Trypanosoma brucei

366: 1065:

of parasites in the salivary gland. 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. 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. Complete development in the fly takes about 20 days. They are injected into the mammalian host along with the saliva on biting, and are known as salivarian.

748: 511:), Bruce and his wife joined Castellani and Christy on 16 March. 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. Castellani left Africa in April and published his report as "On the discovery of a species of 1472: 2397: 818: 917: 854: 58: 1126: 1787:

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. As of 2021 it also remains unexplained how this transition is timed and how the next surface protein gene is chosen. These questions of antigenic variation in

1187:, i.e., a sexual reproduction stage. But it is not always necessary for a complete life cycle. The existence of meiosis-specific proteins was reported in 2011. 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). Thus, in addition to binary fission, 33: 496:), a small roundworm transmitted by flies, and bacteria as possible causes, only to discover that the epidemic was not related to these pathogens. The team was described as an "ill-assorted group" and a "queer lot", and the expedition "a failure." Low, whose conduct was described as "truculent and prone to take offence," left the Commission and Africa after three months. 2163:. 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. Experimental mutations allowing ApoL1 to be protected from neutralization by SRA have been shown capable of conferring trypanolytic activity on 1692:

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.

1990:

The association of HPR with hemoglobin allows TLF-1 binding and uptake via the trypanosome haptoglobin-hemoglobin receptor (TbHpHbR). TLF-2 enters trypanosomes independently of TbHpHbR. TLF-1 uptake increases when haptoglobin level is low. TLF-1 overtakes haptoglobin and binds free hemoglobin in the

1741:

populations can peak at a size of 10 within a host this rapid rate of switching ensures that the parasite population is typically highly diverse. Because host immunity against a specific VSG does not develop immediately, some parasites will have switched to an antigenically distinct VSG variant, and

1691:

and other species of trypanosomes is covered by a dense external coat called variant surface glycoprotein (VSG). VSGs are 60-kDa proteins which are densely packed (~5 x 10 molecules) to form a 12–15 nm surface coat. VSG dimers make up about 90% of all cell surface proteins in trypanosomes. They

1405:

drug families (containing melarsoprol and pentamidine, respectively). This is particularly a problem with the veterinary drug diminazene aceturate. Drug uptake and degradation are two major issues to consider to avoid drug resistance development. In the case of nucleoside analogues, they need to be

1400:

is to target its nucleotide metabolism. The nucleotide metabolism studies have both led to the development of adenosine analogues looking promising in animal studies, and to the finding that downregulation of the P2 adenosine transporter is a common way to acquire partial drug resistance against the

1064:

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

1003:

that transmit other protozoan infections in which only females are involved, both sexes of tsetse flies are blood feeders and equally transmit trypanosomes. The short and stumpy trypomastigotes (SS) are taken up by tsetse flies during a blood meal. Survival in the tsetse midgut is one reason for the

982:

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. Besides preparation to be taken up and vectored to another host by a tsetse fly, transition from

903:

The flagellar function is twofold — locomotion via oscillations along the attached flagellum and cell body in human blood stream and tsetse fly gut, and attachment to the salivary gland epithelium of the fly during the epimastigote stage. The flagellum propels the body in such a way that the axoneme

805:

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. The cell surface of the bloodstream form features a dense coat of variant surface glycoproteins (VSGs)

558:

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. His report in 1902 indicates that he believed it to be a kind of filarial worm. From the same person,

537:

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. Bruce, in the third Sleeping Sickness Commission (1908–1912) that included Albert Ernest Hamerton, H.R. Bateman and

975:. Some of the daughter cells then become short and stumpy again. Some of them remains as intermediate forms, representing a transitional stage between the long and short forms. The long slender forms are able to penetrate the blood vessel endothelium and invade extravascular tissues, including the 899:

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

1051:

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

1834:

family of particles while TLF-2 is a related high molecular weight serum protein binding complex. 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

447:

In Uganda, the first case of human infection was reported in 1898. It was followed by an outbreak in 1900. By 1901, it became severe with death toll estimated to about 20,000. More than 250,000 people died in the epidemic that lasted for two decades. The disease commonly popularised as "negro

1786:

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. It remains unproven whether the regulation of VSG switching is purely stochastic or whether

378:

gave clearer description of the symptoms from Sierra Leone in 1803. 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. The symptom is eponymously known as "Winterbottom's sign."

1372:, and suramin. They are all highly toxic to animals, and drug resistance is prevalent. 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, 1765:

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

347:

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. It was a major infectious diseases in southern and eastern Africa in the 19th century. The

1998:

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. The bound TLF is endocytosed via coated vesicles and then trafficked to the parasite

414:

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

6781:"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" 448:

lethargy." It was not known whether the human sleeping sickness and nagana were similar or the two disease were caused by similar parasites. Even the observations of Forde and Dutton did not indicate that the trypanosome was related to sleeping sickness.

2134:

gene is a truncated version of the major and variable surface antigen of the parasite, the variant surface glycoprotein. However, it has little similarity (low sequence homology) with the VSG gene (<25%). SRA is an expression site associated gene in

1313:

developed in 1990. These drugs are not fully effective and are toxic to humans. In addition, drug resistance has developed in the parasites against all the drugs. The drugs are of limited application since they are effective against specific strains of

1391:

The major challenge against the human disease has been to find drugs that readily pass the blood-brain barrier. The latest drug that has come into clinical use is fexinidazol, but promising results have also been obtained with the benzoxaborole drug

671:

The subspecies cannot be distinguished from their structure as they are all identical under microscopes. Geographical location is the main distinction. Molecular markers have been developed for individual identification. Serum resistance-associated

1288:

may be transferred between mammals via bodily fluid exchange, such as by blood transfusion or sexual contact, although this is thought to be rare. Newborn babies can be infected (vertical or congenital transmission) from infected mothers.

2155:

using a coiled–coiled interaction at the ApoL1 SRA interacting domain while within the trypanosome lysosome. This interaction prevents the release of the ApoL1 protein and the subsequent lysis of the lysosome and death of the parasite.

904:

generates the oscillation and a flagellar wave is created along the undulating membrane. As a result, the body moves in a corkscrew pattern. In flagella of other organisms, the movement starts from the base towards the tip, while in

7607:

Paindavoine P, Pays E, Laurent M, Geltmeyer Y, Le Ray D, Mehlitz D, Steinert M (February 1986). "The use of DNA hybridization and numerical taxonomy in determining relationships between Trypanosoma brucei stocks and subspecies".

1352:

developed the first specific trypanocidal drug in 1904 from a dye, trypan red, which they named Trypanroth. These chemical preparations were effective only at high and toxic dosages, and were not suitable for clinical use.

3335:

Cook GC (1993). "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".

5644:

Van Den Abbeele, J.; Claes, Y.; van Bockstaele, D.; Le Ray, D.; Coosemans, M. (1999). "Trypanosoma brucei spp. development in the tsetse fly: characterization of the post-mesocyclic stages in the foregut and proboscis".

1822:'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 579:) was discovered by British parasitologists John William Watson Stephens and Harold Benjamin Fantham. In 1910, Stephens noted in his experimental infection in rats that the trypanosome, obtained from an individual from 5808:

Lefèvre T, Thomas F, Ravel S, Patrel D, Renault L, Le Bourligu L, et al. (December 2007). "Trypanosoma brucei brucei induces alteration in the head proteome of the tsetse fly vector Glossina palpalis gambiensis".

4175:

Jamonneau, Vincent; Ilboudo, Hamidou; Kaboré, Jacques; Kaba, Dramane; Koffi, Mathurin; Solano, Philippe; Garcia, André; Courtin, David; Laveissière, Claude; Lingue, Kouakou; Büscher, Philippe; Bucheton, Bruno (2012).

1994:

The trypanosome haptoglobin-hemoglobin receptor is an elongated three a-helical bundle with a small membrane distal head. This protein extends above the variant surface glycoprotein layer that surrounds the parasite.

373:

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. Another English physician

1280:

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.

1060:

where they get attached to the salivary gland epithelium. 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.

1396:(SCYX-7158). This drug is currently under evaluation as a single-dose oral treatment, which is a great advantage compared to currently used drugs. Another research field that has been extensively studied in 639:

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.

731:), meaning "body." The specific name is after David Bruce, who discovered the parasites in 1894. The subspecies, the human strains, are named after the regions in Africa where they were first identified: 7463: 567:

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

2459:

Legros D, Ollivier G, Gastellu-Etchegorry M, Paquet C, Burri C, Jannin J, Büscher P (July 2002). "Treatment of human African trypanosomiasis--present situation and needs for research and development".

1923:

The gene encodes a protein of 383 residues, including a typical signal peptide of 12 amino acids. The plasma protein is a single chain polypeptide with an apparent molecular mass of 42 kilodaltons.

1890:

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.

5071:

Woods A, Sherwin T, Sasse R, MacRae TH, Baines AJ, Gull K (July 1989). "Definition of individual components within the cytoskeleton of Trypanosoma brucei by a library of monoclonal antibodies".

1105: 8922:

Pérez-Morga D, Vanhollebeke B, Paturiaux-Hanocq F, Nolan DP, Lins L, Homblé F, et al. (July 2005). "Apolipoprotein L-I promotes trypanosome lysis by forming pores in lysosomal membranes".

4374:

Deborggraeve S, Koffi M, Jamonneau V, Bonsu FA, Queyson R, Simarro PP, et al. (August 2008). "Molecular analysis of archived blood slides reveals an atypical human Trypanosoma infection".

843:, 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. 1004:

particular adaptations of the SS stage. The trypomastigotes enter the midgut of the fly where they become procyclic trypomastigotes as they replace their VSG with other protein coats called

2139:

and is located upstream of the VSGs in the active telomeric expression site. The protein is largely localized to small cytoplasmic vesicles between the flagellar pocket and the nucleus. In

1753:

genes occurs through a number of mechanisms yet to be fully understood. The expressed VSG can be switched either by activating a different expression site (and thus changing to express the

1506:) areas of continental Africa. Hence, the equatorial region of Africa is called the "sleeping sickness" belt. However, the specific type of the trypanosome differs according to geography. 9127:

Vanhollebeke B, De Muylder G, Nielsen MJ, Pays A, Tebabi P, Dieu M, et al. (May 2008). "A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans".

8883:"Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L" 9722:

Richard Seed, John; Seed, Thomas M.; Sechelski, John (January 1978). "The biological effects of tryptophol (indole-3-ethanol): Hemolytic, biochemical and behavior modifying activity".

4518:

Lukeš, Julius; Kachale, Ambar; Votýpka, Jan; Butenko, Anzhelika; Field, Mark (2022). "African trypanosome strategies for conquering new hosts and territories: the end of monophyly?".

2948:

Martini E (1903). "Ueber die Entwickelung der Tsetseparasiten in Säugethieren" [Preliminary note on the morphology and distribution of the parasite found in tsetse disease].

1052:

proliferative epimastigotes. The epimastigotes divide asymmetrically to produce long and short epimastigotes. The long epimastigote cannot move to other places and simply die off by

773:, 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 1080:

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

8635:

Vanhamme L, Paturiaux-Hanocq F, Poelvoorde P, Nolan DP, Lins L, Van Den Abbeele J, et al. (March 2003). "Apolipoprotein L-I is the trypanosome lytic factor of human serum".

1330:. Melarsopol is the only drug effective against the two types of parasite in both infection stages, but is highly toxic, such that 5% of treated individuals die of brain damage ( 872:, 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 403:

in South Africa. The disease caused severe problems among the local cattle and British Army horses. On 27 October 1894, Bruce and his microbiologist-wife Mary Elizabeth Bruce (

273:). 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 220:

parasites that normally infect blood and tissue cells, it is exclusively extracellular and inhabits the blood plasma and body fluids. It causes deadly vector-borne diseases:

7756:

De Greef C, Imberechts H, Matthyssens G, Van Meirvenne N, Hamers R (September 1989). "A gene expressed only in serum-resistant variants of Trypanosoma brucei rhodesiense".

7349:"Methylthioadenosine Phosphorylase Protects the Parasite from the Antitrypanosomal Effect of Deoxyadenosine: implications for the pharmacology of adenosine antimetabolites" 967:

and into the bloodstream. The initial trypomastigotes are short and stumpy (SS). They are protected from the host's immune system by producing antigentic variation called

1141:

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:

908:

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.

9385:

Uzureau P, Uzureau S, Lecordier L, Fontaine F, Tebabi P, Homblé F, et al. (September 2013). "Mechanism of Trypanosoma brucei gambiense resistance to human serum".

1894:

has been identified as the toxic component involved in trypanolysis. ApoLs have been subject to recent selective evolution possibly related to resistance to pathogens.

7066:

Wilson SG (1948). "Further Observations on the Curative Value of Dimidium Bromide (Phenanthridinium 1553) in Trypanosoma Congolense Infections in Bovines in Uganda".

963:

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

4409:

Radwanska, Magdalena; Chamekh, Mustapha; Vanhamme, Luc; Claes, Filip; Magez, Stefan; Magnus, Eddy; de Baetselier, Patrick; Büscher, Philippe; Pays, Etienne (2002).

1854:. 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 663:

by trypanosome lytic factor-1 (TLF-1). However, it is closely related to, and shares fundamental features with the human-infective subspecies. Only rarely can the

1338:(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 5154:

Halliday C, de Castro-Neto A, Alcantara CL, Cunha-E-Silva NL, Vaughan S, Sunter JD (April 2021). "Trypanosomatid Flagellar Pocket from Structure to Function".

1264: 1236: 7887:"A high-order trans-membrane structural linkage is responsible for mitochondrial genome positioning and segregation by flagellar basal bodies in trypanosomes" 1737:

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. As

1258: 8797:

Wasser WG, Tzur S, Wolday D, Adu D, Baumstein D, Rosset S, Skorecki K (2012). "Population genetics of chronic kidney disease: the evolving story of APOL1".

1978:(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 293:. 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. 9620:

Shiflett AM, Faulkner SD, Cotlin LF, Widener J, Stephens N, Hajduk SL (2007). "African trypanosomes: intracellular trafficking of host defense molecules".

1137:

is unusual compared to most eukaryotes. The nuclear membrane remains intact and the chromosomes do not condense during mitosis. The basal body, unlike the

587:. 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 1344:

Historically, arsenic and mercuric compounds were introduced in the early 20th century, with success particularly in animal infections. German physician

1230: 873: 7400:"9-(2'-Deoxy-2'-Fluoro-β-d-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance" 1982:

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.

944: 613:

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

482:, a medical officer on duty in Bombay, India. At the time, a debate remained on the etiology, some favoured bacterial infection while some believed as 849:, 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. 8688:"The apolipoprotein L family of programmed cell death and immunity genes rapidly evolved in primates at discrete sites of host-pathogen interactions" 7144: 7031:

Wilson SG (April 1948). "Further observations on the curative value of dimidium bromide in Trypanosoma congolense infections in bovines in Uganda".

7791:

Ogbadoyi E, Ersfeld K, Robinson D, Sherwin T, Gull K (March 2000). "Architecture of the Trypanosoma brucei nucleus during interphase and mitosis".

522:

By then the Royal Society had already published the report. By August 1903, Bruce and his team established that the disease was transmitted by the

8834:"Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans" 530:

However, Bruce did not understand the trypanosoma life cycle and believed that the parasites were simply transmitted from one person to another.

1379:

Among its products, dimidium bromide and its derivatives were first used in 1948 in animal cases in Africa, and became known as homidium (or as

6288:

Rocha G, Martins A, Gama G, Brandão F, Atouguia J (January 2004). "Possible cases of sexual and congenital transmission of sleeping sickness".

471: 3213:

Köhler W, Köhler M (September 2002). "Zentralblatt für Bakteriologie--100 years ago: sleeping sickness--intoxication or infectious disease?".

1510:

is found primarily in East Africa (Botswana, Democratic Republic of the Congo, Ethiopia, Kenya, Malawi, Tanzania, Uganda and Zimbabwe), while

10193: 8487: 9833: 1040: 550:, in experiments carried out between 1911 and 1912, established how ingested trypanosomes finally reach the salivary glands of the fly. 9337:

Pays E, Vanhollebeke B, Vanhamme L, Paturiaux-Hanocq F, Nolan DP, Pérez-Morga D (June 2006). "The trypanolytic factor of human serum".

1587:

parasites avoid uptake of the TLF particles while those of group 2 are able to either neutralize or compensate for the effects of TLF.

1034: 1028: 1022: 466:

constituted a three-member Sleeping Sickness Commission on 10 May 1902 to investigate the epidemic in Uganda. The Commission comprised

9438:"A single amino acid substitution in the group 1 Trypanosoma brucei gambiense haptoglobin-hemoglobin receptor abolishes TLF-1 binding" 1583:

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

8067:

Turner CM (August 1997). "The rate of antigenic variation in fly-transmitted and syringe-passaged infections of Trypanosoma brucei".

3412:

Cook GC (May 2012). "Patrick Manson (1844-1922) FRS: Filaria (Mansonella) perstans and sleeping sickness (African trypanosomiasis)".

1480: 7705:

Lecordier L, Vanhollebeke B, Poelvoorde P, Tebabi P, Paturiaux-Hanocq F, Andris F, et al. (December 2009). Mansfield JM (ed.).

10180: 4284:

Rifkin MR (August 1984). "Trypanosoma brucei: biochemical and morphological studies of cytotoxicity caused by normal human serum".

1406:

taken up by the P1 nucleoside transporter (instead of P2), and they also need to be resistant against cleavage in the parasite.

7454:

Ibrahim MA, Mohammed A, Isah MB, Aliyu AB (May 2014). "Anti-trypanosomal activity of African medicinal plants: a review update".

6511:

Barrett MP, Vincent IM, Burchmore RJ, Kazibwe AJ, Matovu E (September 2011). "Drug resistance in human African trypanosomiasis".

2112:

into the blood where it is bound by haptoglobin. The haem is then removed along with the bound haptoglobin from the blood by the

2104:

where this parasite is found. Haptoglobin levels are low in malaria because of the hemolysis that occurs with the release of the

365: 6595:

Kennedy PG (February 2013). "Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness)".

9665:"Hydrodynamic gene delivery of baboon trypanosome lytic factor eliminates both animal and human-infective African trypanosomes" 6258: 5593:

Proto, William R.; Coombs, Graham H.; Mottram, Jeremy C. (2013). "Cell death in parasitic protozoa: regulated or incidental?".

5309: 2167:. These mutations resemble those found in baboons, but also resemble natural mutations conferring protection of humans against 955:. When absorbed by other trypanosomes these EVs cause repulsive movement away from the area and so away from bad environments. 8536:

Lugli EB, Pouliot M, Portela Md, Loomis MR, Raper J (November 2004). "Characterization of primate trypanosome lytic factors".

3952:"On the Peculiar Morphology of a Trypanosome From a Case of Sleeping Sickness and the Possibility of Its Being a New Species ( 3915:"On the peculiar morphology of a trypanosome from a case of sleeping sickness and the possibility of its being a new species ( 3606:

Castellani A (1903). "On the discovery of a species of trypanosoma in the cerebrospinal fluid of cases of sleeping sickness".

7991: 7974:

Barry JD, McCulloch R (2001). "Antigenic variation in trypanosomes: enhanced phenotypic variation in a eukaryotic parasite".

7707:"C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense" 3068: 2897: 2736: 1084:

metabolism that causes a perceived need for more calories. (The metabolic change, in turn, being due to complete absence of

7513: 2542:

Joubert JJ, Schutte CH, Irons DJ, Fripp PJ (1993). "Ubombo and the site of David Bruce's discovery of Trypanosoma brucei".

6390:

Nok AJ (May 2003). "Arsenicals (melarsoprol), pentamidine and suramin in the treatment of human African trypanosomiasis".

3373:"Bacteria or parasite? the controversy over the etiology of sleeping sickness and the Portuguese participation, 1898-1904" 503:, following a request from the Royal Society, appointed David Bruce to lead the second Sleeping Sickness Commission. With 10256: 10010: 7653:"Differences between Trypanosoma brucei gambiense groups 1 and 2 in their resistance to killing by trypanolytic factor 1" 2035:

protein then creates anionic pores in the membrane which leads to depolarization of the membrane, a continuous influx of

1093: 3988:

Barrett MP, Burchmore RJ, Stich A, Lazzari JO, Frasch AC, Cazzulo JJ, Krishna S (November 2003). "The trypanosomiases".

9239:"Structure of the trypanosome haptoglobin-hemoglobin receptor and implications for nutrient uptake and innate immunity" 4975:

Bastin P, Matthews KR, Gull K (August 1996). "The paraflagellar rod of kinetoplastida: solved and unsolved questions".

971:

on their body surface. Once inside the bloodstream, they grow into long and slender forms (LS). Then, they multiply by

8304:"Faculty of 1000 evaluation for Genome organization and DNA accessibility control antigenic variation in trypanosomes" 1145:

The basal body duplicates and both remain associated with the kinetoplast. Each basal body forms a separate flagellum.

2887: 1931:. This domain is flanked by the membrane addressing domain and both these domains are required for parasite killing. 1503: 1499: 1495: 1085: 4468:"Diagnostic potential of a conserved genomic rearrangement in the Trypanosoma brucei gambiense-specific TGSGP locus" 10231: 2189: 6951:"Systematic Review and Meta-Analysis on Knowledge Attitude and Practices on African Animal Trypanocide Resistance" 6129:"Phylogenomic analyses support the monophyly of Excavata and resolve relationships among eukaryotic "supergroups"" 3086:"The Changes in the Central Nervous System of Two Cases of Negro Lethargy: Sequel to Dr. Manson's Clinical Report" 1199:

supports the hypothesis that meiosis and sexual reproduction are ancestral and ubiquitous features of eukaryotes.

10198: 9826: 9780: 1148:

Kinetoplast DNA undergoes synthesis then the kinetoplast divides coupled with separation of the two basal bodies.

5753:"A new asymmetric division contributes to the continuous production of infective trypanosomes in the tsetse fly" 1494:

is found where its tsetse fly vectors are prevalent in continental Africa. That is to say, tropical rainforest (

7836:"The genome sequence of Trypanosoma brucei gambiense, causative agent of chronic human african trypanosomiasis" 4411:"The serum resistance-associated gene as a diagnostic tool for the detection of Trypanosoma brucei rhodesiense" 633:, are also infected. It is responsible for 98% of all human African trypanosomiasis, and is roughly 100% fatal. 1835:

containing phospholipids and cholesterol. The protein components of TLF-2 include IgM and apolipoprotein A-I.

762:

as found in the tsetse fly midgut. The cell body is shown in orange and the flagellum is in red. 84 pixels/μm.

546:

An open question, noted by Bruce at this stage, was how the trypanosome finds its way to the salivary glands.

10241: 8881:

Duchateau PN, Pullinger CR, Orellana RE, Kunitake ST, Naya-Vigne J, O'Connor PM, et al. (October 1997).

2193: 1742:

can go on to multiply and continue the infection. The clinical effect of this cycle is successive 'waves' of

968: 375: 362:

word for to be low or depressed in spirit. In other parts of Africa, Europeans called it the "fly disease."

278: 7502:"Cattle trypanosomosis: the diversity of trypanosomes and implications for disease epidemiology and control" 10246: 10236: 1682: 1628:

Around 100 minichromosomes of around 50 to 100 kilobase pairs. These may be present in multiple copies per

751: 457: 392: 331: 5252:

Juan T, Fürthauer M (February 2018). "Biogenesis and function of ESCRT-dependent extracellular vesicles".

10261: 10144: 9959: 5818: 1991:

serum. However the complete absence of haptoglobin is associated with a decreased killing rate by serum.

1823: 1195:

and are one of the earliest diverging lineages among eukaryotes. The discovery of sexual reproduction in

508: 252:, while the latter two are zoonotic infecting both humans and animals and cause African trypanosomiasis. 7101:

Carmichael J (April 1950). "Dimidium bromide or phenanthridinium 1553; a note on the present position".

1594:

is dependent upon the expression of a serum resistance associated (SRA) gene. This gene is not found in

57: 9819: 9579:

Xong HV, Vanhamme L, Chamekh M, Chimfwembe CE, Van Den Abbeele J, Pays A, et al. (December 1998).

2309: 2113: 1089: 7160:"Ethidium bromide provides a simple tool for identifying genuine DNA-independent protein associations" 1761:

gene in the active site to a different variant. The genome contains many hundreds if not thousands of

1552:

evolved from a single progenitor ~10,000 years ago. It is evolving asexually and its genome shows the

1044:

are then hijacked by the parasite to aid its own midgut infection, using them to inactivate bloodmeal

931:) and mammalian hosts, including humans, cattle, horses, and wild animals. In stressful environments, 9180:"Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum" 6188:"An expanded inventory of conserved meiotic genes provides evidence for sex in Trichomonas vaginalis" 4749: 2180: 539: 9581:"A VSG expression site-associated gene confers resistance to human serum in Trypanosoma rhodesiense" 4582:

Krüger T, Schuster S, Engstler M (December 2018). "Beyond Blood: African Trypanosomes on the Move".

2396: 1297:

There are four drugs generally recommended for the first-line treatment of African trypanosomiasis:

352:(now part of South Africa) was severely struck by the disease, which became known to the British as 10251: 8832:

Lipkowitz MS, Freedman BI, Langefeld CD, Comeau ME, Bowden DW, Kao WH, et al. (January 2013).

5540:

Mideo N, Acosta-Serrano A, Aebischer T, Brown MJ, Fenton A, Friman VP, et al. (January 2013).

5359:"Role of the long slender to short stumpy transition in the life cycle of the african trypanosomes" 1831: 388: 9178:

Vanhollebeke B, