Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 21
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Magez, Stefan and Cnops, Jennifer 2016. Encyclopedia of Immunobiology.

    Berkowitz, Aaron L. Raibagkar, Pooja Pritt, Bobbi S. and Mateen, Farrah J. 2015. Neurologic manifestations of the neglected tropical diseases. Journal of the Neurological Sciences, Vol. 349, Issue. 1-2, p. 20.

    Cnops, Jennifer and Magez, Stefan 2015. Human Emerging and Re-emerging Infections.

    Faria do Amaral, Lázaro Luís Nunes, Renato Hoffmann and da Rocha, Antonio Jose 2015. Parasitic and Rare Spinal Infections. Neuroimaging Clinics of North America, Vol. 25, Issue. 2, p. 259.

    Morriswood, Brooke 2015. Form, Fabric, and Function of a Flagellum-Associated Cytoskeletal Structure. Cells, Vol. 4, Issue. 4, p. 726.

    Tiberti, Natalia Lejon, Veerle Mumba Ngoyi, Dieudonné Matovu, Enock Enyaru, John Walter, Nadia Fouda, Catherine Lutumba, Pascal Kristensson, Krister Bisser, Sylvie Mathu Ndung’u, Joseph Büscher, Philippe and Sanchez, Jean-Charles 2015. Increased acute immune response during the meningo-encephalitic stage of Trypanosoma brucei rhodesiense sleeping sickness compared to Trypanosoma brucei gambiense. Translational Proteomics, Vol. 6, p. 1.

    Burri, Christian Chappuis, François and Brun, Reto 2014. Manson's Tropical Infectious Diseases.

    Kisalu, Neville K. Langousis, Gerasimos Bentolila, Laurent A. Ralston, Katherine S. and Hill, Kent L. 2014. Mouse infection and pathogenesis byTrypanosoma bruceimotility mutants. Cellular Microbiology, Vol. 16, Issue. 6, p. 912.

    Ranjithkumar, Muthusamy Saravanan, Buddhi Chandrasekaran Yadav, Suresh Chandra Kumar, Rajender Singh, Rajendra and Dey, Sahadeb 2014. Neurological trypanosomiasis in quinapyramine sulfate-treated horses—a breach of the blood–brain barrier?. Tropical Animal Health and Production, Vol. 46, Issue. 2, p. 371.

    Bossard, Géraldine Cuny, Gérard and Geiger, Anne 2013. Secreted proteases ofTrypanosoma brucei gambiense: Possible targets for sleeping sickness control?. BioFactors, Vol. 39, Issue. 4, p. 407.

    Finsterer, J. and Auer, H. 2013. Parasitoses of the human central nervous system. Journal of Helminthology, Vol. 87, Issue. 03, p. 257.

    Lejon, Veerle Bentivoglio, Marina and Franco, José Ramon 2013. Neuroparasitology and Tropical Neurology.

    Pittella, José Eymard Homem 2013. Neuroparasitology and Tropical Neurology.

    Tiberti, Natalia Hainard, Alexandre and Sanchez, Jean-Charles 2013. Translation of human African trypanosomiasis biomarkers towards field application. Translational Proteomics, Vol. 1, Issue. 1, p. 12.

    Tiberti, Natalia Matovu, Enock Hainard, Alexandre Enyaru, John Charles Lejon, Veerle Robin, Xavier Turck, Natacha Ngoyi, Dieudonné Mumba Krishna, Sanjeev Bisser, Sylvie Courtioux, Bertrand Büscher, Philippe Kristensson, Krister Ndung'u, Joseph Mathu and Sanchez, Jean-Charles 2013. New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients. Clinical and Translational Medicine, Vol. 2, Issue. 1, p. 1.

