View source for Biology:Trypanosoma brucei

{{Short description|Species of protozoan parasite}}
{{Speciesbox
| image = tb_brucei.jpg
| image_alt = "Trypanosoma brucei brucei" TREU667 (Bloodstream form, phase-contrast picture. Black bar indicates 10 µm.)
| image_caption = ''T. b. brucei'' TREU667 (Bloodstream form, phase-contrast picture. Black bar indicates 10&nbsp;µm.)
| genus = Trypanosoma
| species = brucei
| authority = Plimmer & Bradford, 1899
| synonyms =
| synonyms_ref =
| subdivision_ranks = Subspecies
| subdivision =
* ''Trypanosoma brucei brucei'' <small></small>
* ''Trypanosoma brucei gambiense'' <small></small>
* ''Trypanosoma brucei rhodesiense'' <small></small>
}}

'''''Trypanosoma brucei''''' is a species of parasitic kinetoplastid belonging to the genus ''[[Biology:Trypanosoma|Trypanosoma]]'' that is present in [[Place:Sub-Saharan Africa|sub-Saharan Africa]]. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellular and inhabits the blood plasma and body fluids.<ref name=":9">{{Cite journal |last1=Romero-Meza |first1=Gabriela |last2=Mugnier |first2=Monica R. |date=2020 |title=Trypanosoma brucei |journal=Trends in Parasitology |volume=36 |issue=6 |pages=571–572 |doi=10.1016/j.pt.2019.10.007 |pmc=7375462 |pmid=31757771}}</ref> It causes deadly vector-borne diseases: [[Medicine:African trypanosomiasis|African trypanosomiasis]] or sleeping sickness in humans, and [[Physics:Animal trypanosomiasis|animal trypanosomiasis]] or ''nagana'' in cattle and horses.<ref name="Luzak-et-al-2021">{{cite journal |vauthors=Luzak V, López-Escobar L, Siegel TN, Figueiredo LM |date=October 2021 |title=Cell-to-Cell Heterogeneity in Trypanosomes |journal=Annual Review of Microbiology |publisher=Annual Reviews |volume=75 |issue=1 |pages=107–128 |doi=10.1146/annurev-micro-040821-012953 |pmid=34228491 |s2cid=235759288|doi-access=free }}</ref> It is a [[Biology:Species complex|species complex]] grouped into three subspecies: ''T. b. brucei'', ''T. b. gambiense'' and ''T. b. rhodesiense''.<ref name="Baker1995">{{cite journal | vauthors = Baker JR | title = The subspecific taxonomy of Trypanosoma brucei | journal = Parasite | volume = 2 | issue = 1 | pages = 3–12 | date = March 1995 | pmid = 9137639 | doi = 10.1051/parasite/1995021003 | doi-access = free }} {{open access}}</ref> The first is a parasite of non-human mammals and causes ''nagana'', while the latter two are zoonotic infecting both humans and animals and cause African trypanosomiasis.

''T. brucei'' is transmitted between mammal hosts by an [[Biology:Insect|insect]] [[Biology:Vector (epidemiology)|vector]] belonging to different species of [[Biology:Tsetse fly|tsetse fly]] (''Glossina''). Transmission occurs by biting during the insect's blood meal. The parasites undergo complex morphological changes as they move between insect and mammal over the course of their life cycle. The mammalian bloodstream forms are notable for their cell surface proteins, variant surface glycoproteins, which undergo remarkable [[Biology:Antigenic variation|antigenic variation]], enabling persistent evasion of host adaptive immunity leading to chronic infection. ''T. brucei'' is one of only a few pathogens known to cross the blood brain barrier.<ref>{{cite journal | vauthors = Masocha W, Kristensson K | title = Passage of parasites across the blood-brain barrier | journal = Virulence | volume = 3 | issue = 2 | pages = 202–212 | year = 2012 | pmid = 22460639 | pmc = 3396699 | doi = 10.4161/viru.19178 }}</ref> There is an urgent need for the development of new drug therapies, as current treatments can have severe side effects and can prove fatal to the patient.<ref>{{cite journal | vauthors = Legros D, Ollivier G, Gastellu-Etchegorry M, Paquet C, Burri C, Jannin J, Büscher P | title = Treatment of human African trypanosomiasis--present situation and needs for research and development | journal = The Lancet. Infectious Diseases | volume = 2 | issue = 7 | pages = 437–440 | date = July 2002 | pmid = 12127356 | doi = 10.1016/S1473-3099(02)00321-3 | hdl-access = free | hdl = 10144/18268 }}</ref>

Whilst not historically regarded as ''T. brucei'' subspecies due to their different means of transmission, clinical presentation, and loss of [[Biology:Kinetoplast|kinetoplast]] DNA, genetic analyses reveal that ''[[Biology:Trypanosoma equiperdum|T. equiperdum]]'' and ''[[Biology:Trypanosoma evansi|T. evansi]]'' are evolved from parasites very similar to ''T. b. brucei'', and are thought to be members of the ''brucei'' [[Biology:Clade|clade]].<ref>{{cite journal | vauthors = Gibson W | title = Resolution of the species problem in African trypanosomes | journal = International Journal for Parasitology | volume = 37 | issue = 8–9 | pages = 829–838 | date = July 2007 | pmid = 17451719 | doi = 10.1016/j.ijpara.2007.03.002 }}</ref>

The parasite was discovered in 1894 by Sir David Bruce, after whom the scientific name was given in 1899.<ref name=":6">{{cite journal | vauthors = Joubert JJ, Schutte CH, Irons DJ, Fripp PJ | title = Ubombo and the site of David Bruce's discovery of Trypanosoma brucei | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 87 | issue = 4 | pages = 494–495 | year = 1993 | pmid = 8249096 | doi = 10.1016/0035-9203(93)90056-v }}</ref><ref name=":7">{{cite journal | vauthors = Cook GC | title = Sir David Bruce's elucidation of the aetiology of nagana--exactly one hundred years ago | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 88 | issue = 3 | pages = 257–258 | year = 1994 | pmid = 7974656 | doi = 10.1016/0035-9203(94)90068-x | doi-access = free }}</ref>

== History and discovery ==

=== Early records ===
Sleeping sickness in animals were described in ancient Egyptian writings. During the Middle Ages, Arabian traders noted the prevalence of sleeping sickness among Africans and their dogs.<ref name=":04">{{cite journal | vauthors = Steverding D | title = The history of African trypanosomiasis | journal = Parasites & Vectors | volume = 1 | issue = 1 | pages = 3 | date = February 2008 | pmid = 18275594 | pmc = 2270819 | doi = 10.1186/1756-3305-1-3 | doi-access = free }}</ref> It was a major infectious diseases in southern and eastern Africa in the 19th century.<ref name=":1">{{cite journal | vauthors = Berrang-Ford L, Odiit M, Maiso F, Waltner-Toews D, McDermott J | title = Sleeping sickness in Uganda: revisiting current and historical distributions | journal = African Health Sciences | volume = 6 | issue = 4 | pages = 223–231 | date = December 2006 | pmid = 17604511 | pmc = 1832067 | doi = | url = https://www.ajol.info/index.php/ahs/article/view/6958 }}</ref> The Zulu Kingdom (now part of South Africa) was severely struck by the disease, which became known to the British as ''nagana'',<ref name="Luzak-et-al-2021" /> a [[Biography:Zulu language|Zulu]] word for  to be low or depressed in spirit. In other parts of Africa, Europeans called it the "fly disease."<ref>{{Cite book| vauthors = Mullen GR, Durden LA |url=https://books.google.com/books?id=T8CWvVGwKhoC|title=Medical and Veterinary Entomology |date=2009 |publisher=Academic Press|isbn=978-0-08-091969-0|edition=2|pages=297|language=en}}</ref><ref>{{Cite book| vauthors = Bruce D |url=https://archive.org/details/b21364655/page/n13/mode/2up|title=Preliminary Report on the Tsetse Fly Disease or Nagana, in Zululand|publisher=Bennett & Davis|year=1895|location=Durban (South Africa)|pages=1}}</ref>
[[File:An inhabitant of Buruma Island, Uganda, suffering from sleep Wellcome V0029100.jpg|thumb|A man having sleeping sickness at Buruma Island, Uganda.]]
John Aktins, an English naval surgeon, gave first medical description of human sleeping sickness in 1734. He attributed deaths which he called "sleepy distemper" in Guinea  to the infection.<ref name=":3">{{cite journal | vauthors = Kennedy PG | title = Human African trypanosomiasis of the CNS: current issues and challenges | journal = The Journal of Clinical Investigation | volume = 113 | issue = 4 | pages = 496–504 | date = February 2004 | pmc = 2214720 | doi = 10.1172/JCI34802 | pmid = 14966556 }}</ref> Another English physician Thomas Masterman Winterbottom gave clearer description of the symptoms from Sierra Leone in 1803.<ref name=":42">{{cite journal | vauthors = Cox FE | title = History of sleeping sickness (African trypanosomiasis) | journal = Infectious Disease Clinics of North America | volume = 18 | issue = 2 | pages = 231–245 | date = June 2004 | pmid = 15145378 | doi = 10.1016/j.idc.2004.01.004 }}</ref> Winterbottom described a key feature of the disease as swollen posterior cervical lymph nodes and slaves who developed such swellings were ruled unfit for trade.<ref name=":3" /> The symptom is eponymously known as "Winterbottom's sign."<ref>{{cite journal | vauthors = Ormerod WE | title = Hypothesis: the significance of Winterbottom's sign | journal = The Journal of Tropical Medicine and Hygiene | volume = 94 | issue = 5 | pages = 338–340 | date = October 1991 | pmid = 1942213 }}</ref>

=== Discovery of the parasite ===
The Royal Army Medical Corps appointed David Bruce, who at the time was assistant professor of pathology at the Army Medical School in Netley with a rank of Captain in the army, in 1894 to investigate a disease known as ''nagana'' in South Africa. The disease caused severe problems among the local cattle and British Army horses.<ref name="Baker1995" /> On 27 October 1894, Bruce and his microbiologist-wife Mary Elizabeth Bruce (''née'' Steele) moved to Ubombo Hill, where the disease was most prevalent.<ref name="cook">{{cite book| vauthors = Cook GC |url=https://books.google.com/books?id=iB_ibIXxhOMC&q=tropical+medicine+illustrated|title=Tropical Medicine: An Illustrated History of The Pioneers|date=2007|publisher=Elsevier Ltd.|isbn=978-0-08-055939-1|location=Burlington (US)|pages=145–156}}</ref>

On the sixth day of investigation, Bruce identified parasites from the blood of diseased cows. He initially noted them as a kind of filaria (tiny roundworms), but by the end of the year established that the parasites were "haematozoa" (protozoan) and were the cause of ''nagana'' .<ref name="Baker1995" /> It was the discovery of ''Trypanosoma brucei.''<ref>{{cite journal | vauthors = Ellis H | title = Sir David Bruce, a pioneer of tropical medicine | journal = British Journal of Hospital Medicine | volume = 67 | issue = 3 | pages = 158 | date = March 2006 | pmid = 16562450 | doi = 10.12968/hmed.2006.67.3.20624 }}</ref> The scientific name was created by British zoologists Henry George Plimmer and John Rose Bradford in 1899 as ''Trypanosoma brucii'' due to printer's error.<ref name="Baker1995" /><ref>{{Cite journal| vauthors = Martini E |date=1903|title=Ueber die Entwickelung der Tsetseparasiten in Säugethieren|trans-title=Preliminary note on the morphology and distribution of the parasite found in tsetse disease|journal=Zeitschrift für Hygiene und Infektionskrankheiten|language=de|volume=42|issue=1|pages=341–351|doi=10.1007/BF02217469|s2cid=12816407}}</ref> The genus ''Trypanosoma'' was already introduced by Hungarian physician David Gruby in his description of ''T. sanguinis,'' a species he discovered in frogs in 1843.<ref>{{Cite journal| vauthors = Novy FG |date=1907|title=Trypanosomes|journal=Journal of the American Medical Association|language=en|volume=XLVIII|issue=1|pages=1–10|doi=10.1001/jama.1907.25220270001001}}</ref>

=== Outbreaks ===
In Uganda, the first case of human infection was reported in 1898.<ref name=":1" /> It was followed by an outbreak in 1900.<ref name=":2">{{cite journal | vauthors = Fèvre EM, Coleman PG, Welburn SC, Maudlin I | title = Reanalyzing the 1900-1920 sleeping sickness epidemic in Uganda | journal = Emerging Infectious Diseases | volume = 10 | issue = 4 | pages = 567–573 | date = April 2004 | pmid = 15200843 | doi = 10.3201/eid1004.020626 | doi-access = free }}</ref> By 1901, it became severe with death toll estimated to about 20,000.<ref name=":63">{{Cite book| vauthors = Cook G |url=https://books.google.com/books?id=iB_ibIXxhOMC|title=Tropical Medicine: An Illustrated History of The Pioneers|date=2007|publisher=Elsevier|isbn=978-0-08-055939-1|location=London|pages=133–135|language=en}}</ref> More than 250,000 people died in the epidemic that lasted for two decades.<ref name=":2" /> The disease commonly popularised as "negro lethargy."<ref>{{cite journal | vauthors = Mott FW | title = The Changes in the Central Nervous System of Two Cases of Negro Lethargy: Sequel to Dr. Manson's Clinical Report | journal = British Medical Journal | volume = 2 | issue = 2033 | pages = 1666–1669 | date = December 1899 | pmid = 20758763 | pmc = 2412509 | doi = 10.1136/bmj.2.2033.1666 }}</ref><ref>{{cite journal | vauthors = Cook GC | title = The 'Negro lethargy' in Uganda | journal = Parasitology Today | volume = 12 | issue = 1 | pages = 41 | date = January 1996 | pmid = 15275309 | doi = 10.1016/0169-4758(96)90083-6 }}</ref> It was not known whether the human sleeping sickness and nagana were similar or the two disease were caused by similar parasites.<ref>{{Cite journal| vauthors = Castellani A |date=1903|title=The history of the association of ''Trypanosoma'' with sleeping sickness|journal=British Medical Journal|volume=2|issue=2241|pages=1565|doi=10.1136/bmj.2.2241.1565-a |pmc=2514975}}</ref> Even the observations of Forde and Dutton did not indicate that the trypanosome was related to sleeping sickness.<ref>{{cite journal | vauthors = Köhler W, Köhler M | title = Zentralblatt für Bakteriologie--100 years ago: sleeping sickness--intoxication or infectious disease? | journal = International Journal of Medical Microbiology | volume = 292 | issue = 3–4 | pages = 141–147 | date = September 2002 | pmid = 12398205 | doi = 10.1078/1438-4221-00190 }}</ref>

=== Sleeping Sickness Commission ===
The Royal Society constituted a three-member Sleeping Sickness Commission on 10 May 1902 to investigate the epidemic in Uganda.<ref name=":52">{{cite journal | vauthors = Boyd J | title = Sleeping sickness. The Castellani-Bruce controversy | journal = Notes and Records of the Royal Society of London | volume = 28 | pages = 93–110 | date = June 1973 | pmid = 11615538 | doi = 10.1098/rsnr.1973.0008 | s2cid = 37631020 }}</ref> The Commission comprised George Carmichael Low from the London [[Organization:London School of Hygiene and Tropical Medicine|School of Hygiene and Tropical Medicine]] as the leader, his colleague Aldo Castellani and Cuthbert Christy, a medical officer on duty in Bombay, India.<ref>{{cite journal | vauthors = Cook GC | title = George Carmichael Low FRCP: an underrated figure in British tropical medicine | journal = Journal of the Royal College of Physicians of London | volume = 27 | issue = 1 | pages = 81–82 | date = January 1993 | pmid = 8426352 | pmc = 5396591 }}</ref><ref>{{cite journal | vauthors = Cook GC | title = Royal Society of Tropical Medicine and Hygiene meeting at Manson House, London, 10 December 1992. George Carmichael Low FRCP: twelfth president of the Society and underrated pioneer of tropical medicine | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 87 | issue = 4 | pages = 355–360 | date = 1993 | pmid = 8249057 | doi = 10.1016/0035-9203(93)90002-8 }}</ref> At the time, a debate remained on the etiology, some favoured bacterial infection while some believed as helminth infection.<ref>{{cite journal | vauthors = Amaral I | title = Bacteria or parasite? the controversy over the etiology of sleeping sickness and the Portuguese participation, 1898-1904 | journal = Historia, Ciencias, Saude--Manguinhos | volume = 19 | issue = 4 | pages = 1275–1300 | date = December 2012 | pmid = 23184240 | doi = 10.1590/s0104-59702012005000004 | doi-access = free }}</ref> The first investigation focussed on ''Filaria perstans'' (later renamed ''[[Biology:Mansonella perstans|Mansonella perstans]]''), a small roundworm transmitted by flies, and bacteria as possible causes, only to discover that the epidemic was not related to these pathogens.<ref>{{cite journal | vauthors = Cook GC | title = Patrick Manson (1844-1922) FRS: Filaria (Mansonella) perstans and sleeping sickness (African trypanosomiasis) | journal = Journal of Medical Biography | volume = 20 | issue = 2 | pages = 69 | date = May 2012 | pmid = 22791871 | doi = 10.1258/jmb.2010.010051 | s2cid = 33661530 }}</ref><ref name=":72">{{cite journal | vauthors = Lumsden WH | title = Some episodes in the history of African trypanosomiasis | journal = Proceedings of the Royal Society of Medicine | volume = 67 | issue = 8 | pages = 789–796 | date = August 1974 | pmid = 4607392 | pmc = 1645813 | doi = 10.1177/003591577406700846 }}</ref> The team was described as an "ill-assorted group"<ref name=":72" /> and a "queer lot",<ref>{{cite journal | vauthors = Wiggins CA | title = Early days in East Africa and Uganda | journal = East African Medical Journal | volume = 37 | pages = 699–708 contd | date = November 1960 | pmid = 13785176 }}</ref> and the expedition "a failure."<ref name=":63" /> Low, whose conduct was described as "truculent and prone to take offence," left the Commission and Africa after three months.<ref>{{cite journal | vauthors = Davies JN | title = The cause of sleeping-sickness? Entebbe 1902-03. I | journal = East African Medical Journal | volume = 39 | pages = 81–99 | date = March 1962 | pmid = 13883839 }}</ref>

In February 1902, the British War Office, following a request from the Royal Society, appointed David Bruce to lead the second Sleeping Sickness Commission.<ref name=":8">{{Cite journal|last=J.R. B.|date=1932|title=Sir David Bruce. 1855-1931|journal=Obituary Notices of Fellows of the Royal Society|volume=1|issue=1|pages=79–85|doi=10.1098/rsbm.1932.0017|issn=1479-571X|jstor=768965}}</ref> With David Nunes Nabarro (from the University College Hospital), Bruce and his wife joined Castellani and Christy on 16 March.<ref name=":72" /> In November 1902, Castellani had found the trypanosomes in the cerebrospinal fluid of an infected person. He was convinced that the trypanosome was the causative parasite of sleeping sickness. Like Low, his conduct has been criticised and the Royal Society refused to publish his report. He was further infuriated when Bruce advised him not to make rash conclusion without further evidences, as there were many other parasites to consider.<ref name=":52"/> Castellani left Africa in April and published his report as "On the discovery of a species of ''Trypanosoma'' in the cerebrospinal fluid of cases of sleeping sickness" in ''The Lancet.''<ref>{{Cite journal| vauthors = Castellani A |date=1903|title=On the discovery of a species of trypanosoma in the cerebrospinal fluid of cases of sleeping sickness|journal=The Lancet|language=en|volume=161|issue=4164|pages=1735–1736|doi=10.1016/S0140-6736(01)70338-8}}</ref> By then the Royal Society had already published the report.<ref>{{Cite journal| vauthors = Castellani A |date=1903 |title=On the discovery of a species of ''trypanosoma'' in the cerebrospinal fluid of cases of sleeping sickness|journal=Proceedings of the Royal Society of London|language=en|volume=71|issue=467–476|pages=501–508|doi=10.1098/rspl.1902.0134|s2cid=59110369 }}</ref> By August 1903, Bruce and his team established that the disease was transmitted by the [[Biology:Tsetse fly|tsetse fly]], ''Glossina palpalis.''<ref>{{cite journal | vauthors = Welburn SC, Maudlin I, Simarro PP | title = Controlling sleeping sickness - a review | journal = Parasitology | volume = 136 | issue = 14 | pages = 1943–1949 | date = December 2009 | pmid = 19691861 | doi = 10.1017/S0031182009006416 | s2cid = 41052902 | url = http://doc.rero.ch/record/298806/files/S0031182009006416.pdf }}</ref> However, Bruce did not understand the trypanosoma life cycle and believed that the parasites were simply transmitted from one person to another.<ref name=":04" />

Around the same time, Germany sent an expeditionary team led by [[Biography:Robert Koch|Robert Koch]] to investigate the epidemic in Togo and East Africa. In 1909, one of the team members, Friedrich Karl Kleine discovered that the parasite had developmental stages in the tsetse flies.<ref name=":04" /> Bruce, in the third Sleeping Sickness Commission (1908–1912) that included Albert Ernest Hamerton, H.R. Bateman and Frederick Percival Mackie, established the basic developmental cycle through which the trypanosome in tsetse fly must pass''.''<ref>{{Cite journal| vauthors = Bruce D, Hamerton AE, Bateman HR, Mackie FP |date=1909|title=The development of ''Trypanosoma gambiense'' in ''Glossina palpalis''|journal=Proceedings of the Royal Society of London. Series B|volume=81|issue=550|pages=405–414|doi=10.1098/rspb.1909.0041|doi-access=}}</ref><ref>{{Cite journal| vauthors =  Bruce D, Hamerton AE, Bateman HR, Mackie FP |date=1911|title=Further researches on the development of ''Trypanosoma gambiense'' in ''Glossina palpalis''|journal=Proceedings of the Royal Society of London. Series B|volume=83|issue=567|pages=513–527|doi=10.1098/rspb.1911.0034|doi-access=free}}</ref> An open question, noted by Bruce at this stage, was how the trypanosome finds its way to the salivary glands. [[Biography:Muriel Robertson|Muriel Robertson]],<ref>{{Cite journal |last=Miles |first=A. A.YR 1976 |title=MURIEL ROBERTSON, 1883–1973 |journal=Microbiology |year=1976 |volume=95 |issue=1 |pages=1–8 |doi=10.1099/00221287-95-1-1 |pmid=784900 |issn=1465-2080|doi-access=free }}</ref><ref>{{Cite journal |date=1911-05-31 |title=Further researches on the development of trypanosoma gambiense in glossina palpalis |journal=Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character |language=en |volume=83 |issue=567 |pages=513–527 |doi=10.1098/rspb.1911.0034 |issn=0950-1193|doi-access=free }}</ref> in experiments carried out between 1911 and 1912, established how ingested trypanosomes finally reach the salivary glands of the fly.

=== Discovery of human trypanosomes ===
British Colonial Surgeon Robert Michael Forde was the first to find the parasite in human. He found it from an English steamboat captain who was admitted to a hospital at Bathurst, Gambia, in 1901.<ref name=":04" /> His report in 1902 indicates that he believed it to be a kind of filarial worm.<ref name=":42" /> From the same person, Forde's colleague Joseph Everett Dutton identified it as a protozoan belonging to the genus ''Trypanosoma.<ref name="Baker1995" />'' Knowing the distinct features, Dutton proposed a new species name in 1902:
{{Blockquote|At present then it is impossible to decide definitely as to the species, but if on further study it should be found to differ from other disease-producing trypanosomes I would suggest that it be called ''Trypanosoma gambiense.''<ref>{{Cite web| vauthors = Dutton JE |date=1902|title=Preliminary note upon a trypanosome occurring in the blood of man|url=https://wellcomecollection.org/works/w3s9ydrt|access-date=2021-03-21|website=Wellcome Collection|language=en}}</ref>}}

Another human trypanosome (now called ''T. brucei rhodesiense'') was discovered by British parasitologists John William Watson Stephens and Harold Benjamin Fantham.<ref name=":04" /> In 1910, Stephens noted in his experimental infection in rats that the trypanosome, obtained from an individual from Northern Rhodesia (later Zambia), was not the same as ''T. gambiense''. The source of the parasite, an Englishman travelling in Rhodesia was found with the blood parasites in 1909, and was transported to and admitted at the Royal Southern Hospital in Liverpool under the care of [[Biography:Ronald Ross|Ronald Ross]].<ref name="Baker1995" />  Fantham described the parasite's morphology and found that it was a different trypanosome.<ref>{{Cite journal| vauthors = Stephens JW, Fantham HB, Ross R |date=1910|title=On the peculiar morphology of a trypanosome from a case of sleeping sickness and the possibility of its being a new species (''T. rhodesiense'')|journal=Proceedings of the Royal Society of London. Series B|volume=83|issue=561|pages=28–33|doi=10.1098/rspb.1910.0064|doi-access=free}}</ref><ref>{{Cite journal| vauthors = Stephens JW, Fantham HB |date=1910 |title=On the Peculiar Morphology of a Trypanosome From a Case of Sleeping Sickness and the Possibility of Its Being a New Species (''T. Rhodesiense'')|journal=Annals of Tropical Medicine & Parasitology|language=en|volume=4|issue=3|pages=343–350|doi=10.1080/00034983.1910.11685723|url=https://zenodo.org/record/1429906 }}</ref>

==Species==
''T. brucei'' is a species complex that includes:
# ''T. brucei gambiense'' which causes slow onset chronic trypanosomiasis in humans. It is most common in central and western Africa, where humans are thought to be the primary [[Biology:Natural reservoir|reservoir]].<ref name="Barrett">{{cite journal | vauthors = Barrett MP, Burchmore RJ, Stich A, Lazzari JO, Frasch AC, Cazzulo JJ, Krishna S | title = The trypanosomiases | journal = Lancet | volume = 362 | issue = 9394 | pages = 1469–1480 | date = November 2003 | pmid = 14602444 | doi = 10.1016/S0140-6736(03)14694-6 | s2cid = 7917540 }}</ref> In 1973, David Hurst Molyneux was the first to find infection of this strain in wildlife and domestic animals.<ref>{{cite journal | vauthors = Molyneux DH | title = Animal reservoirs and Gambian trypanosomiasis | journal = Annales de la Société Belge de Médecine Tropicale | volume = 53 | issue = 6 | pages = 605–618 | date = 1973 | pmid = 4204667 | author-link = David Hurst Molyneux }}</ref><ref name="Buscher-et-al-2017" /> Since 2002, there are several reports showing that animals, including [[Biology:Cattle|cattle]], are also infected.<ref name="Buscher-et-al-2017">{{cite journal | vauthors = Büscher P, Cecchi G, Jamonneau V, Priotto G | title = Human African trypanosomiasis | journal = Lancet | volume = 390 | issue = 10110 | pages = 2397–2409 | date = November 2017 | pmid = 28673422 | doi = 10.1016/S0140-6736(17)31510-6 | s2cid = 4853616 }}</ref> It is responsible for 98% of all human African trypanosomiasis,<ref name=":10">{{Cite journal |last1=Franco |first1=Jose R |last2=Simarro |first2=Pere P |last3=Diarra |first3=Abdoulaye |last4=Jannin |first4=Jean G |date=2014 |title=Epidemiology of human African trypanosomiasis |journal=Clinical Epidemiology |volume=6 |pages=257–275 |doi=10.2147/CLEP.S39728 |issn=1179-1349 |pmc=4130665 |pmid=25125985 |doi-access=free }}</ref> and is roughly 100% fatal.<ref>{{Cite journal |last1=Jamonneau |first1=Vincent |last2=Ilboudo |first2=Hamidou |last3=Kaboré |first3=Jacques |last4=Kaba |first4=Dramane |last5=Koffi |first5=Mathurin |last6=Solano |first6=Philippe |last7=Garcia |first7=André |last8=Courtin |first8=David |last9=Laveissière |first9=Claude |last10=Lingue |first10=Kouakou |last11=Büscher |first11=Philippe |last12=Bucheton |first12=Bruno |date=2012 |title=Untreated human infections by Trypanosoma brucei gambiense are not 100% fatal |journal=PLOS Neglected Tropical Diseases |volume=6 |issue=6 |pages=e1691 |doi=10.1371/journal.pntd.0001691 |issn=1935-2735 |pmc=3373650 |pmid=22720107 |doi-access=free }}</ref>
# ''T. brucei rhodesiense'' which causes fast onset acute trypanosomiasis in humans. A highly zoonotic parasite, it is prevalent in southern and eastern Africa, where game animals and livestock are thought to be the primary reservoir.<ref name="Barrett" /><ref name=":10" />
# ''T. brucei brucei'' which causes [[Physics:Animal trypanosomiasis|animal trypanosomiasis]], along with several other species of ''[[Biology:Trypanosoma|Trypanosoma]]''. ''T. b. brucei'' is not infective to humans due to its susceptibility to [[Biology:Lysis|lysis]] by trypanosome lytic factor-1 (TLF-1).<ref>{{cite journal | vauthors = Stephens NA, Kieft R, Macleod A, Hajduk SL | title = Trypanosome resistance to human innate immunity: targeting Achilles' heel | journal = Trends in Parasitology | volume = 28 | issue = 12 | pages = 539–545 | date = December 2012 | pmid = 23059119 | pmc = 4687903 | doi = 10.1016/j.pt.2012.09.002 }}</ref><ref name="Rifkin-1984">{{cite journal | vauthors = Rifkin MR | title = Trypanosoma brucei: biochemical and morphological studies of cytotoxicity caused by normal human serum | journal = Experimental Parasitology | volume = 58 | issue = 1 | pages = 81–93 | date = August 1984 | pmid = 6745390 | doi = 10.1016/0014-4894(84)90023-7 | publisher = [[Company:Elsevier|Elsevier]] }}</ref> However, it is closely related to, and shares fundamental features with the human-infective subspecies.<ref>{{cite journal | vauthors = Balmer O, Beadell JS, Gibson W, Caccone A | title = Phylogeography and taxonomy of Trypanosoma brucei | journal = PLOS Neglected Tropical Diseases | volume = 5 | issue = 2 | pages = e961 | date = February 2011 | pmid = 21347445 | pmc = 3035665 | doi = 10.1371/journal.pntd.0000961 | doi-access = free }}</ref> Only rarely can the ''T. b. brucei'' infect a human.<ref>{{cite journal |display-authors=6 |vauthors=Deborggraeve S, Koffi M, Jamonneau V, Bonsu FA, Queyson R, Simarro PP, Herdewijn P, Büscher P |date=August 2008 |title=Molecular analysis of archived blood slides reveals an atypical human Trypanosoma infection |journal=Diagnostic Microbiology and Infectious Disease |volume=61 |issue=4 |pages=428–433 |doi=10.1016/j.diagmicrobio.2008.03.006 |pmid=18455900}}</ref>

The subspecies cannot be distinguished from their structure as they are all identical under microscopes. Geographical location is the main distinction.<ref name=":10" /> Molecular markers have been developed for individual identification. Serum resistance-associated (''SRA'') gene is used to differentiate ''T. b. rhodesiense'' from other subspecies.<ref>{{Cite journal |last1=Radwanska |first1=Magdalena |last2=Chamekh |first2=Mustapha |last3=Vanhamme |first3=Luc |last4=Claes |first4=Filip |last5=Magez |first5=Stefan |last6=Magnus |first6=Eddy |last7=de Baetselier |first7=Patrick |last8=Büscher |first8=Philippe |last9=Pays |first9=Etienne |date=2002 |title=The serum resistance-associated gene as a diagnostic tool for the detection of Trypanosoma brucei rhodesiense |journal=The American Journal of Tropical Medicine and Hygiene |volume=67 |issue=6 |pages=684–690 |doi=10.4269/ajtmh.2002.67.684 |issn=0002-9637 |pmid=12518862|s2cid=3232109 |doi-access=free }}</ref> ''TgsGP'' gene, found only in type 1 ''T. b. gambiense'' is also a specific distinction between ''T. b. gambiense'' strains.<ref>{{Cite journal |last1=Felu |first1=Cecile |last2=Pasture |first2=Julie |last3=Pays |first3=Etienne |last4=Pérez-Morga |first4=David |date=2007 |title=Diagnostic potential of a conserved genomic rearrangement in the Trypanosoma brucei gambiense-specific TGSGP locus |journal=The American Journal of Tropical Medicine and Hygiene |volume=76 |issue=5 |pages=922–929 |doi=10.4269/ajtmh.2007.76.922 |issn=0002-9637 |pmid=17488917|doi-access=free }}</ref>

The subspecies lack many of the features commonly considered necessary to constitute [[Biology:Monophyly|monophyly]].<ref name="End-of-Monophyly" /> As such Lukeš ''et al.'', 2022 proposes a new [[Biology:Polyphyly|polyphyly]] by [[Earth:Ecotype|ecotype]].<ref name="End-of-Monophyly">{{cite journal | year=2022 | issue=9 | volume=38 | publisher=Cell Press | issn=1471-4922 | journal=Trends in Parasitology | pages=724–736 | first5=Mark | first3=Jan | first1=Julius | last5=Field | first4=Anzhelika | first2=Ambar | last3=Votýpka | last4=Butenko | last2=Kachale | last1=Lukeš | doi=10.1016/j.pt.2022.05.011 | title=African trypanosome strategies for conquering new hosts and territories: the end of monophyly?| pmid=35680542 | s2cid=249448815 }}</ref>

=== Etymology ===
The genus name is derived from two Greek words:  τρυπανον (''trypanon'' or ''trupanon''), which means "borer" or "auger", referring to the corkscrew-like movement;<ref name=":0" /> and σῶμα (''sôma''), meaning "body."<ref>{{Cite journal |date=2006 |title=Etymologia: Trypanosoma |journal=Emerging Infectious Diseases |volume=12 |issue=9 |pages=1473 |doi=10.3201/eid1209.ET1209 |issn=1080-6040 |pmc=3293449}}</ref><ref>{{Cite journal |last=Morriswood |first=Brooke |date=2015 |title=Form, Fabric, and Function of a Flagellum-Associated Cytoskeletal Structure |journal=Cells |volume=4 |issue=4 |pages=726–747 |doi=10.3390/cells4040726 |issn=2073-4409 |pmc=4695855 |pmid=26540076|doi-access=free }}</ref> The specific name is after David Bruce, who discovered the parasites in 1894.<ref name=":6" /><ref name=":7" /> The subspecies, the human strains, are named after the regions in Africa where they were first identified: ''T. brucei gambiense'' was described from an Englishman in Gambia in 1901; ''T. brucei rhodesiense'' was found from another Englishman in Northern Rhodesia in 1909.<ref name="Baker1995" />

==Structure==
[[Image:TrypanosomaBrucei ProcyclicTrypomastigote SEM.jpg|thumb|right|250px| [[Physics:Scanning electron microscope|SEM]] false colour [[Micrograph|micrograph]] of the procyclic form as found in the tsetse fly midgut. The cell body is shown in orange and the flagellum is in red. 84 pixels/μm.]]''T. brucei'' is a typical unicellular eukaryotic cell, and measures 8 to 50 μm in length. It has an elongated body having a streamlined and tapered shape. Its cell membrane (called pellicle) encloses the cell organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and ribosomes. In addition, there is an unusual organelle called the kinetoplast, which is a complex of thousands of mitochondria.<ref name="Amodeo-et-al-2018">{{cite journal | vauthors = Amodeo S, Jakob M, Ochsenreiter T | title = Characterization of the novel mitochondrial genome replication factor MiRF172 in ''Trypanosoma brucei'' | journal = Journal of Cell Science | volume = 131 | issue = 8 | page = jcs211730 | date = April 2018 | pmid = 29626111 | pmc = 5963845 | doi = 10.1242/jcs.211730 | publisher = The Company of Biologists | doi-access = free }}</ref> The kinetoplast lies near the basal body with which it is indistinguishable under microscope. From the basal body arises a single [[Biology:Flagellum|flagellum]] that run towards the anterior end. Along the body surface, the flagellum is attached to the cell membrane forming an undulating membrane. Only the tip of the flagellum is free at the anterior end.<ref name="fao">{{cite web|title=African animal trypanosomes|url=http://www.fao.org/docrep/006/x0413e/x0413e02.htm#ref1.2.1.1|publisher=Food and Agricultural Organization|access-date=28 January 2016}}</ref> The cell surface of the bloodstream form features a dense coat of variant surface glycoproteins (VSGs) which is replaced by an equally dense coat of procyclins when the parasite differentiates into the procyclic phase in the tsetse fly midgut.<ref>{{cite journal | vauthors = Romero-Meza G, Mugnier MR | title = ''Trypanosoma brucei'' | journal = Trends in Parasitology | volume = 36 | issue = 6 | pages = 571–572 | date = June 2020 | pmid = 31757771 | pmc = 7375462 | doi = 10.1016/j.pt.2019.10.007 }}</ref>

[[File:TrypanosomatidMorphologies PlainSVG.svg|thumb|right|The six main morphologies of trypanosomatids. The different life cycle stages of ''T brucei'' fall into the trypomastigote and epimastigote morphological categories.]]
[[Biology:Trypanosomatida|Trypanosomatids]] show several different classes of cellular organisation of which two are adopted by ''T. brucei'' at different stages of the life cycle:<ref name=fao/>
* [[Biology:Trypanosomatida#Morphologies|Epimastigote]], which is found in tsetse fly. Its kinetoplast and basal body lie anterior to the nucleus, with a long flagellum attached along the cell body. The flagellum starts from the centre of the body.
* [[Biology:Trypanosomatida#Morphologies|Trypomastigote]], which is found in mammalian hosts. The kinetoplast and basal body are posterior of nucleus. The flagellum arises from the posterior end of the body.
[[Image:Trypanosome Flagellum Structure.png|thumbnail|Flagellar structure]]
These names are derived from the [[Social:Ancient Greek|Greek]] ''mastig-'' meaning whip, referring to the trypanosome's whip-like flagellum. The trypanosome flagellum has two main structures. It is made up of a typical flagellar axoneme, which lies parallel to the paraflagellar rod,<ref>{{cite journal | vauthors = Koyfman AY, Schmid MF, Gheiratmand L, Fu CJ, Khant HA, Huang D, He CY, Chiu W | display-authors = 6 | title = Structure of Trypanosoma brucei flagellum accounts for its bihelical motion | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 27 | pages = 11105–11108 | date = July 2011 | pmid = 21690369 | pmc = 3131312 | doi = 10.1073/pnas.1103634108 | bibcode = 2011PNAS..10811105K | doi-access = free }}</ref> a lattice structure of proteins unique to the kinetoplastids, euglenoids and [[Biology:Dinoflagellate|dinoflagellate]]s.<ref>{{Cite journal | vauthors = v |date=1988 |title=The paraflagellar rod: a structure in search of a function |journal=Biology of the Cell |language=en |volume=63 |issue=2 |pages=169–181 |issn=0248-4900 | doi=10.1016/0248-4900(88)90056-1 | s2cid=86009836}}</ref><ref>{{cite journal | vauthors = Bastin P, Matthews KR, Gull K | title = The paraflagellar rod of kinetoplastida: solved and unsolved questions | journal = Parasitology Today | volume = 12 | issue = 8 | pages = 302–307 | date = August 1996 | pmid = 15275181 | doi = 10.1016/0169-4758(96)10031-4 }}</ref>

The [[Biology:Microtubule|microtubule]]s of the flagellar [[Biology:Axoneme|axoneme]] lie in the normal 9+2 arrangement, orientated with the + at the anterior end and the − in the basal body. The cytoskeletal structure extends from the basal body to the kinetoplast. The flagellum is bound to the cytoskeleton of the main cell body by four specialised microtubules, which run parallel and in the same direction to the flagellar tubulin.<ref name="Sunter-Gull-2016">{{cite journal | vauthors = Sunter JD, Gull K | title = The Flagellum Attachment Zone: 'The Cellular Ruler' of Trypanosome Morphology | journal = Trends in Parasitology | volume = 32 | issue = 4 | pages = 309–324 | date = April 2016 | pmid = 26776656 | pmc = 4827413 | doi = 10.1016/j.pt.2015.12.010 | publisher = Cell Press | s2cid = 1080165 }}</ref><ref>{{cite journal | vauthors = Woods A, Sherwin T, Sasse R, MacRae TH, Baines AJ, Gull K | title = Definition of individual components within the cytoskeleton of Trypanosoma brucei by a library of monoclonal antibodies | journal = Journal of Cell Science | volume = 93 ( Pt 3) | pages = 491–500 | date = July 1989 | issue = 3 | pmid = 2606940 | doi = 10.1242/jcs.93.3.491 }}</ref>

The flagellar function is twofold — locomotion via oscillations along the attached flagellum and cell body in human blood stream and tsetse fly gut,<ref name=lang>{{cite journal | vauthors = Langousis G, Hill KL | title = Motility and more: the flagellum of Trypanosoma brucei | journal = Nature Reviews. Microbiology | volume = 12 | issue = 7 | pages = 505–518 | date = July 2014 | pmid = 24931043 | pmc = 4278896 | doi = 10.1038/nrmicro3274 }}</ref><ref>{{cite journal | vauthors = Halliday C, de Castro-Neto A, Alcantara CL, Cunha-E-Silva NL, Vaughan S, Sunter JD | title = Trypanosomatid Flagellar Pocket from Structure to Function | journal = Trends in Parasitology | volume = 37 | issue = 4 | pages = 317–329 | date = April 2021 | pmid = 33308952 | doi = 10.1016/j.pt.2020.11.005 | s2cid = 229179306 }}</ref> and attachment to the salivary gland epithelium of the fly during the epimastigote stage.<ref name=":0">{{cite journal | vauthors = Krüger T, Schuster S, Engstler M | title = Beyond Blood: African Trypanosomes on the Move | journal = Trends in Parasitology | volume = 34 | issue = 12 | pages = 1056–1067 | date = December 2018 | pmid = 30181072 | doi = 10.1016/j.pt.2018.08.002 | s2cid = 52154369 }}</ref><ref name=":4">{{cite journal | vauthors = Ralston KS, Kabututu ZP, Melehani JH, Oberholzer M, Hill KL | title = The Trypanosoma brucei flagellum: moving parasites in new directions | journal = Annual Review of Microbiology | volume = 63 | pages = 335–362 | date = 2009 | pmid = 19575562 | pmc = 3821760 | doi = 10.1146/annurev.micro.091208.073353 }}</ref> The flagellum propels the body in such a way that the axoneme generates the oscillation and a flagellar wave is created along the undulating membrane. As a result, the body moves in a corkscrew pattern.<ref name=":0" /> In flagella of other organisms, the movement starts from the base towards the tip, while in ''T. brucei'' and other trypanosomatids, the beat originates from the tip and progresses towards the base, forcing the body to move towards the direction of the tip of the flagellum.<ref name=":4" />

==Life cycle==
[[File:Trypanosoma brucei Life Cycle.svg|thumb|right|Life cycle]]
''T. brucei'' completes its life cycle between tsetse fly (of the genus ''Glossina'') and mammalian hosts, including humans, cattle, horses, and wild animals. In stressful environments, ''T. brucei'' produces [[Biology:Exosome (vesicle)|exosome]]s containing the spliced leader RNA and uses the endosomal sorting complexes required for transport (ESCRT) system to [[Biology:Secretion|secrete]] them as [[Biology:Extracellular vesicle|extracellular vesicle]]s.<ref name="Juan-Furthauer-2018">{{cite journal | vauthors = Juan T, Fürthauer M | title = Biogenesis and function of ESCRT-dependent extracellular vesicles | journal = Seminars in Cell & Developmental Biology | volume = 74 | pages = 66–77 | date = February 2018 | pmid = 28807885 | doi = 10.1016/j.semcdb.2017.08.022 | publisher = [[Company:Elsevier|Elsevier]] }}</ref> When absorbed by other trypanosomes these EVs cause repulsive movement away from the area and so away from bad environments.<ref name="Juan-Furthauer-2018" />

===In mammalian host===
Infection occurs when a vector tsetse fly bites a mammalian host. The fly injects the metacyclic trypomastigotes into the skin tissue. The trypomastigotes enter the [[Biology:Lymphatic system|lymphatic system]] and into the bloodstream. The initial trypomastigotes are short and stumpy (SS).<ref name="kdc">{{cite book |url=https://books.google.com/books?id=UknhQgAACAAJ |title=Parasitology (Protozoology and Helminthology) in relation to clinical medicine |vauthors=Chatterjee KD |date=2009 |publisher=CBC Publishers |isbn=978-8-12-39-1810-5 |edition=13 |location=New Delhi |pages=56–57}}</ref> They are protected from the host's immune system by producing antigentic variation called variant surface glycoproteins on their body surface.<ref name=":9" /> Once inside the bloodstream, they grow into long and slender forms (LS). Then, they multiply by [[Biology:Fission|binary fission]]. Some of the daughter cells then become short and stumpy again.<ref name=cdc>{{cite web|title=Parasites - African Trypanosomiasis (also known as Sleeping Sickness)|url=https://www.cdc.gov/parasites/sleepingsickness/biology.html|publisher=Centers for Disease Control and Prevention|access-date=29 January 2016}}</ref><ref name="Seed-Wenck-2003">{{cite journal | vauthors = Seed JR, Wenck MA | title = Role of the long slender to short stumpy transition in the life cycle of the african trypanosomes | journal = Kinetoplastid Biology and Disease | volume = 2 | issue = 1 | pages = 3 | date = June 2003 | pmid = 12844365 | doi = 10.1186/1475-9292-2-3 | publisher = [[Company:BioMed Central|BioMed Central]] | pmc = 165594 | doi-access = free }}</ref><ref name="Luzak-et-al-2021" /> Some of them remains as intermediate forms, representing a transitional stage between the long and short forms.<ref name=":10" /> The long slender forms are able to penetrate the blood vessel endothelium and invade extravascular tissues, including the [[Biology:Central nervous system|central nervous system]] (CNS)<ref name=lang/> and placenta in pregnant women.<ref>{{Cite journal |last1=McClure |first1=Elizabeth M. |last2=Goldenberg |first2=Robert L. |date=2009 |title=Infection and stillbirth |journal=Seminars in Fetal & Neonatal Medicine |volume=14 |issue=4 |pages=182–189 |doi=10.1016/j.siny.2009.02.003 |issn=1878-0946 |pmc=3962114 |pmid=19285457}}</ref>

Sometimes, wild animals can be infected by the tsetse fly and they act as reservoirs. In these animals, they do not produce the disease, but the live parasite can be transmitted back to the normal hosts.<ref name="kdc" /> Besides preparation to be taken up and vectored to another host by a tsetse fly, transition from LS to SS in the mammal serves to prolong the host's lifespan {{endash}} controlling [[Medicine:Parasitemia|parasitemia]] aids in increasing the total transmitting duration of any particular infested host.<ref name="Seed-Wenck-2003" /><ref name="Luzak-et-al-2021" />

===In tsetse fly===
Unlike [[Biology:Anopheles|anopheline mosquitos]] and sandflies that transmit other protozoan infections in which only females are involved, both sexes of tsetse flies are blood feeders and equally transmit trypanosomes.<ref name=":11">{{Cite journal |last1=Rotureau |first1=Brice |last2=Van Den Abbeele |first2=Jan |date=2013 |title=Through the dark continent: African trypanosome development in the tsetse fly |journal=Frontiers in Cellular and Infection Microbiology |volume=3 |pages=53 |doi=10.3389/fcimb.2013.00053 |issn=2235-2988 |pmc=3776139 |pmid=24066283|doi-access=free }}</ref> The short and stumpy trypomastigotes (SS) are taken up by tsetse flies during a blood meal.<ref name="Seed-Wenck-2003" /><ref name="Luzak-et-al-2021" /> Survival in the tsetse midgut is one reason for the particular adaptations of the SS stage.<ref name="Seed-Wenck-2003" /><ref name="Luzak-et-al-2021" /> The trypomastigotes enter the midgut of the fly where they become procyclic trypomastigotes as they replace their VSG with other protein coats called procyclins.<ref name=":9" /> Because the fly faces digestive damage from immune factors in the bloodmeal, it produces [[Biology:Serpin|serpin]]s to suppress the infection. The serpins including ''GmmSRPN3'', ''GmmSRPN5'', ''GmmSRPN9'', and especially ''GmmSRPN10'' are then hijacked by the parasite to aid its own midgut infection, using them to inactivate bloodmeal trypanolytic factors which would otherwise make the fly host inhospitable.<ref name="Mideo-et-al-2013">{{cite journal | vauthors = Mideo N, Acosta-Serrano A, Aebischer T, Brown MJ, Fenton A, Friman VP, Restif O, Reece SE, Webster JP, Brown SP | display-authors = 6 | title = Life in cells, hosts, and vectors: parasite evolution across scales | journal = Infection, Genetics and Evolution | volume = 13 | pages = 344–347 | date = January 2013 | pmid = 22465537 | doi = 10.1016/j.meegid.2012.03.016 | url = https://researchonline.rvc.ac.uk/id/eprint/8749/1/8749.pdf }} {{small|1=(VPF [[Company:ORCID|ORCID]] [http://orcid.org/0000-0002-1592-157X 0000-0002-1592-157X])}}.</ref>{{rp|346}}

The procyclic trypomastigotes cross the peritrophic matrix, undergo slight elongation and migrate to the anterior part of the midgut as non-proliferative long mesocyclic trypomastigotes. As they reach the proventriculus, they became thinner and undergo cytoplasmic rearrangement to give rise to proliferative epimastigotes.<ref name=":11" /> The epimastigotes divide asymmetrically to produce long and short epimastigotes. The long epimastigote cannot move to other places and simply die off by [[Biology:Apoptosis|apoptosis]].<ref>{{Cite journal |last1=Proto |first1=William R. |last2=Coombs |first2=Graham H. |last3=Mottram |first3=Jeremy C. |date=2013 |title=Cell death in parasitic protozoa: regulated or incidental? |url=https://pubmed.ncbi.nlm.nih.gov/23202528 |journal=Nature Reviews. Microbiology |volume=11 |issue=1 |pages=58–66 |doi=10.1038/nrmicro2929 |issn=1740-1534 |pmid=23202528|s2cid=1633550 }}</ref><ref>{{Cite journal |last1=Van Den Abbeele |first1=J. |last2=Claes |first2=Y. |last3=van Bockstaele |first3=D. |last4=Le Ray |first4=D. |last5=Coosemans |first5=M. |date=1999 |title=Trypanosoma brucei spp. development in the tsetse fly: characterization of the post-mesocyclic stages in the foregut and proboscis |url=https://pubmed.ncbi.nlm.nih.gov/10363280 |journal=Parasitology |volume=118 ( Pt 5) |issue=5 |pages=469–478 |doi=10.1017/s0031182099004217 |issn=0031-1820 |pmid=10363280|s2cid=32217938 }}</ref> The short epimastigote migrate from the proventriculus via the foregut and proboscis to the salivary glands where they get attached to the salivary gland epithelium.<ref name=":0" /> Even all the short forms do not succeed in the complete migration to the salivary glands as most of them perish on the way–only up to five may survive.<ref name=":11" /><ref>{{Cite journal |last1=Oberle |first1=Michael |last2=Balmer |first2=Oliver |last3=Brun |first3=Reto |last4=Roditi |first4=Isabel |date=2010 |title=Bottlenecks and the maintenance of minor genotypes during the life cycle of Trypanosoma brucei |journal=PLOS Pathogens |volume=6 |issue=7 |pages=e1001023 |doi=10.1371/journal.ppat.1001023 |issn=1553-7374 |pmc=2912391 |pmid=20686656 |doi-access=free }}</ref>

In the salivary glands, the survivors undergo phases of reproduction. The first cycle in an equal mitosis by which a mother cell produces two similar daughter epimastigotes. They remain attach to the epithelium. This phase is the main reproduction in first-stage infection to ensure sufficient number of parasites in the salivary gland.<ref name=":11" /> The second cycle, which usually occurs in late-stage infection, involves unequal mitosis that produces two different daughter cells from the mother epimastigote. One daughter is an epimastigote that remains non-infective and the other is a trypomastigote.<ref>{{Cite journal |last1=Rotureau |first1=Brice |last2=Subota |first2=Ines |last3=Buisson |first3=Johanna |last4=Bastin |first4=Philippe |date=2012 |title=A new asymmetric division contributes to the continuous production of infective trypanosomes in the tsetse fly |journal=Development |volume=139 |issue=10 |pages=1842–1850 |doi=10.1242/dev.072611 |issn=1477-9129 |pmid=22491946|s2cid=7068417 |doi-access=free }}</ref> The trypomastigote detach from the epithelium and undergo transformation into short and stumpy trypomastigotes. The surface procyclins are replaced with VSGs and become the infective metacyclic trypomastigotes.<ref name=":10" /> Complete development in the fly takes about 20 days.<ref name="kdc" /><ref name="cdc" /> They are injected into the mammalian host along with the saliva on biting, and are known as salivarian.<ref name=":11" />

In the case of ''T. b. brucei'' infecting ''Glossina palpalis gambiensis'', the parasite changes the [[Biology:Proteome|proteome]] contents of the fly's head and causes behavioral changes such as unnecessarily increased feeding frequency, which increases transmission opportunities. This is related to altered [[Chemistry:Glucose|glucose]] metabolism that causes a perceived need for more calories. (The metabolic change, in turn, being due to complete absence of [[Biology:Glucose-6-phosphate dehydrogenase|glucose-6-phosphate 1-dehydrogenase]] in infected flies.) [[Biology:Monoamine neurotransmitter|Monoamine neurotransmitter]] synthesis is also altered: production of [[Biology:Aromatic L-amino acid decarboxylase|aromatic L-amino acid decarboxylase]] involved in [[Biology:Dopamine|dopamine]] and [[Chemistry:Serotonin|serotonin]] synthesis, and α-methyldopa hypersensitive protein was induced. This is similar to the alterations in other [[Biology:Fly|dipteran]] vectors' head proteomes under infection by other eukaryotic parasites of mammals.<ref name="Lefevre-et-al-2007">{{cite journal | vauthors = Lefèvre T, Thomas F, Ravel S, Patrel D, Renault L, Le Bourligu L, Cuny G, Biron DG | display-authors = 6 | title = Trypanosoma brucei brucei induces alteration in the head proteome of the tsetse fly vector Glossina palpalis gambiensis | journal = Insect Molecular Biology | volume = 16 | issue = 6 | pages = 651–660 | date = December 2007 | pmid = 18092995 | doi = 10.1111/j.1365-2583.2007.00761.x | publisher = Royal Entomological Society (Wiley) | s2cid = 3134104 }}</ref>

==Reproduction==
===Binary fission===
[[Image:Trypanosome Cell Cycle.png|thumbnail|Trypanosome cell cycle (procyclic form)]]
The reproduction of ''T. brucei'' is unusual compared to most eukaryotes. The nuclear membrane remains intact and the chromosomes do not condense during mitosis. The basal body, unlike the [[Biology:Centrosome|centrosome]] of most eukaryotic cells, does not play a role in the organisation of the spindle and instead is involved in division of the kinetoplast. The events of reproduction are:<ref name=fao/>
# The basal body duplicates and both remain associated with the kinetoplast. Each basal body forms a separate flagellum.
# Kinetoplast DNA undergoes synthesis then the kinetoplast divides coupled with separation of the two basal bodies.
# [[Biology:Nuclear DNA|Nuclear DNA]] undergoes synthesis while a new flagellum extends from the younger, more posterior, basal body.
# The nucleus undergoes mitosis.
# [[Biology:Cytokinesis|Cytokinesis]] progresses from the anterior to posterior.
# Division completes with [[Biology:Abscission|abscission]].

===Meiosis===
In the 1980s, DNA analyses of the developmental stages of ''T. brucei'' started to indicate that the trypomastigote in the tsetse fly undergoes [[Biology:Meiosis|meiosis]], i.e., a sexual reproduction stage.<ref>{{cite journal | vauthors = Zampetti-Bosseler F, Schweizer J, Pays E, Jenni L, Steinert M | title = Evidence for haploidy in metacyclic forms of Trypanosoma brucei | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 16 | pages = 6063–6064 | date = August 1986 | pmid = 3461475 | pmc = 386438 | doi = 10.1073/pnas.83.16.6063 | doi-access = free | bibcode = 1986PNAS...83.6063Z }}</ref> But it is not always necessary for a complete life cycle.<ref>{{cite journal | vauthors = Jenni L | title = Sexual stages in trypanosomes and implications | journal = Annales de Parasitologie Humaine et Comparée | volume = 65 | issue = Suppl 1 | pages = 19–21 | date = 1990 | pmid = 2264676 | doi = 10.1051/parasite/1990651019 | doi-access = free }}</ref> The existence of meiosis-specific proteins was reported in 2011.<ref>{{cite journal | vauthors = Peacock L, Ferris V, Sharma R, Sunter J, Bailey M, Carrington M, Gibson W | title = Identification of the meiotic life cycle stage of Trypanosoma brucei in the tsetse fly | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 9 | pages = 3671–3676 | date = March 2011 | pmid = 21321215 | pmc = 3048101 | doi = 10.1073/pnas.1019423108 | doi-access = free | bibcode = 2011PNAS..108.3671P }}</ref> The haploid gametes (daughter cells produced after meiosis) were discovered in 2014. The haploid trypomastigote-like gametes can interact with each other via their flagella and undergo cell fusion (the process is called syngamy).<ref>{{cite journal | vauthors = Peacock L, Bailey M, Carrington M, Gibson W | title = Meiosis and haploid gametes in the pathogen Trypanosoma brucei | journal = Current Biology | volume = 24 | issue = 2 | pages = 181–186 | date = January 2014 | pmid = 24388851 | pmc = 3928991 | doi = 10.1016/j.cub.2013.11.044 }}</ref><ref>{{cite journal | vauthors = Peacock L, Ferris V, Bailey M, Gibson W | title = Mating compatibility in the parasitic protist Trypanosoma brucei | journal = Parasites & Vectors | volume = 7 | issue = 1 | pages = 78 | date = February 2014 | pmid = 24559099 | pmc = 3936861 | doi = 10.1186/1756-3305-7-78 | doi-access = free }}</ref> Thus, in addition to binary fission, ''T. brucei'' can multiply by sexual reproduction. Trypanosomes belong to the supergroup [[Biology:Excavata|Excavata]] and are one of the earliest diverging lineages among eukaryotes.<ref name="pmid19237557">{{cite journal | vauthors = Hampl V, Hug L, Leigh JW, Dacks JB, Lang BF, Simpson AG, Roger AJ | title = Phylogenomic analyses support the monophyly of Excavata and resolve relationships among eukaryotic "supergroups" | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 10 | pages = 3859–3864 | date = March 2009 | pmid = 19237557 | pmc = 2656170 | doi = 10.1073/pnas.0807880106 | doi-access = free | bibcode = 2009PNAS..106.3859H }}</ref> The discovery of sexual reproduction in ''T. brucei'' supports the hypothesis that meiosis and sexual reproduction are ancestral and ubiquitous features of eukaryotes.<ref name="pmid18663385">{{cite journal | vauthors = Malik SB, Pightling AW, Stefaniak LM, Schurko AM, Logsdon JM | title = An expanded inventory of conserved meiotic genes provides evidence for sex in Trichomonas vaginalis | journal = PLOS ONE | volume = 3 | issue = 8 | pages = e2879 | date = August 2007 | pmid = 18663385 | pmc = 2488364 | doi = 10.1371/journal.pone.0002879 | doi-access = free | bibcode = 2008PLoSO...3.2879M }}</ref>

==Infection and pathogenicity==
{{Main|Medicine:African trypanosomiasis}}

The insect vectors for ''T. brucei'' are different species of [[Biology:Tsetse fly|tsetse fly]] (genus ''Glossina''). The major vectors of ''T. b. gambiense'', causing West African sleeping sickness, are ''G. palpalis'', ''G. tachinoides'', and [[Biology:Glossina fuscipes|''G. fuscipes'']]. While the principal vectors of ''T. b. rhodesiense'', causing East African sleeping sickness, are [[Biology:Glossina morsitans|''G. morsitans'']], ''G. pallidipes'', and ''G. swynnertoni''. Animal trypanosomiasis is transmitted by a dozen species of ''Glossina''.<ref>{{cite book| vauthors = Krisnky WL | veditors = Mullen GR, Durden L |title=Medical and Veterinary Entomology|date=2009|publisher=Elsevier|location=Amsterdam|isbn=978-0-0-80-91969-0|page=296|edition=2|chapter-url=https://books.google.com/books?id=T8CWvVGwKhoC|chapter=Tsetse fly (Glossinidae)}}</ref>

In later stages of a ''T. brucei'' infection of a mammalian host the parasite may migrate from the bloodstream to also infect the lymph and cerebrospinal fluids. It is under this tissue invasion that the parasites produce the sleeping sickness.<ref name=kdc/>

In addition to the major form of transmission via the tsetse fly, ''T. brucei'' may be transferred between mammals via bodily fluid exchange, such as by blood transfusion or sexual contact, although this is thought to be rare.<ref name=CDC_epi>{{cite web|title=African Trypanosomes: epidemiology and risk factors|url=https://www.cdc.gov/parasites/sleepingsickness/epi.html|publisher=Centers for Disease Control|date=2017-05-02}}</ref><ref name=Rocha>{{cite journal | vauthors = Rocha G, Martins A, Gama G, Brandão F, Atouguia J | title = Possible cases of sexual and congenital transmission of sleeping sickness | journal = Lancet | volume = 363 | issue = 9404 | pages = 247 | date = January 2004 | pmid = 14738812 | doi = 10.1016/S0140-6736(03)15345-7 | s2cid = 5311361 }}</ref> Newborn babies can be infected (vertical or congenital transmission) from infected mothers.<ref>{{Cite journal |last1=Lindner |first1=Andreas K. |last2=Priotto |first2=Gerardo |date=2010 |title=The unknown risk of vertical transmission in sleeping sickness--a literature review |journal=PLOS Neglected Tropical Diseases |volume=4 |issue=12 |pages=e783 |doi=10.1371/journal.pntd.0000783 |issn=1935-2735 |pmc=3006128 |pmid=21200416 |doi-access=free }}</ref>

==Chemotherapy==
There are four drugs generally recommended for the first-line treatment of African trypanosomiasis: [[Chemistry:Suramin|suramin]] developed in 1921, [[Chemistry:Pentamidine|pentamidine]] developed in 1941, [[Chemistry:Melarsoprol|melarsoprol]] developed in 1949 and [[Chemistry:Eflornithine|eflornithine]] developed in 1990.<ref>{{cite journal | vauthors = Nok AJ | title = Arsenicals (melarsoprol), pentamidine and suramin in the treatment of human African trypanosomiasis | journal = Parasitology Research | volume = 90 | issue = 1 | pages = 71–79 | date = May 2003 | pmid = 12743807 | doi = 10.1007/s00436-002-0799-9 | s2cid = 35019516 }}</ref><ref>{{cite journal | vauthors = Burri C, Brun R | title = Eflornithine for the treatment of human African trypanosomiasis | journal = Parasitology Research | volume = 90 Supp 1 | pages = S49–S52 | date = June 2003 | pmid = 12811548 | doi = 10.1007/s00436-002-0766-5 | s2cid = 35509112 }}</ref> These drugs are not fully effective and are toxic to humans.<ref>{{cite journal | vauthors = Docampo R, Moreno SN | title = Current chemotherapy of human African trypanosomiasis | journal = Parasitology Research | volume = 90 Supp 1 | pages = S10–S13 | date = June 2003 | pmid = 12811544 | doi = 10.1007/s00436-002-0752-y | s2cid = 21917230 }}</ref> In addition, drug resistance has developed in the parasites against all the drugs.<ref>{{cite journal | vauthors = Barrett MP, Vincent IM, Burchmore RJ, Kazibwe AJ, Matovu E | title = Drug resistance in human African trypanosomiasis | journal = Future Microbiology | volume = 6 | issue = 9 | pages = 1037–1047 | date = September 2011 | pmid = 21958143 | doi = 10.2217/fmb.11.88 }}</ref> The drugs are of limited application since they are effective against specific strains of ''T. brucei'' and the life cycle stages of the parasites. Suram is used only for first-stage infection of ''T. b. rhodensiense'',  pentamidine for first-stage infection of ''T. b. gambiense'', and eflornithine for second-stage infection of ''T. b. gambiense''. Melarsopol is the only drug effective against the two types of parasite in both infection stages,<ref>{{cite journal | vauthors = Babokhov P, Sanyaolu AO, Oyibo WA, Fagbenro-Beyioku AF, Iriemenam NC | title = A current analysis of chemotherapy strategies for the treatment of human African trypanosomiasis | journal = Pathogens and Global Health | volume = 107 | issue = 5 | pages = 242–252 | date = July 2013 | pmid = 23916333 | pmc = 4001453 | doi = 10.1179/2047773213Y.0000000105 }}</ref> but is highly toxic, such that 5% of treated individuals die of brain damage (reactive encephalopathy).<ref>{{cite journal | vauthors = Kennedy PG | title = Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness) | journal = The Lancet. Neurology | volume = 12 | issue = 2 | pages = 186–194 | date = February 2013 | pmid = 23260189 | doi = 10.1016/S1474-4422(12)70296-X | s2cid = 8688394 }}</ref> Another drug, nifurtimox, recommended for [[Medicine:Chagas disease|Chagas disease]] (American trypanosomiasis), is itself a weak drug but in combination with melarsopol, it is used as the first-line medication against second-stage infection of ''T. b. gambiense.''<ref>{{cite journal | vauthors = Lutje V, Seixas J, Kennedy A | title = Chemotherapy for second-stage human African trypanosomiasis | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD006201 | date = June 2013 | volume = 2013 | pmid = 23807762 | pmc = 6532745 | doi = 10.1002/14651858.CD006201.pub3 }}</ref><ref>{{cite journal | vauthors = Bottieau E, Clerinx J | title = Human African Trypanosomiasis: Progress and Stagnation | journal = Infectious Disease Clinics of North America | volume = 33 | issue = 1 | pages = 61–77 | date = March 2019 | pmid = 30712768 | doi = 10.1016/j.idc.2018.10.003 | s2cid = 73432597 }}</ref>

Historically, arsenic and mercuric compounds were introduced in the early 20th century, with success particularly in animal infections.<ref>{{cite journal | vauthors = Thomas HW | title = Some Experiments in the Treatment of Trypanosomiasis | journal = British Medical Journal | volume = 1 | issue = 2317 | pages = 1140–1143 | date = May 1905 | pmid = 20762118 | pmc = 2320665 | doi = 10.1136/bmj.1.2317.1140 }}</ref><ref>{{cite journal | vauthors = Moore B, Nierenstein M, Todd JL | title = On the Treatment of Trypanosomiasis by Atoxyl (an Organic Arsenical Compound), followed by a Mercuric Salt (Mercuric Chloride) being a Bio-Chemical Study of the Reaction of a Parasitic Protozoon to Different Chemical Reagents at Different Stages of its Life History | journal = The Biochemical Journal | volume = 2 | issue = 5–6 | pages = 300–324 | date = 1907 | pmid = 16742071 | pmc = 1276215 | doi = 10.1042/bj0020300 }}</ref> German physician [[Biography:Paul Ehrlich|Paul Ehrlich]] and his Japanese associate Kiyoshi Shiga developed the first specific trypanocidal drug in 1904 from a dye, trypan red, which they named Trypanroth.<ref>{{cite journal | vauthors = Wenyon CM | title = Action of the Colours of Benzidine on Mice Infected with Trypanosoma dimorphon | journal = The Journal of Hygiene | volume = 7 | issue = 2 | pages = 273–290 | date = April 1907 | pmid = 20474312 | pmc = 2236235 | doi = 10.1017/s0022172400033295 }}</ref> These chemical preparations were effective only at high and toxic dosages, and were not suitable for clinical use.<ref>{{Cite journal | vauthors = Nocht B  |date=1935 |title=Present state of knowledge of chemotherapy | url=https://mednexus.org/doi/10.5555/cmj.0366-6999.49.05.p479.01 |journal=Chinese Medical Journal |language=en |volume=49 |issue=5 |pages=479–489 }}</ref>

Animal trypanosomiasis is treated with six drugs: diminazene aceturate, homidium (homidium bromide and homidium chloride), [[Chemistry:Isometamidium chloride|isometamidium chloride]], [[Chemistry:Melarsomine|melarsomine]], [[Chemistry:Quinapyramine|quinapyramine]], and suramin. They are all highly toxic to animals,<ref>{{cite journal | vauthors = Giordani F, Morrison LJ, Rowan TG, DE Koning HP, Barrett MP | title = The animal trypanosomiases and their chemotherapy: a review | journal = Parasitology | volume = 143 | issue = 14 | pages = 1862–1889 | date = December 2016 | pmid = 27719692 | pmc = 5142301 | doi = 10.1017/S0031182016001268 }}</ref> and drug resistance is prevalent.<ref>{{cite journal | vauthors = Kasozi KI, MacLeod ET, Waiswa C, Mahero M, Ntulume I, Welburn SC | title = Systematic Review and Meta-Analysis on Knowledge Attitude and Practices on African Animal Trypanocide Resistance | journal = Tropical Medicine and Infectious Disease | volume = 7 | issue = 9 | pages = 205 | date = August 2022 | pmid = 36136616 | pmc = 9503918 | doi = 10.3390/tropicalmed7090205 | doi-access = free }}</ref> Homidium is the first prescription anti-trypanosomal drug. It was developed as a modified compound of phenantridine, which was found in 1938 to have trypanocidal activity against the bovine parasite, ''[[Biology:Trypanosoma congolense|T. congolense]].''<ref>{{Cite journal | vauthors = Walls LP |date=1947 |title=The chemotherapy of phenanthridine compounds |url=https://onlinelibrary.wiley.com/doi/10.1002/jctb.5000660604 |journal=Journal of the Society of Chemical Industry |language=en |volume=66 |issue=6 |pages=182–187 |doi=10.1002/jctb.5000660604}}</ref> Among its products, dimidium bromide and its derivatives were first used in 1948 in animal cases in Africa,<ref>{{cite journal | vauthors = Wilson SG | title = Further observations on the curative value of dimidium bromide in Trypanosoma congolense infections in bovines in Uganda | journal = The Journal of Comparative Pathology and Therapeutics | volume = 58 | issue = 2 | pages = 94–106 | date = April 1948 | pmid = 18861668 | doi = 10.1016/s0368-1742(48)80008-1 }}</ref><ref>{{Cite journal | vauthors = Wilson SG |date=1948 |title=Further Observations on the Curative Value of Dimidium Bromide (Phenanthridinium 1553) in Trypanosoma Congolense Infections in Bovines in Uganda |journal=Journal of Comparative Pathology and Therapeutics |language=en |volume=58 |issue=2 |pages=94–106 |doi=10.1016/S0368-1742(48)80008-1|pmid=18861668 }}</ref><ref>{{cite journal | vauthors = Carmichael J | title = Dimidium bromide or phenanthridinium 1553; a note on the present position | journal = The Veterinary Record | volume = 62 | issue = 17 | pages = 257 | date = April 1950 | pmid = 15418753 | doi = 10.1136/vr.62.17.257-a | s2cid = 33016283 }}</ref> and became known as homidium (or as [[Chemistry:Ethidium bromide|ethidium bromide]] in molecular biology<ref>{{cite journal | vauthors = Lai JS, Herr W | title = Ethidium bromide provides a simple tool for identifying genuine DNA-independent protein associations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 15 | pages = 6958–6962 | date = August 1992 | pmid = 1495986 | pmc = 49624 | doi = 10.1073/pnas.89.15.6958 | bibcode = 1992PNAS...89.6958L | doi-access = free }}</ref>).<ref>{{Cite journal | vauthors = Elslager EF, Thompson PE |date=1962 |title=Parasite Chemotherapy |journal=Annual Review of Pharmacology |language=en |volume=2 |issue=1 |pages=193–214 |doi=10.1146/annurev.pa.02.040162.001205 |issn=0066-4251}}</ref><ref>{{cite journal | vauthors = Kasozi KI, MacLeod ET, Ntulume I, Welburn SC | title = An Update on African Trypanocide Pharmaceutics and Resistance | journal = Frontiers in Veterinary Science | volume = 9 | pages = 828111 | date = 2022 | pmid = 35356785 | pmc = 8959112 | doi = 10.3389/fvets.2022.828111 | doi-access = free }}</ref>

=== Alternative therapy ===
Some [[Chemistry:Phytochemical|phytochemical]]s have shown research promise against the ''T. b. brucei'' strain.<ref name="Ibrahim-et-al-2014">{{cite journal | vauthors = Ibrahim MA, Mohammed A, Isah MB, Aliyu AB | title = Anti-trypanosomal activity of African medicinal plants: a review update | journal = Journal of Ethnopharmacology | volume = 154 | issue = 1 | pages = 26–54 | date = May 2014 | pmid = 24742753 | doi = 10.1016/j.jep.2014.04.012 | publisher = International Society of Ethnopharmacology ([[Company:Elsevier|Elsevier]]) }}</ref> Aderbauer ''et al.'', 2008 and Umar ''et al.'', 2010 find ''[[Biology:Khaya senegalensis|Khaya senegalensis]]'' is effective [[In vitro|in vitro]] and Ibrahim ''et al.'', 2013 and 2008 [[Biology:In vivo|in vivo]] (in [[Organization:Laboratory rat|rats]]).<ref name="Ibrahim-et-al-2014" /> Ibrahim ''et al.'', 2013 find a lower dose reduces [[Medicine:Parasitemia|parasitemia]] by this subspecies and a higher dose is curative and prevents injury.<ref name="Ibrahim-et-al-2014" />

==Distribution==
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''T. brucei'' is found where its tsetse fly vectors are prevalent in continental Africa. That is to say, tropical rainforest ([[Earth:Köppen climate classification#Af|Af]]), tropical monsoon ([[Earth:Köppen climate classification#Am|Am]]), and tropical savannah ([[Earth:Köppen climate classification#Aw|Aw]]) areas of continental Africa.<ref name=fao/> Hence, the equatorial region of Africa is called the "sleeping sickness" belt. However, the specific type of the trypanosome differs according to geography. ''T. b. rhodesiense'' is found primarily in East Africa (Botswana, Democratic Republic of the Congo, Ethiopia, Kenya, Malawi, Tanzania, Uganda and Zimbabwe), while ''T. b. gambiense'' is found in Central and West Africa.

==Impact==
''T. brucei'' is a major cause of livestock disease in [[Place:Sub-Saharan Africa|sub-Saharan Africa]].<ref name="Luzak-et-al-2021" /><ref name="Auty-et-al-2015">{{cite journal | vauthors = Auty H, Torr SJ, Michoel T, Jayaraman S, Morrison LJ | title = Cattle trypanosomosis: the diversity of trypanosomes and implications for disease epidemiology and control | journal = Revue Scientifique et Technique | volume = 34 | issue = 2 | pages = 587–598 | date = August 2015 | pmid = 26601459 | doi = 10.20506/rst.34.2.2382 | publisher = O.I.E ([[Organization:World Organisation for Animal Health|World Organisation for Animal Health]]) | s2cid = 42700199 | doi-access = free }}</ref> It is thus of tremendous [[Biology:Veterinary parasitology|veterinary concern]] and one of the greatest limitations on agriculture in Africa and the economic life of sub-Saharan Africa.<ref name="Luzak-et-al-2021" /><ref name="Auty-et-al-2015" />

==Evolution==
''Trypanosoma brucei gambiense'' evolved from a single progenitor ~10,000 years ago.<ref name=Weir2016>{{cite journal | vauthors = Weir W, Capewell P, Foth B, Clucas C, Pountain A, Steketee P, Veitch N, Koffi M, De Meeûs T, Kaboré J, Camara M, Cooper A, Tait A, Jamonneau V, Bucheton B, Berriman M, MacLeod A | display-authors = 6 | title = Population genomics reveals the origin and asexual evolution of human infective trypanosomes | journal = eLife | volume = 5 | pages = e11473 | date = January 2016 | pmid = 26809473 | pmc = 4739771 | doi = 10.7554/eLife.11473 | doi-access = free }}</ref> It is evolving asexually and its genome shows the Meselson effect.<ref name=Weir2016 />

==Genetics==
There are two subpopulations of  ''T. b. gambiense'' that possesses two distinct groups that differ in genotype and phenotype. Group 2 is more akin to ''T. b. brucei'' than group 1 ''T. b. gambiense''.<ref name=Paindavoine1986>{{cite journal | vauthors = Paindavoine P, Pays E, Laurent M, Geltmeyer Y, Le Ray D, Mehlitz D, Steinert M | title = The use of DNA hybridization and numerical taxonomy in determining relationships between Trypanosoma brucei stocks and subspecies | journal = Parasitology | volume = 92 | issue = Pt 1 | pages = 31–50 | date = February 1986 | pmid = 3960593 | doi = 10.1017/S0031182000063435 | s2cid = 33529173 }}</ref>

All ''T. b. gambiense''  are resistant to killing by a serum component — trypanosome lytic factor (TLF) of which there are two types: TLF-1 and TLF-2. Group 1 ''T. b. gambiense'' parasites avoid uptake of the TLF particles while those of group 2 are able to either neutralize or compensate for the effects of TLF.<ref name=Capewell2011>{{cite journal | vauthors = Capewell P, Veitch NJ, Turner CM, Raper J, Berriman M, Hajduk SL, MacLeod A | title = Differences between Trypanosoma brucei gambiense groups 1 and 2 in their resistance to killing by trypanolytic factor 1 | journal = PLOS Neglected Tropical Diseases | volume = 5 | issue = 9 | pages = e1287 | date = September 2011 | pmid = 21909441 | pmc = 3167774 | doi = 10.1371/journal.pntd.0001287 | doi-access = free }}</ref>

In contrast, resistance in ''T. b. rhodesiense'' is dependent upon the expression of a serum resistance associated (SRA) gene.<ref name=Lecordier2009>{{cite journal | vauthors = Lecordier L, Vanhollebeke B, Poelvoorde P, Tebabi P, Paturiaux-Hanocq F, Andris F, Lins L, Pays E | display-authors = 6 | title = C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense | journal = PLOS Pathogens | volume = 5 | issue = 12 | pages = e1000685 | date = December 2009 | pmid = 19997494 | pmc = 2778949 | doi = 10.1371/journal.ppat.1000685 | veditors = Mansfield JM | doi-access = free }}</ref> This gene is not found in ''T. b. gambiense''.<ref name=DeGreef1989>{{cite journal | vauthors = De Greef C, Imberechts H, Matthyssens G, Van Meirvenne N, Hamers R | title = A gene expressed only in serum-resistant variants of Trypanosoma brucei rhodesiense | journal = Molecular and Biochemical Parasitology | volume = 36 | issue = 2 | pages = 169–176 | date = September 1989 | pmid = 2528066 | doi = 10.1016/0166-6851(89)90189-8 }}</ref>

===Genome===
The [[Biology:Genome|genome]] of ''T. brucei'' is made up of:<ref>{{cite journal | vauthors = Ogbadoyi E, Ersfeld K, Robinson D, Sherwin T, Gull K | title = Architecture of the Trypanosoma brucei nucleus during interphase and mitosis | journal = Chromosoma | volume = 108 | issue = 8 | pages = 501–513 | date = March 2000 | pmid = 10794572 | doi = 10.1007/s004120050402 | s2cid = 3850480 }}</ref>
* 11 pairs of large [[Biology:Chromosome|chromosome]]s of 1 to 6 megabase pairs.
* 3–5 intermediate chromosomes of 200 to 500 kilobase pairs.
* Around 100 minichromosomes of around 50 to 100 kilobase pairs. These may be present in multiple copies per [[Biology:Haploid|haploid]] genome.
Most genes are held on the large chromosomes, with the minichromosomes carrying only ''VSG'' genes. The genome has been sequenced and is available on [[Biology:GeneDB|GeneDB]].<ref>{{cite journal | vauthors = Jackson AP, Sanders M, Berry A, McQuillan J, Aslett MA, Quail MA, Chukualim B, Capewell P, MacLeod A, Melville SE, Gibson W, Barry JD, Berriman M, Hertz-Fowler C | display-authors = 6 | title = The genome sequence of Trypanosoma brucei gambiense, causative agent of chronic human african trypanosomiasis | journal = PLOS Neglected Tropical Diseases | volume = 4 | issue = 4 | pages = e658 | date = April 2010 | pmid = 20404998 | pmc = 2854126 | doi = 10.1371/journal.pntd.0000658 | doi-access = free }}</ref>

The mitochondrial genome is found condensed into the [[Biology:Kinetoplast|kinetoplast]], an unusual feature unique to the kinetoplastid protozoans. The kinetoplast and the [[Biology:Basal body|basal body]] of the [[Biology:Flagellum|flagellum]] are strongly associated via a cytoskeletal structure<ref>{{cite journal | vauthors = Ogbadoyi EO, Robinson DR, Gull K | title = A high-order trans-membrane structural linkage is responsible for mitochondrial genome positioning and segregation by flagellar basal bodies in trypanosomes | journal = Molecular Biology of the Cell | volume = 14 | issue = 5 | pages = 1769–1779 | date = May 2003 | pmid = 12802053 | pmc = 165075 | doi = 10.1091/mbc.E02-08-0525 }}</ref>

In 1993, a new base, ß-d-glucopyranosyloxymethyluracil ([[Chemistry:Base J|base J]]), was identified in the nuclear DNA of ''T. brucei.''<ref>{{cite journal | vauthors = Borst P, Sabatini R | title = Base J: discovery, biosynthesis, and possible functions | journal = Annual Review of Microbiology | volume = 62 | pages = 235–251 | date = 2008 | pmid = 18729733 | doi = 10.1146/annurev.micro.62.081307.162750 }}</ref>

== VSG coat ==
The surface of ''T. brucei'' and other species of trypanosomes is covered by a dense external coat called variant surface glycoprotein (VSG).<ref name="Barry">{{cite book | vauthors = Barry JD, McCulloch R | title = Advances in Parasitology Volume 49 | chapter = Antigenic variation in trypanosomes: enhanced phenotypic variation in a eukaryotic parasite | volume = <!-- --> | pages = 1–70 | year = 2001 | pmid = 11461029 | doi = 10.1016/S0065-308X(01)49037-3 | isbn = 978-0-12-031749-3  }}</ref> VSGs are 60-kDa proteins which are densely packed (~5 x 10<sup>6</sup> molecules) to form a 12–15&nbsp;nm surface coat. VSG dimers make up about 90% of all cell surface proteins in trypanosomes. They also make up ~10% of total cell protein. For this reason, these proteins are highly immunogenic and an immune response raised against a specific VSG coat will rapidly kill trypanosomes expressing this variant. However, with each cell division there is a possibility that the progeny will switch expression to change the VSG that is being expressed.<ref name="Barry"/><ref name="Morrison-et-al-2009">{{cite journal | vauthors = Morrison LJ, Marcello L, McCulloch R | title = Antigenic variation in the African trypanosome: molecular mechanisms and phenotypic complexity | journal = Cellular Microbiology | volume = 11 | issue = 12 | pages = 1724–1734 | date = December 2009 | pmid = 19751359 | doi = 10.1111/j.1462-5822.2009.01383.x | s2cid = 26552797 | doi-access = free }}</ref>

This VSG coat enables an infecting ''T. brucei'' population to persistently evade the host's [[Biology:Immune system|immune system]], allowing chronic infection. VSG is highly immunogenic, and an immune response raised against a specific VSG coat rapidly kills trypanosomes expressing this variant. [[Biology:Antibody|Antibody]]-mediated trypanosome killing can also be observed [[In vitro|in vitro]] by a [[Biology:Complement system|complement-mediated]] [[Biology:Lysis|lysis]] [[Biology:Assay|assay]]. However, with each [[Biology:Cell division|cell division]] there is a possibility that one or both of the [[Biology:Offspring|progeny]] will switch expression to change the VSG that is being expressed. The frequency of VSG switching has been measured to be approximately 0.1% per division.<ref>{{cite journal | vauthors = Turner CM | title = The rate of antigenic variation in fly-transmitted and syringe-passaged infections of Trypanosoma brucei | journal = FEMS Microbiology Letters | volume = 153 | issue = 1 | pages = 227–231 | date = August 1997 | pmid = 9252591 | doi = 10.1111/j.1574-6968.1997.tb10486.x }}</ref>  As ''T. brucei'' populations can peak at a size of 10<sup>11</sup> within a host<ref name="Barry2012">{{cite journal | vauthors = Barry JD, Hall JP, Plenderleith L | title = Genome hyperevolution and the success of a parasite | journal = Annals of the New York Academy of Sciences | volume = 1267 | issue = 1 | pages = 11–17 | date = September 2012 | pmid = 22954210 | pmc = 3467770 | doi = 10.1111/j.1749-6632.2012.06654.x | bibcode = 2012NYASA1267...11B }}</ref> this rapid rate of switching ensures that the parasite population is typically highly diverse.<ref>{{cite journal | vauthors = Hall JP, Wang H, Barry JD | title = Mosaic VSGs and the scale of Trypanosoma brucei antigenic variation | journal = PLOS Pathogens | volume = 9 | issue = 7 | pages = e1003502 | date = 11 July 2013 | pmid = 23853603 | pmc = 3708902 | doi = 10.1371/journal.ppat.1003502 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mugnier MR, Cross GA, Papavasiliou FN | title = The in vivo dynamics of antigenic variation in Trypanosoma brucei | journal = Science | volume = 347 | issue = 6229 | pages = 1470–1473 | date = March 2015 | pmid = 25814582 | pmc = 4514441 | doi = 10.1126/science.aaa4502 | bibcode = 2015Sci...347.1470M }}</ref> Because host immunity against a specific VSG does not develop immediately, some parasites will have switched to an antigenically distinct VSG variant, and can go on to multiply and continue the infection. The clinical effect of this cycle is successive 'waves' of [[Medicine:Parasitemia|parasitemia]] (trypanosomes in the blood).<ref name="Barry" />

Expression of ''VSG'' genes occurs through a number of mechanisms yet to be fully understood.<ref>{{cite journal | vauthors = Pays E | title = Regulation of antigen gene expression in Trypanosoma brucei | journal = Trends in Parasitology | volume = 21 | issue = 11 | pages = 517–520 | date = November 2005 | pmid = 16126458 | doi = 10.1016/j.pt.2005.08.016 }}</ref> The expressed VSG can be switched either by activating a different expression site (and thus changing to express the ''VSG'' in that site), or by changing the ''VSG'' gene in the active site to a different variant. The genome contains many hundreds if not thousands of ''VSG'' genes, both on minichromosomes and in repeated sections ('arrays') in the interior of the chromosomes. These are transcriptionally silent, typically with omitted sections or premature stop codons, but are important in the evolution of new VSG genes. It is estimated up to 10% of the ''T. brucei'' genome may be made up of VSG genes or [[Biology:Pseudogenes|pseudogenes]]. It is thought that any of these genes can be moved into the active site by [[Biology:Genetic recombination|recombination]] for expression.<ref name="Morrison-et-al-2009" /> VSG silencing is largely due to the effects of [[Biology:Histone|histone]] variants H3.V and H4.V. These histones cause changes in the three-dimensional structure of the ''T. brucei'' genome that results in a lack of expression. VSG genes are typically located in the subtelomeric regions of the chromosomes, which makes it easier for them to be silenced when they are not being used.<ref name="F1000-of-Mueller">{{Cite journal|title=Faculty of 1000 evaluation for Genome organization and DNA accessibility control antigenic variation in trypanosomes| vauthors = Rudenko G |date=2018-10-26|website=F1000|doi=10.3410/f.734240334.793552268|doi-access=free}}</ref><ref name="Mueller-et-al-2018">{{cite journal | vauthors = Müller LS, Cosentino RO, Förstner KU, Guizetti J, Wedel C, Kaplan N, Janzen CJ, Arampatzi P, Vogel J, Steinbiss S, Otto TD, Saliba AE, Sebra RP, Siegel TN | display-authors = 6 | title = Genome organization and DNA accessibility control antigenic variation in trypanosomes | journal = Nature | volume = 563 | issue = 7729 | pages = 121–125 | date = November 2018 | pmid = 30333624 | pmc = 6784898 | doi = 10.1038/s41586-018-0619-8 | publisher = [[Company:Nature Research|Nature Research]] | doi-access = free | bibcode = 2018Natur.563..121M }}</ref> It remains unproven whether the regulation of VSG switching is purely stochastic or whether environmental stimuli affect switching frequency. Switching is linked to two factors: variation in activation of individual VSG genes; and differentiation to the "short stumpy" stage - triggered by conditions of high population density - which is the nonreproductive, interhost transmission stage.<ref name="Mideo-et-al-2013" /> {{As of|2021}} it also remains unexplained how this transition is timed and how the next surface protein gene is chosen.<ref name="Luzak-et-al-2021" /> These questions of antigenic variation in ''T. brucei'' and other parasites are among the most interesting in the field of [[Medicine:Infection|infection]].<ref name="Luzak-et-al-2021" />

==Killing by human serum and resistance to human serum killing==
''Trypanosoma brucei brucei'' (as well as related species ''[[Biology:Trypanosoma equiperdum|T. equiperdum]]'' and ''[[Biology:Trypanosoma evansi|T. evansi]]'') is not human infective because it is susceptible to innate immune system 'trypanolytic' factors present in the serum of some primates, including humans. These trypanolytic factors have been identified as two serum complexes designated trypanolytic factors (TLF-1 and −2) both of which contain [[Biology:Haptoglobin-related protein|haptoglobin-related protein]] (HPR) and apolipoprotein LI (ApoL1). TLF-1 is a member of the high density lipoprotein family of particles while TLF-2 is a related high molecular weight serum protein binding complex.<ref name=Hajduk1989>{{cite journal | vauthors = Hajduk SL, Moore DR, Vasudevacharya J, Siqueira H, Torri AF, Tytler EM, Esko JD | title = Lysis of Trypanosoma brucei by a toxic subspecies of human high density lipoprotein | journal = The Journal of Biological Chemistry | volume = 264 | issue = 9 | pages = 5210–5217 | date = March 1989 | pmid = 2494183 | doi = 10.1016/S0021-9258(18)83720-6 | doi-access = free }}</ref><ref name=Raper1999>{{cite journal | vauthors = Raper J, Fung R, Ghiso J, Nussenzweig V, Tomlinson S | title = Characterization of a novel trypanosome lytic factor from human serum | journal = Infection and Immunity | volume = 67 | issue = 4 | pages = 1910–1916 | date = April 1999 | pmid = 10085035 | pmc = 96545 | doi = 10.1128/IAI.67.4.1910-1916.1999 }}</ref> The protein components of TLF-1 are haptoglobin related protein (HPR), apolipoprotein L-1 (apoL-1) and apolipoprotein A-1 (apoA-1). These three proteins are colocalized within spherical particles containing phospholipids and cholesterol. The protein components of TLF-2 include IgM and apolipoprotein A-I.<ref>{{cite journal | vauthors = Vanhollebeke B, Pays E | title = The trypanolytic factor of human serum: many ways to enter the parasite, a single way to kill | journal = Molecular Microbiology | volume = 76 | issue = 4 | pages = 806–814 | date = May 2010 | pmid = 20398209 | doi = 10.1111/j.1365-2958.2010.07156.x | s2cid = 7740199 | url = https://hal.archives-ouvertes.fr/hal-00552632/file/PEER_stage2_10.1111%252Fj.1365-2958.2010.07156.x.pdf }}</ref>

Trypanolytic factors are found only in a few species, including humans, [[Biology:Gorilla|gorilla]]s, [[Biology:Mandrill|mandrill]]s, [[Biology:Baboon|baboon]]s and [[Biology:Sooty mangabey|sooty mangabey]]s. This appears to be because haptoglobin-related protein and apolipoprotein L-1 are unique to primates. This suggests these genes originated in the primate genome {{Ma|25}}-{{Ma|35}}.<ref name="Lugli2004">{{cite journal | vauthors = Lugli EB, Pouliot M, ((Portela Md)), Loomis MR, Raper J | title = Characterization of primate trypanosome lytic factors | journal = Molecular and Biochemical Parasitology | volume = 138 | issue = 1 | pages = 9–20 | date = November 2004 | pmid = 15500911 | doi = 10.1016/j.molbiopara.2004.07.004 }}</ref>

Human infective subspecies ''T. b. gambiense'' and ''T. b. rhodesiense'' have evolved mechanisms of resisting the trypanolytic factors, described below.

===ApoL1===
ApoL1 is a member of a six gene family, ApoL1-6, that have arisen by tandem duplication. These proteins are normally involved in host apoptosis or autophagic death and possess a Bcl-2 homology domain 3.<ref>{{cite journal | vauthors = Vanhollebeke B, Pays E | title = The function of apolipoproteins L | journal = Cellular and Molecular Life Sciences | volume = 63 | issue = 17 | pages = 1937–1944 | date = September 2006 | pmid = 16847577 | doi = 10.1007/s00018-006-6091-x | s2cid = 12713960 }}</ref> ApoL1 has been identified as the toxic component involved in trypanolysis.<ref name=Vanhamme2003>{{cite journal | vauthors = Vanhamme L, Paturiaux-Hanocq F, Poelvoorde P, Nolan DP, Lins L, Van Den Abbeele J, Pays A, Tebabi P, Van Xong H, Jacquet A, Moguilevsky N, Dieu M, Kane JP, De Baetselier P, Brasseur R, Pays E | display-authors = 6 | title = Apolipoprotein L-I is the trypanosome lytic factor of human serum | journal = Nature | volume = 422 | issue = 6927 | pages = 83–87 | date = March 2003 | pmid = 12621437 | doi = 10.1038/nature01461 | s2cid = 4310920 | bibcode = 2003Natur.422...83V }}</ref> ApoLs have been subject to recent selective evolution possibly related to resistance to pathogens.<ref name=Smith2009>{{cite journal | vauthors = Smith EE, Malik HS | title = The apolipoprotein L family of programmed cell death and immunity genes rapidly evolved in primates at discrete sites of host-pathogen interactions | journal = Genome Research | volume = 19 | issue = 5 | pages = 850–858 | date = May 2009 | pmid = 19299565 | pmc = 2675973 | doi = 10.1101/gr.085647.108 }}</ref>

The gene encoding ApoL1 is found on the long arm of [[Biology:Chromosome 22|chromosome 22]] (22q12.3). Variants of this gene, termed G1 and G2, provide protection against ''T. b. rhodesiense''.<ref name=Genovese2010/> These benefits are not without their downside as a specific ApoL1 [[Medicine:Glomerulopathy|glomerulopathy]] has been identified.<ref name=Genovese2010>{{cite journal | vauthors = Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR | display-authors = 6 | title = Association of trypanolytic ApoL1 variants with kidney disease in African Americans | journal = Science | volume = 329 | issue = 5993 | pages = 841–845 | date = August 2010 | pmid = 20647424 | pmc = 2980843 | doi = 10.1126/science.1193032 | bibcode = 2010Sci...329..841G }}</ref><ref name=Wasser2012>{{cite journal | vauthors = Wasser WG, Tzur S, Wolday D, Adu D, Baumstein D, Rosset S, Skorecki K | title = Population genetics of chronic kidney disease: the evolving story of APOL1 | journal = Journal of Nephrology | volume = 25 | issue = 5 | pages = 603–618 | year = 2012 | pmid = 22878977 | doi = 10.5301/jn.5000179 }}</ref> This glomerulopathy may help to explain the greater prevalence of [[Medicine:Hypertension|hypertension]] in African populations.<ref>{{cite journal | vauthors = Lipkowitz MS, Freedman BI, Langefeld CD, Comeau ME, Bowden DW, Kao WH, Astor BC, Bottinger EP, Iyengar SK, Klotman PE, Freedman RG, Zhang W, Parekh RS, Choi MJ, Nelson GW, Winkler CA, Kopp JB | display-authors = 6 | title = Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans | journal = Kidney International | volume = 83 | issue = 1 | pages = 114–120 | date = January 2013 | pmid = 22832513 | pmc = 3484228 | doi = 10.1038/ki.2012.263 }}</ref>

The gene encodes a protein of 383 residues, including a typical signal peptide of 12 amino acids.<ref name=Duchateau1997>{{cite journal | vauthors = Duchateau PN, Pullinger CR, Orellana RE, Kunitake ST, Naya-Vigne J, O'Connor PM, Malloy MJ, Kane JP | display-authors = 6 | title = Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L | journal = The Journal of Biological Chemistry | volume = 272 | issue = 41 | pages = 25576–25582 | date = October 1997 | pmid = 9325276 | doi = 10.1074/jbc.272.41.25576 | doi-access = free }}</ref> The plasma protein is a single chain polypeptide with an apparent molecular mass of 42 kilodaltons. ApoL1 has a membrane pore forming domain functionally similar to that of bacterial [[Biology:Colicin|colicin]]s.<ref name="Pérez-Morga2005">{{cite journal | vauthors = Pérez-Morga D, Vanhollebeke B, Paturiaux-Hanocq F, Nolan DP, Lins L, Homblé F, Vanhamme L, Tebabi P, Pays A, Poelvoorde P, Jacquet A, Brasseur R, Pays E | display-authors = 6 | title = Apolipoprotein L-I promotes trypanosome lysis by forming pores in lysosomal membranes | journal = Science | volume = 309 | issue = 5733 | pages = 469–472 | date = July 2005 | pmid = 16020735 | doi = 10.1126/science.1114566 | s2cid = 33189804 | bibcode = 2005Sci...309..469P }}</ref> This domain is flanked by the membrane addressing domain and both these domains are required for parasite killing.

Within the kidney, ApoL1 is found in the [[Biology:Podocyte|podocyte]]s in the glomeruli, the proximal tubular epithelium and the arteriolar endothelium.<ref name=Madhavan2011>{{cite journal | vauthors = Madhavan SM, O'Toole JF, Konieczkowski M, Ganesan S, Bruggeman LA, Sedor JR | title = APOL1 localization in normal kidney and nondiabetic kidney disease | journal = Journal of the American Society of Nephrology | volume = 22 | issue = 11 | pages = 2119–2128 | date = November 2011 | pmid = 21997392 | pmc = 3231786 | doi = 10.1681/ASN.2011010069 }}</ref> It has a high affinity for [[Biology:Phosphatidic acid|phosphatidic acid]] and [[Chemistry:Cardiolipin|cardiolipin]] and can be induced by [[Biology:Interferon|interferon]] gamma and [[Biology:Tumor necrosis factor|tumor necrosis factor]] alpha.<ref name=Zhaorigetu2008>{{cite journal | vauthors = Zhaorigetu S, Wan G, Kaini R, Jiang Z, Hu CA | title = ApoL1, a BH3-only lipid-binding protein, induces autophagic cell death | journal = Autophagy | volume = 4 | issue = 8 | pages = 1079–1082 | date = November 2008 | pmid = 18927493 | pmc = 2659410 | doi = 10.4161/auto.7066 }}</ref>

===Hpr===
Hpr is 91% identical to [[Biology:Haptoglobin|haptoglobin]] (Hp), an abundant acute phase serum protein, which possesses a high affinity for [[Biology:Hemoglobin|hemoglobin]] (Hb). When Hb is released from erythrocytes undergoing intravascular hemolysis Hp forms a complex with the Hb and these are removed from circulation by the [[Biology:CD163|CD163]] scavenger receptor. In contrast to Hp–Hb, the Hpr–Hb complex does not bind CD163 and the Hpr serum concentration appears to be unaffected by hemolysis.<ref>{{cite journal | vauthors = Widener J, Nielsen MJ, Shiflett A, Moestrup SK, Hajduk S | title = Hemoglobin is a co-factor of human trypanosome lytic factor | journal = PLOS Pathogens | volume = 3 | issue = 9 | pages = 1250–1261 | date = September 2007 | pmid = 17845074 | pmc = 1971115 | doi = 10.1371/journal.ppat.0030129 | doi-access = free }}</ref>

===Killing mechanism===
The association of HPR with hemoglobin allows TLF-1 binding and uptake via the trypanosome haptoglobin-hemoglobin receptor (TbHpHbR).<ref name=Vanhollebeke2008>{{cite journal | vauthors = Vanhollebeke B, De Muylder G, Nielsen MJ, Pays A, Tebabi P, Dieu M, Raes M, Moestrup SK, Pays E | display-authors = 6 | title = A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans | journal = Science | volume = 320 | issue = 5876 | pages = 677–681 | date = May 2008 | pmid = 18451305 | doi = 10.1126/science.1156296 | s2cid = 206512161 | bibcode = 2008Sci...320..677V }}</ref> TLF-2 enters trypanosomes independently of TbHpHbR.<ref name=Vanhollebeke2008/> TLF-1 uptake increases when haptoglobin level is low. TLF-1 overtakes haptoglobin and binds free hemoglobin in the serum. However the complete absence of haptoglobin is associated with a decreased killing rate by serum.<ref name=Vanhollebeke2007>{{cite journal | vauthors = Vanhollebeke B, Nielsen MJ, Watanabe Y, Truc P, Vanhamme L, Nakajima K, Moestrup SK, Pays E | display-authors = 6 | title = Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 10 | pages = 4118–4123 | date = March 2007 | pmid = 17360487 | pmc = 1820718 | doi = 10.1073/pnas.0609902104 | doi-access = free | bibcode = 2007PNAS..104.4118V }}</ref>

The trypanosome haptoglobin-hemoglobin receptor is an elongated three a-helical bundle with a small membrane distal head.<ref name=Higgins2013>{{cite journal | vauthors = Higgins MK, Tkachenko O, Brown A, Reed J, Raper J, Carrington M | title = Structure of the trypanosome haptoglobin-hemoglobin receptor and implications for nutrient uptake and innate immunity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 5 | pages = 1905–1910 | date = January 2013 | pmid = 23319650 | pmc = 3562850 | doi = 10.1073/pnas.1214943110 | doi-access = free | bibcode = 2013PNAS..110.1905H }}</ref> This protein extends above the variant surface glycoprotein layer that surrounds the parasite.

The first step in the killing mechanism is the binding of TLF to high affinity receptors—the haptoglobin-hemoglobin receptors—that are located in the flagellar pocket of the parasite.<ref name=Vanhollebeke2008/><ref name=Green2003>{{cite journal | vauthors = Green HP, Del Pilar Molina Portela M, St Jean EN, Lugli EB, Raper J | title = Evidence for a Trypanosoma brucei lipoprotein scavenger receptor | journal = The Journal of Biological Chemistry | volume = 278 | issue = 1 | pages = 422–427 | date = January 2003 | pmid = 12401813 | doi = 10.1074/jbc.M207215200 | doi-access = free }}</ref> The bound TLF is endocytosed via coated vesicles and then trafficked to the parasite [[Biology:Lysosome|lysosome]]s. ApoL1 is the main lethal factor in the TLFs and kills trypanosomes after insertion into [[Biology:Endosome|endosomal]] / [[Biology:Lysosome|lysosomal]] membranes.<ref name=Vanhamme2003/> After ingestion by the parasite, the TLF-1 particle is trafficked to the [[Biology:Lysosome|lysosome]] wherein ApoL1 is activated by a pH mediated conformational change. After fusion with the [[Biology:Lysosome|lysosome]] the pH drops from ~7 to ~5. This induces a conformational change in the ApoL1 membrane addressing domain which in turn causes a salt bridge linked hinge to open. This releases ApoL1 from the HDL particle to insert in the lysosomal membrane. The ApoL1 protein then creates anionic pores in the membrane which leads to depolarization of the membrane, a continuous influx of [[Chemistry:Chloride|chloride]] and subsequent osmotic swelling of the [[Biology:Lysosome|lysosome]]. This influx in its turn leads to rupture of the [[Biology:Lysosome|lysosome]] and the subsequent death of the parasite.<ref>{{cite journal | vauthors = Pays E, Vanhollebeke B, Vanhamme L, Paturiaux-Hanocq F, Nolan DP, Pérez-Morga D | title = The trypanolytic factor of human serum | journal = Nature Reviews. Microbiology | volume = 4 | issue = 6 | pages = 477–486 | date = June 2006 | pmid = 16710327 | doi = 10.1038/nrmicro1428 | s2cid = 6151924 }}</ref>

===Resistance mechanisms: ''T. b. gambiense''===
''Trypanosoma brucei gambiense'' causes 97% of human cases of sleeping sickness. Resistance to ApoL1 is principally mediated by the hydrophobic β-sheet of the ''T. b. gambiense'' specific [[Chemistry:Glycoprotein|glycoprotein]].<ref name=Uzureau2013/> Other factors involved in resistance appear to be a change in the [[Biology:Cysteine protease|cysteine protease]] activity and TbHpHbR inactivation due to a [[Chemistry:Leucine|leucine]] to [[Chemistry:Serine|serine]] substitution (L210S) at codon 210.<ref name=Uzureau2013>{{cite journal | vauthors = Uzureau P, Uzureau S, Lecordier L, Fontaine F, Tebabi P, Homblé F, Grélard A, Zhendre V, Nolan DP, Lins L, Crowet JM, Pays A, Felu C, Poelvoorde P, Vanhollebeke B, Moestrup SK, Lyngsø J, Pedersen JS, Mottram JC, Dufourc EJ, Pérez-Morga D, Pays E | display-authors = 6 | title = Mechanism of Trypanosoma brucei gambiense resistance to human serum | journal = Nature | volume = 501 | issue = 7467 | pages = 430–434 | date = September 2013 | pmid = 23965626 | doi = 10.1038/nature12516 | s2cid = 4400057 | bibcode = 2013Natur.501..430U }}</ref> This is due to a [[Chemistry:Thymidine|thymidine]] to [[Chemistry:Cytosine|cytosine]] mutation at the second codon position.<ref>{{cite journal | vauthors = DeJesus E, Kieft R, Albright B, Stephens NA, Hajduk SL | title = A single amino acid substitution in the group 1 Trypanosoma brucei gambiense haptoglobin-hemoglobin receptor abolishes TLF-1 binding | journal = PLOS Pathogens | volume = 9 | issue = 4 | pages = e1003317 | year = 2013 | pmid = 23637606 | pmc = 3630162 | doi = 10.1371/journal.ppat.1003317 | doi-access = free }}</ref>

These mutations may have evolved due to the coexistence of [[Medicine:Malaria|malaria]] where this parasite is found.<ref name=Uzureau2013/> Haptoglobin levels are low in malaria because of the hemolysis that occurs with the release of the merozoites into the blood. The rupture of the erythrocytes results in the release of free [[Biology:Heme|haem]] into the blood where it is bound by haptoglobin. The haem is then removed along with the bound haptoglobin from the blood by the [[Biology:Reticuloendothelial system|reticuloendothelial system]].<ref>{{cite journal | vauthors = Smith A, McCulloh RJ | title = Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders | journal = Frontiers in Physiology | volume = 6 | pages = 187 | date = 2015 | pmid = 26175690 | pmc = 4485156 | doi = 10.3389/fphys.2015.00187 | doi-access = free }}</ref>

===Resistance mechanisms: ''T. b. rhodesiense''===
''Trypanosoma brucei rhodesiense'' relies on a different mechanism of resistance: the serum resistance associated protein (SRA). The ''SRA'' gene is a truncated version of the major and variable surface antigen of the parasite, the variant surface glycoprotein.<ref name=Pays2008>{{cite journal | vauthors = Pays E, Vanhollebeke B | title = Mutual self-defence: the trypanolytic factor story | journal = Microbes and Infection | volume = 10 | issue = 9 | pages = 985–989 | date = July 2008 | pmid = 18675374 | doi = 10.1016/j.micinf.2008.07.020 }}</ref> However, it has little similarity (low sequence homology) with the VSG gene (<25%). SRA is an expression site associated gene in ''T. b. rhodesiense'' and is located upstream of the VSGs in the active telomeric expression site.<ref name=Xong1998>{{cite journal | vauthors = Xong HV, Vanhamme L, Chamekh M, Chimfwembe CE, Van Den Abbeele J, Pays A, Van Meirvenne N, Hamers R, De Baetselier P, Pays E | display-authors = 6 | title = A VSG expression site-associated gene confers resistance to human serum in Trypanosoma rhodesiense | journal = Cell | volume = 95 | issue = 6 | pages = 839–846 | date = December 1998 | pmid = 9865701 | doi = 10.1016/S0092-8674(00)81706-7 | doi-access = free }}</ref> The protein is largely localized to small cytoplasmic vesicles between the flagellar pocket and the nucleus. In ''T. b. rhodesiense'' the TLF is directed to SRA containing [[Biology:Endosome|endosome]]s while some dispute remains as to its presence in the [[Biology:Lysosome|lysosome]].<ref name=Vanhamme2003/><ref name=Shiflett2007>{{cite journal | vauthors = Shiflett AM, Faulkner SD, Cotlin LF, Widener J, Stephens N, Hajduk SL | title = African trypanosomes: intracellular trafficking of host defense molecules | journal = The Journal of Eukaryotic Microbiology | volume = 54 | issue = 1 | pages = 18–21 | year = 2007 | pmid = 17300512 | doi = 10.1111/j.1550-7408.2006.00228.x | s2cid = 20054667 }}</ref> SRA binds to ApoL1 using a coiled–coiled interaction at the ApoL1 SRA interacting domain while within the trypanosome lysosome.<ref name=Vanhamme2003/> This interaction prevents the release of the ApoL1 protein and the subsequent lysis of the lysosome and death of the parasite.

Baboons are known to be resistant to ''T. b. rhodesiense''. The baboon version of the ApoL1 gene differs from the human gene in a number of respects including two critical lysines near the C terminus that are necessary and sufficient to prevent baboon ApoL1 binding to SRA.<ref name=Thomson2009>{{cite journal | vauthors = Thomson R, Molina-Portela P, Mott H, Carrington M, Raper J | title = Hydrodynamic gene delivery of baboon trypanosome lytic factor eliminates both animal and human-infective African trypanosomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 46 | pages = 19509–19514 | date = November 2009 | pmid = 19858474 | pmc = 2780755 | doi = 10.1073/pnas.0905669106 | doi-access = free | bibcode = 2009PNAS..10619509T }}</ref> Experimental mutations allowing ApoL1 to be protected from neutralization by SRA have been shown capable of conferring trypanolytic activity on ''T. b. rhodesiense''.<ref name=Lecordier2009/> These mutations resemble those found in baboons, but also resemble natural mutations conferring protection of humans against ''T. b. rhodesiense'' which are linked to kidney disease.<ref name=Genovese2010/>

== See also ==
* List of parasites (human)
* Simon Gaskell, professor of chemistry and current principal of Queen Mary, University of London, researches various forms of [[Biology:Mass spectrometry data format|mass spectrometry]] to determine the quantity and longevity of these proteins.
* [[Chemistry:Tryptophol|Tryptophol]], a chemical compound produced by the ''T. brucei'' which induces sleep in humans<ref>{{cite journal |last1=Richard Seed |first1=John |last2=Seed |first2=Thomas M. |last3=Sechelski |first3=John |title=The biological effects of tryptophol (indole-3-ethanol): Hemolytic, biochemical and behavior modifying activity |journal=Comparative Biochemistry and Physiology Part C: Comparative Pharmacology |date=January 1978 |volume=60 |issue=2 |pages=175–185 |doi=10.1016/0306-4492(78)90091-6|pmid=28889 }}</ref>

== References ==
{{Reflist|32em}}

== External links ==
* {{cite web |title=Trypanosomiasis, African (''Trypanosoma brucei gambiense'') (''Trypanosoma brucei rhodesiense'') |date=29 November 2013 |work=DPDx—Laboratory Identification of Parasitic Diseases of Public Health Concern |publisher=Centers for Disease Control and Prevention |url=https://www.cdc.gov/dpdx/trypanosomiasisAfrican/index.html}}
* {{cite web |title=''Trypanosoma brucei'' |work=NCBI Taxonomy Browser |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=5691 |id=5691}}
* {{cite web |title=''Parasites – African Trypanosomiasis (also known as Sleeping Sickness)'' |work=Centers for Disease Control and Prevention |url=https://www.cdc.gov/parasites/sleepingsickness/biology.html|date=2018-06-08 }}

{{Protozoal diseases}}
{{Taxonbar|from=Q33244}}

[[Category:Trypanosomatida]]

{{Sourceattribution|Trypanosoma brucei}}