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Motility and more: the flagellum of Trypanosoma brucei

Key Points

  • The African trypanosome Trypanosoma brucei is a unicellular pathogen that causes lethal sleeping sickness in humans, which is a devastating and neglected tropical disease that is endemic to vast regions of Africa. T. brucei also infects wild and domestic livestock, which limits sustainable development, and it is thus considered to be both a cause and consequence of poverty.

  • T. brucei has a single flagellum that is present throughout the parasite and its life cycle. The flagellum has conserved and unique features. It emerges from a membrane invagination at the posterior end of the cell and remains attached to the cell body for most of its length.

  • The flagellum contains cytoskeletal structures, which are ensheathed by a specialized flagellar membrane that interfaces with the external environment and that has a protein and lipid composition that is distinct from the rest of the cell surface. The T. brucei flagellum has multiple functions and is essential for parasite motility, viability, transmission and pathogenesis.

  • Flagellum-mediated motility is powered by the axoneme, which is a biological machine that converts dynein motor structural changes into flagellum beating and parasite propulsion. T. brucei motility is crucial for movement through host tissues and provides a surprising immune-evasion mechanism.

  • In addition to motility, the T. brucei flagellum is an important morphogenetic hub that controls cell shape and size, directs organelle segregation and governs cell division. These functions are modulated during developmental transitions of the parasite and are achieved by the direct or indirect physical connections of the flagellum to other cellular elements.

  • The flagellum is a crucial host–pathogen interface that has important roles in parasite transmission and virulence. Flagellar proteins mediate attachment to host tissues, carry out uptake of host growth factors and promote parasite survival by inhibiting host immunity.

  • T. brucei is an excellent model system to study the biology of the highly conserved eukaryotic flagellum and offers valuable insights into how flagella assemble, move and sense the environment. Continued studies of the T.brucei flagellum hold the promise of having a great impact on human health, as human flagella are paramount in human development and physiology. In addition, the flagella of many human pathogens are salient but unexplained structures that await further study.

Abstract

Trypanosoma brucei is a pathogenic unicellular eukaryote that infects humans and other mammals in sub-Saharan Africa. A central feature of trypanosome biology is the single flagellum of the parasite, which is an essential and multifunctional organelle that facilitates cell propulsion, controls cell morphogenesis and directs cytokinesis. Moreover, the flagellar membrane is a specialized subdomain of the cell surface that mediates attachment to host tissues and harbours multiple virulence factors. In this Review, we discuss the structure, assembly and function of the trypanosome flagellum, including canonical roles in cell motility as well as novel and emerging roles in cell morphogenesis and host–parasite interactions.

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Figure 1: Overview of the Trypanosoma brucei flagellum.
Figure 2: The axoneme and PFR structure.
Figure 3: The flagellum in cell division and cell morphogenesis.
Figure 4: The flagellum as a platform for host–pathogen interactions.

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Acknowledgements

The authors thank J. Buisson and P. Bastin (Institut Pasteur, Paris, France) for providing the live-cell video of IFT as well as N. Kisalu (University of California, Los Angeles (UCLA), USA) for providing the trypanosome motility video. They thank M. Shimogawa and other members of the Hill laboratory for helpful comments on the manuscript. The authors apologize to those colleagues whose work could not be cited owing to space limitations. K.L.H. is supported by grants from the US National Institutes of Health (NIH) (R01AI052348 and R21AI094333) and a Burroughs Wellcome Fund PATH award. G.L. is supported by a Warsaw Fellowship and a UCLA dissertation year fellowship.

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Correspondence to Kent L. Hill.

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Supplementary information

Supplementary information S1 (movie)

Real time video of bloodstream T. brucei motility. The parasite moves with the flagellum tip leading. Video courtesy of Neville Kisalu, University of California, Los Angeles, USA. (MOV 6867 kb)

Supplementary information S2 (movie)

Video of GFP-IFT52 trafficking in live procyclic T. brucei. Particles can be seen moving in both the anterograde (towards flagellum tip) and retrograde (towards flagellum base) direction. Video reproduced, with permission, from Buisson, J. et al. Intraflagellar transport proteins cycle between the flagellum and its base. J. Cell Sci. 126, 327–338 10.1242/jcs.117069 (2013) © The Company of Biologists Ltd. (MOV 6871 kb)

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Glossary

Kinetoplastid

A term used to describe a group of flagellated protozoa within the phylum Euglenozoa. The defining feature of kinetoplastids is that their mitochondrial DNA is arranged into a tightly packed network that is known as the kinetoplast.

African trypanosomiasis

A lethal disease that is prevalent in sub-Saharan Africa. Two specific subspecies of Trypanosoma brucei, known as Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, cause disease in humans. A third subspecies, Trypanosoma brucei brucei, and the related trypanosomes Trypanosoma congolense and Trypanosoma vivax, infect only non-primates, causing wasting disease, which limits economic development in endemic areas.

Ciliary necklace

A specialized region of the flagellar or ciliary membrane that surrounds the transition zone; it is defined by chalice-shaped filaments that extend outwards from the axoneme and form indentations in the ciliary membrane.

Subpellicular microtubules

A cage-like array of microtubules that subtend the plasma membrane (pellicle) and run parallel to the long axis of the cell.

Microtubule quartet

Four specialized subpellicular microtubules that extend from the basal body to the anterior of the cell and subtend the region of plasma membrane where the flagellum attaches to the cell body. These four microtubules constitute part of the flagellum attachment zone, are associated with a subdomain of the smooth endoplasmic reticulum and are antiparallel to the other subpellicular microtubules.

Trypomastigotes

Parasite morphotypes in which the basal body is posterior to the nucleus.

Epimastigote

A parasite morphotype in which the basal body is anterior to the nucleus.

Propulsive parasite motility

A sustained, forwards movement of a parasite. Propulsive motility is distinguished from general writhing of the parasite, which is generated by unregulated beating of the flagellum.

Trypanosomatids

A group of parasitic protozoa that infect mammals (Trypanosoma spp. and Leishmania spp.), plants (Phytomonas spp.) and insects (Crithidia spp.).

Reynolds number

A dimensionless number that describes the relative contribution of inertial and viscous forces to cell movement. Microorganisms operate at low Reynolds numbers, for example, <10−3, at which viscous forces dominate.

Bloodstream-form

A Trypanosoma brucei life cycle stage that is found in the bloodstream of the mammalian host and is commonly cultivated in vitro.

Procyclic-form

A Trypanosoma brucei life cycle stage that is found in the midgut of the tsetse fly and is commonly cultivated in vitro.

Variant surface glycoprotein

(VSG). A surface glycoprotein encoded by Trypanosoma brucei. T. brucei encodes thousands of different VSGs and the surface of bloodstream-form T. brucei is covered with approximately 107 VSG molecules of a single variant. Cells in the population periodically change to an alternate VSG variant, thereby avoiding destruction by the host immune system.

Choroid plexus

A network of vessels in the brain that produce the cerebrospinal fluid.

Pia mater

The innermost layer of membranous connective tissue that surrounds the brain and spinal cord.

Pleomorphic

Having many forms. The term is used to describe the isolates of Trypanosoma brucei that produce both long slender and short stumpy morphotypes during the mammalian bloodstream stage of the life cycle.

Monomorphic

Having a single form. The term is used to refer to those isolates of Trypanosoma brucei that produce only a single morphotype during the mammalian bloodstream stage of the life cycle; that is, they do not exhibit the long slender-to-short stumpy form transition. Monomorphic forms generally occur as a result of prolonged laboratory cultivation and tend to produce an acute, highly virulent infection in mice, which is marked by the absence of the multiple waves of parasitaemia that are typically seen in infections with field isolates.

Flagellar matrix

A luminal compartment of the flagellum. Although the matrix is contiguous with the cytoplasm, protein entry is restricted by a diffusion barrier at the base of the flagellum.

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Langousis, G., Hill, K. Motility and more: the flagellum of Trypanosoma brucei. Nat Rev Microbiol 12, 505–518 (2014). https://doi.org/10.1038/nrmicro3274

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