    Caljon, G Caveliers, V Lahoutte, T Stijlemans, B Ghassabeh, GH Van Den Abbeele, J Smolders, I De Baetselier, P Michotte, Y Muyldermans, S Magez, S and Clinckers, R 2012. Using microdialysis to analyse the passage of monovalent nanobodies through the blood-brain barrier. British Journal of Pharmacology, Vol. 165, Issue. 7, p. 2341.

    Gamaldo, Charlene E. Shaikh, Annum K. and McArthur, Justin C. 2012. The Sleep-Immunity Relationship. Neurologic Clinics, Vol. 30, Issue. 4, p. 1313.

    Geurts, Nathalie Opdenakker, Ghislain and Van den Steen, Philippe E. 2012. Matrix metalloproteinases as therapeutic targets in protozoan parasitic infections. Pharmacology & Therapeutics, Vol. 133, Issue. 3, p. 257.

    Masocha, Willias and Kristensson, Krister 2012. Passage of parasites across the blood-brain barrier. Virulence, Vol. 3, Issue. 2, p. 202.

    Sternberg, Jeremy 2012. Immunity to Parasitic Infection.


Trypanosomiasis and the brain

  • DOI:
  • Published online: 23 December 2009

Neurological involvement following trypanosome infection has been recognised for over a century. However, there are still many unanswered questions concerning the mechanisms used by the parasite to gain entry to the CNS and the pathogenesis of the resulting neuroinflammatory reaction. There is a paucity of material from human cases of the disease therefore the majority of current research relies on the use of animal models of trypanosome infection. This review reports contemporary knowledge, from both animal models and human samples, regarding parasite invasion of the CNS and the neuropathological changes that accompany trypanosome infection and disease progression. The effects of trypanosomes on the blood-brain barrier are discussed and possible key molecules in parasite penetration of the barrier highlighted. Changes in the balance of CNS cytokines and chemokines are also described. The article closes by summarising the effects of trypanosome infection on the circadian sleep-wake cycle, and sleep structure, in relation to neuroinflammation and parasite location within the CNS. Although a great deal of progress has been made in recent years, the advent and application of sophisticated analysis techniques, to decipher the complexities of HAT pathogenesis, herald an exciting and rewarding period for advances in trypanosome research.

Corresponding author
*Tel.: +44 101 330 3797. Fax: +44 141 330 5603. Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

N. J. Abbott , L. Ronnback and E. Hansson (2006). Astrocyte-endothelial interactions at the blood-brain barrier. Nature Reviews in Neuroscience 7, 4153.

M. H. Abdulla , T. O'Brien , Z. B. Mackey , M. Sajid , D. J. Grab and J. H. McKerrow (2008). RNA Interference of Trypanosoma brucei Cathepsin B and L affects disease progression in a mouse model. PLoS Neglected Tropical Diseases 2, e298.

J. H. Adams , L. Haller , F. Y. Boa , F. Doua , A. Dago and K. Konian (1986). Human African trypanosomiasis (T. b. gambiense): a study of 16 fatal cases of sleeping sickness with some observations on acute reactive arsenical encephalopathy. Neuropathology and Applied Neurobiology 12, 8194.

D. N. Amin , W. Masocha , K. Ngan'dwe , M. Rottenberg and K. Kristensson (2008). Suramin and minocycline treatment of experimental African trypanososmiasis at an early stage of parasite brain invasion. Acta Tropica 106, 7274.

J. A. M. S. Anthoons , E. A. E. Van Marck , P. L. J. Gigase and W. J. Stevens (1989). Immunohistochemical characterization of the mononuclear cells in the brain of the rat with experimental chronic Trypanosoma brucei gambiense infection. Parasitology Research 75, 251256.

M. P. Barrett , D. W. Boykin , R. Brun and R. R. Tidwell (2007). Human African trypanosomiasis: pharmacological re-engagement with a neglected disease. British Journal of Pharmacology 152, 11551171.

M. Bentivoglio , G. Grassi-Zucconi , T. Olsson and K. Kristensson (1994). Trypanosoma brucei and the nervous system. Trends in Neuroscience 17, 325329.

M. Bentivoglio and K. Kristensson (2007). Neural-immune interactions in disorders of sleep-wakefulness organization. Trends in Neuroscience 30, 645652.

H. M. Braakman , F. J. van de Molengraft , W. W. Hubert and D. H. Boerman (2006). Lethal African trypanosomiasis in a traveler: MRI and neuropathology. Neurology 66, 10941096.

A. Buguet , S. Bisser , T. Josenando , F. Chapotot and R. Cespuglio (2005). Sleep structure: a new diagnostic tool for stage determination in sleeping sickness. Acta Tropica 93, 107117.

A. Buguet , L. Bourdon , B. Bouteille , R. Cespuglio , P. Vincendeau , M. W. Radomski and M. Dumas (2001). The duality of sleeping sickness: focusing on sleep. Sleep Medicine Reviews 5, 139153.

H. Calwell (1937). The pathology of the brain in Rhodesian trypanosomiasis. Transactions of the Royal Society of Tropical Medical and Hygiene 30, 611624.

A. M. Checkley , J. Pepin , W. C. Gibson , M. N. Taylor , H. R. Jager and D. C. Mabey (2007). Human African trypanosomiasis: diagnosis, relapse and survival after severe melarsoprol-induced encephalopathy. Transactions of the Royal Society of Tropical Medical and Hygiene 101, 523526.

S. Chianella , M. Semprevivo , Z. C. Peng , D. Zaccheo , M. Bentivoglio and G. Grassi-Zucconi (1999). Microglia activation in a model of sleep disorder: an immunohistochemical study in the rat brain during Trypanosoma brucei infection. Brain Research 832, 5462.

A. N. Coogan and C. A. Wyse (2008). Neuroimmunology of the circadian clock. Brain Research 1232, 104112.

B. Courtioux , C. Boda , G. Vatunga , L. Pervieux , T. Josenando , P. M. M'Eyi , B. Bouteille , M. O. Jauberteau-Marchan and S. Bisser (2006). A link between chemokine levels and disease severity in human African trypanosomiasis. International Journal for Parasitology 36, 10571065.

D. J. Grab and P. G. Kennedy (2008). Traversal of human and animal trypanosomes across the blood-brain barrier. Journal of NeuroVirology 14, 344351.

D. J. Grab , O. Nikolskaia , Y. V. Kim , J. D. Lonsdale-Eccles , S. Ito , T. Hara , T. Fukuma , E. Nyarko , K. J. Kim , M. F. Stins , M. J. Delannoy , J. Rodgers and K. S. Kim (2004). African trypanosome interactions with an in vitro model of the human blood-brain barrier. Journal of Parasitology 90, 970979.

G. Grassi-Zucconi , J. A. Harris , A. H. Mohammed , M. V. Ambrosini , K. Kristensson and M. Bentivoglio (1995). Sleep fragmentation, and changes in locomotor activity and body temperature in trypanosome-infected rats. Brain Research Bulletin 37, 123129.

G. Grassi-Zucconi , M. Semprevivo , E. Mocaer , K. Kristensson and M. Bentivoglio (1996). Melatonin and its new agonist S-20098 restore synchronized sleep fragmented by experimental trypanosome infection in the rat. Brain Research Bulletin 39, 6368.

B. T. Hawkins and T. P. Davis (2005). The blood-brain barrier/neurovascular unit in health and disease. Pharmacological Reviews 57, 173185.

C. A. Hunter , F. W. Jennings , J. H. Adams , M. Murray and P. G. Kennedy (1992 a). Subcurative chemotherapy and fatal post-treatment reactive encephalopathies in African trypanosomiasis. Lancet 339, 956958.

C. A. Hunter and P. G. Kennedy (1992). Immunopathology in central nervous system human African trypanosomiasis. Journal of Neuroimmunology 36, 9195.

