc. Natl Acad. Sci. USA 107, 16137-16141 (2010).
120. Hager, K. M. et al. Endocytosis of a cytotoxic human high density lipoprotein results in disruption of acidic intracellular vesicles and subsequent killing of African trypanosomes. J. Cell Biol. 126, 155-167 (1994).
121. Vanhollebeke, B. et al. A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans. Science 320, 677-681 (2008).
122. Sunter, J., Webb, H. &Carrington, M. Determinants of GPI-PLC localisation to the flagellum and access to GPI-anchored substrates in trypanosomes. PLoS Pathog. 9, e1003566 (2013).
123. Webb, H. et al. The GPI-phospholipase C of Trypanosoma brucei is nonessential but influences parasitemia in mice. J. Cell Biol. 139, 103-114 (1997).
124. Grandgenett, P. M., Otsu, K., Wilson, H. R., Wilson, M. E. &Donelson, J. E. A function for a specific zinc metalloprotease of African trypanosomes. PLoS Pathog. 3, 1432-1445 (2007).
125. Proto, W. R. et al. Trypanosoma brucei metacaspase 4 is a pseudopeptidase and a virulence factor. J. Biol. Chem. 286, 39914-39925 (2011).
126. Emmer, B. T. et al. Identification of a palmitoyl acyltransferase required for protein sorting to the flagellar membrane. J. Cell Sci. 122, 867-874 (2009).
127. Emmer, B. T., Daniels, M. D., Taylor, J. M., Epting, C. L. &Engman, D. M. Calflagin inhibition prolongs host survival and suppresses parasitemia in Trypanosoma brucei infection. Eukaryot. Cell 9, 934-942 (2010).
128. Paindavoine, P. et al. A gene from the variant surface glycoprotein expression site encodes one of several transmembrane adenylate cyclases located on the flagellum of Trypanosoma brucei. Mol. Cell. Biol. 12, 1218-1225 (1992).
129. Salmon, D. et al. Adenylate cyclases of Trypanosoma brucei inhibit the innate immune response of the host. Science 337, 463-466 (2012).
130. Oberholzer, M. et al. 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 (2011).
131. Mony, B. M. et al. Genome-wide dissection of the quorum sensing signalling pathway in Trypanosoma brucei. Nature 505, 681-685 (2013).
132. Gould, M. K. et al. Cyclic AMP effectors in African trypanosomes revealed by genome-scale RNA interference library screening for resistance to the phosphodiesterase inhibitor CpdA. Antimicrob. Agents Chemother. 57, 4882-4893 (2013).
133. Subota I. et al. Proteomic analysis of intact flagella of procyclic Trypanosoma brucei cells identifies novel flagellar proteins with unique sub-localisation and dynamics. Mol. Cell Proteomics http://dx.doi.org/10.1074/ mcp.M113.033357 (2014).
134. Fliegauf, M., Benzing, T. &Omran, H. When cilia go bad: cilia defects and ciliopathies. Nature Rev. Mol. Cell Biol. 8, 880-893 (2007).
135. Gerdes, J. M., Davis, E. E. &Katsanis, N. The vertebrate primary cilium in development, homeostasis, and disease. Cell 137, 32-45 (2009).
136. MacGregor, P., Savill, N. J., Hall, D. &Matthews, K. R. Transmission stages dominate trypanosome within-host dynamics during chronic infections. Cell Host Microbe 9, 310-318 (2011).
137. Rosenbaum, J. L. &Witman, G. B. Intraflagellar transport. Nature Rev. Mol. Cell Biol. 3, 813-825 (2002).
138. Huet, D., Blisnick, T., Perrot, S. &Bastin, P. The GTPase IFT27 is involved in both anterograde and retrograde intraflagellar transport. eLife 3, e02419 (2014).
139. Absalon, S. et al. Intraflagellar transport and functional analysis of genes required for flagellum formation in trypanosomes. Mol. Biol. Cell 19, 929-944 (2008).
140. Buisson, J. et al. Intraflagellar transport proteins cycle between the flagellum and its base. J. Cell Sci. 126, 327-338 (2013).
141. Nachury, M. V. et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201-1213 (2007).
142. Price, H. P. et al. A role for the vesicle-associated tubulin binding protein ARL6 (BBS3) in flagellum extension in Trypanosoma brucei. Biochim. Biophys. Acta 1823, 1178-1191 (2012).
143. Hoog, J. L. et al. Modes of flagellar assembly in Chlamydomonas reinhardtii and Trypanosoma brucei. eLife 3, e01479 (2014).
144. Bastin, P., Pullen, T. J., Sherwin, T. &Gull, K. Protein transport and flagellum assembly dynamics revealed by analysis of the paralysed trypanosome mutant snl-1. J. Cell Sci. 112, 3769-3777 (1999).
145. Maga, J. A., Sherwin, T., Francis, S., Gull, K. &LeBowitz, J. H. Genetic dissection of the Leishmania paraflagellar rod, a unique flagellar cytoskeleton structure. J. Cell Sci. 112, 2753-2763 (1999).
146. Demonchy, R. et al. Kinesin 9 family members perform separate functions in the trypanosome flagellum. J. Cell Biol. 187, 615-622 (2009).
147. Carvalho-Santos, Z., Azimzadeh, J., Pereira-Leal, J. B. &Bettencourt-Dias, M. Evolution: tracing the origins of centrioles, cilia, and flagella. J. Cell Biol. 194, 165-175 (2011).
148. Fritz-Laylin, L. K. et al. The genome of Naegleria gruberi illuminates early eukaryotic versatility. Cell 140, 631-642 (2010).
149. Finetti, F. et al. Intraflagellar transport is required for polarized recycling of the TCR/CD3 complex to the immune synapse. Nature Cell Biol. 11, 1332-1339 (2009).
150. Mitchell, D. R. The evolution of eukaryotic cilia and flagella as motile and sensory organelles. Adv. Exp. Med. Biol. 607, 130-140 (2007).
151. Kozminski, K. G., Johnson, K. A., Forscher, P. &Rosenbaum, J. L. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc. Natl Acad. Sci. USA 90, 5519-5523 (1993).
152. Pazour, G. J., Agrin, N., Leszyk, J. &Witman, G. B. Proteomic analysis of a eukaryotic cilium. J. Cell Biol. 170, 103-113 (2005).
153. Morga, B. &Bastin, P. Getting to the heart of intraflagellar transport using Trypanosoma and Chlamydomonas models: the strength is in their differences. Cilia 2, 16 (2013).
154. Baron, D. M., Ralston, K. S., Kabututu, Z. P. &Hill, K. L. Functional genomics in Trypanosoma brucei identifies evolutionarily conserved components of motile flagella. J. Cell Sci. 120, 478-491 (2007).
155. McGraw, E. A. &O'Neill, S. L. Beyond insecticides: new thinking on an ancient problem. Nature Rev. Microbiol. 11, 181-193 (2013).
156. Haas, B. J. et al. Genome sequence and analysis of the Irish potato famine pathogen Phytophthora infestans. Nature 461, 393-398 (2009).
157. Greenwood, B. M., Bojang, K., Whitty, C. J. &Targett, G. A. Malaria. Lancet 365, 1487-1498 (2005).
158. Carlton, J. M. et al. Draft genome sequence of the sexually transmitted pathogen Trichomonas vaginalis. Science 315, 207-212 (2007).
159. Gryseels, B., Polman, K., Clerinx, J. &Kestens, L. Human schistosomiasis. Lancet 368, 1106-1118 (2006).
160. Desjardins, C. A. et al. Genomics of Loa loa, a Wolbachia-free filarial parasite of humans. Nature Genet. 45, 495-500 (2013).
161. Morrison, H. G. et al. Genomic minimalism in the early diverging intestinal parasite Giardia lamblia. Science 317, 1921-1926 (2007).
162. Bloodgood, R. A. From central to rudimentary to primary: the history of an underappreciated organelle whose time has come. The primary cilium. Methods Cell Biol. 94, 3-52 (2009).