F. W. Jennings , C. W. Gichuki , P. G. Kennedy , J. Rodgers , C. A. Hunter , M. Murray and J. M. Burke (1997). The role of the polyamine inhibitor eflornithine in the neuropathogenesis of experimental murine African trypanosomiasis. Neuropathology and Applied Neurobiology 23, 225234.

P. A. Johansson , K. M. Dziegielewska , S. A. Liddelow and N. R. Saunders (2008). The blood-CSF barrier explained: when development is not immaturity. Bioessays 30, 237248.

P. G. Kennedy (1999). The pathogenesis and modulation of the post-treatment reactive encephalopathy in a mouse model of Human African Trypanosomiasis. Journal of Neuroimmunology 100, 3641.

P. G. Kennedy (2004). Human African trypanosomiasis of the CNS: current issues and challenges. Journal of Clinical Investigation 113, 496504.

P. G. Kennedy (2006). Diagnostic and neuropathogenesis issues in human African trypanosomiasis. International Journal for Parasitology 36, 505512.

P. G. Kennedy , J. Rodgers , B. Bradley , S. P. Hunt , G. Gettinby , S. E. Leeman , C. de Felipe and M. Murray (2003). Clinical and neuroinflammatory responses to meningoencephalitis in substance P receptor knockout mice. Brain 126, 16831690.

P. G. Kennedy , J. Rodgers , F. W. Jennings , M. Murray , S. E. Leeman and J. M. Burke (1997). A substance P antagonist, RP-67,580, ameliorates a mouse meningoencephalitic response to Trypanosoma brucei brucei. Proceedings of the National Academy of Sciences, USA 94, 41674170.

J. M. Krueger , F. J. Obal , J. Fang , T. Kubota and P. Taishi (2001). The role of cytokines in physiological sleep regulation. Annals of New York Academy of Sciences 933, 211221.

V. Lejon , J. Lardon , G. Kenis , L. Pinoges , D. Legros , S. Bisser , X. N'Siesi , E. Bosmans and P. Buscher (2002). Interleukin (IL)-6, IL-8 and IL-10 in serum and CSF of Trypanosoma brucei gambiense sleeping sickness patients before and after treatment. Transactions of the Royal Society of Tropical Medical and Hygiene 96, 329333.

V. Lejon , D. Legros , A. Savignoni , M. G. Etchegorry , D. Mbulamberi and P. Buscher (2003 a). Neuro-inflammatory risk factors for treatment failure in “early second stage” sleeping sickness patients treated with pentamidine. Journal of Neuroimmunology 144, 132138.

V. Lejon , H. Reiber , D. Legros , N. Dje , E. Magnus , I. Wouters , C. J. Sindic and P. Buscher (2003 b). Intrathecal immune response pattern for improved diagnosis of central nervous system involvement in trypanosomiasis. Journal of Infectious Diseases 187, 14751483.

G. B. Lundkvist , J. Christenson , R. A. K. ElTayeb , Z.-C. Peng , P. Grillner , J. Mhlanga , M. Bentivoglio and K. Kristensson (1998 a). Altered neuronal activity rhythm and glutamate receptor expression in the suprachiasmatic nuclei of Trypanosoma brucei infected rats. Journal of Neuropathology and Experimental Neurology 57, 2129.

G. B. Lundkvist , R. H. Hill and K. Kristensson (2002). Disruption of circadian rhythms in synaptic activity of the suprachiasmatic nuclei by African trypanosomes and cytokines. Neurobiology of Disease 11, 2027.

G. B. Lundkvist , K. Kristensson and M. Bentivoglio (2004). Why trypanosomes cause sleeping sickness. Physiology (Bethesda) 19, 198206.

G. B. Lundkvist , B. Robertson , D. M. Mhlanga , M. E. Rottenberg and K. Kristensson (1998 b). Expression of an oscillating interferon-gamma receptor in the suprachiasmstic nuclei. NeuroReport 9, 10591063.

L. MacLean , M. Odiit , A. MacLeod , L. Morrison , L. Sweeney , A. Cooper , P. G. Kennedy and J. M. Sternberg (2007). Spatially and genetically distinct African Trypanosome virulence variants defined by host interferon-gamma response. Journal of Infectious Diseases 196, 16201628.

L. MacLean , M. Odiit and J. M. Sternberg (2001). Nitric oxide and cytokine synthesis in human African trypanosomiasis. Journal of Infectious Diseases 184, 10861090.

L. MacLean , M. Odiit , and J. M. Sternberg (2006). Intrathecal cytokine responses in Trypanosoma brucei rhodesiense sleeping sickness patients. Transactions of the Royal Society of Tropical Medical and Hygiene 100, 270275.

S. Man , E. E. Ubogu and R. M. Ransohoff (2007). Inflammatory cell migration into the central nervous system: a few new twists on an old tale. Brain Pathology 17, 243250.

W. Masocha , B. Robertson , M. E. Rottenberg , J. Mhlanga , L. Sorokin and K. Kristensson (2004). Cerebral vessel laminins and IFN-gamma define Trypanosoma brucei brucei penetration of the blood-brain barrier. Journal of Clinical Investigation 114, 689694.

W. Masocha , M. E. Rottenberg and K. Kristensson (2006). Minocycline impedes African trypanosome invasion of the brain in a murine model. Antimicrobial Agents and Chemotherapy 50, 17981804.

W. Masocha , M. E. Rottenberg , and K. Kristensson (2007). Migration of African trypanosomes across the blood-brain barrier. Physiology and Behavior 92, 110114.

R. W. McCarley (2007). Neurobiology of REM and NREM sleep. Sleep Medicine 8, 302330.

C. Mulenga , J. D. Mhlanga , K. Kristensson and B. Robertson (2001). Trypanosoma brucei brucei crosses the blood-brain barrier while tight junction proteins are preserved in a rat chronic disease model. Neuropathology and Applied Neurobiology 27, 7785.

O. V. Nikolskaia , A. P. de A. Lima , Y. V. Kim , J. D. Lonsdale-Eccles , T. Fukuma , J. Scharfstein and D. J. Grab (2006 a). Blood-brain barrier traversal by African trypanosomes requires calcium signaling induced by parasite cysteine protease. Journal of Clinical Investigation 116, 27392747.

O. V. Nikolskaia , A. P. de A. Lima , Y. V. Kim , J. D. Lonsdale-Eccles , T. Fukuma , J. Scharfstein and D. J. Grab (2008). Blood-brain barrier traversal by African trypanosomes requires calcium signaling induced by parasite cysteine protease (corrigendum). Journal of Clinical Investigation 118, 1974.

O. V. Nikolskaia , Y. V. Kim , O. Kovbasnjuk , K. J. Kim and D. J. Grab (2006 b). Entry of Trypanosoma brucei gambiense into microvascular endothelial cells of the human blood-brain barrier. International Journal for Parasitology 36, 513519.

M. R. Opp (2005). Cytokines and sleep. Sleep Medicine Reviews 9, 355364.

O. Ouwe-Missi-Oukem-Boyer , J. Mezui-Me-Ndong , C. Boda , I. Lamine , F. Labrousse , S. Bisser and B. Bouteille (2006). The vervet monkey (Chlorocebus aethiops) as an experimental model for Trypanosoma brucei gambiense human African trypanosomiasis: a clinical, biological and pathological study. Transactions of the Royal Society of Tropical Medical and Hygiene 100, 427436.

Z. C. Peng , K. Kristensson and M. Bentivoglio (1994). Dysregulation of photic induction of Fos-related protein in the biological clock during experimental trypanosomiasis. Neuroscience Letters 182, 104106.

V. W. Pentreath (1989). Neurobiology of sleeping sickness. Parasitology Today 5, 215218.

J. Pepin and F. Milord (1994). The treatment of human African trypanosomiasis. Advances in Parasitology 33, 147.

A. A. Poltera , P. D. Sayer , G. Brighouse , D. Bovell and W. Rudin (1985). Immunopathological aspects of trypanosomal meningoencephalitis in vervet monkeys after relapse following Berenil treatment. Transactions of the Royal Society of Tropical Medical and Hygiene 79, 527531.

N. Quan , L. He and W. Lai (2003). Intraventricular infusion of antagonists of IL-1 and TNF alpha attenuates neurodegeneration induced by the infection of Trypanosoma brucei. Journal of Neuroimmunology 138, 9298.

N. Quan , J. D. Mhlanga , M. B. Whiteside , A. N. McCoy , K. Kristensson and M. Herkenham (1999). Chronic overexpression of proinflammatory cytokines and histopathology in the brains of rats infected with Trypanosoma brucei. Journal of Comparative Neurology 414, 114130.

J. Rodgers , B. Bradley and P. G. Kennedy (2007). Combination chemotherapy with a substance P receptor antagonist (aprepitant) and melarsoprol in a mouse model of human African trypanosomiasis. Parasitology International 56, 321324.

J. Rodgers , T. Stone , M. P. Barrett , B. Bradley and P. G. E. Kennedy (2009). Kynurenine pathway inhibition reduces CNS inflammation in a model of human African trypanosomiasis. Brain 132, 12591267.

P. Sabbah , C. Brosset , P. Imbert , G. Bonardel , P. Jeandel and J. F. Briant (1997). Human African trypanosomiasis: MRI. Neuroradiology 39, 708710.

M. Sajid and J. H. McKerrow (2002). Cysteine proteases of parasitic organisms. Molecular and Biochemical Parasitology 120, 121.

N. R. Saunders , C. J. Ek , M. D. Habgood and K. M. Dziegielewska (2008). Barriers in the brain: a renaissance? Trends in Neuroscience 31, 279286.

H. Schmidt (1983). The pathogenesis of trypanosomiasis of the CNS. Studies on parasitological and neurohistological findings in trypanosoma rhodesiense infected vervet monkeys. Virchows Archiv A – Pathological Anatomy and Histopathology 399, 333343.

M. Schultzberg , M. Ambatsis , E. B. Samuelsson , K. Kristensson and N. Van Meirvenne (1988). Spread of Trypanosoma brucei to the nervous system: early attack on circumventricular organs and sensory ganglia. Journal of Neuroscience Research 21, 5661.

A. Sharafeldin , R. Eltayeb , M. Pashenkov and M. Bakhiet (2000). Chemokines are produced in the brain early during the course of experimental African trypanosomiasis. Journal of Neuroimmunology 103, 165170.

A. Sharafeldin , M. Hamadien , A. Diab , H. Li , F. Shi and M. Bakhiet (1999). Cytokine profiles in the central nervous system and the spleen during the early course of experimental African trypanosomiasis. Scandanavian Journal of Immunology 50, 256261.

M. Sixt , B. Engelhardt , F. Pausch , R. Hallmann , O. Wendler and L. M. Sorokin (2001). Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. Journal of Cell Biology 153, 933946.

J. M. Sternberg , J. Rodgers , B. Bradley , L. MacLean , M. Murray and P. G. Kennedy (2005). Meningoencephalitic African trypanosomiasis: Brain IL-10 and IL-6 are associated with protection from neuro-inflammatory pathology. Journal of Neuroimmunology 167, 8189.

L. A. Toth , E. A. Tolley , R. Broady , B. Blakely and J. M. Krueger (1994). Sleep during experimental trypanosomiasis in rabbits. Proceedings of the Society for Experimental Biology and Medicine 205, 174181.

B. V. Zlokovic (2008). The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178201.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

  • ISSN: 0031-1820
  • EISSN: 1469-8161
  • URL: /core/journals/parasitology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *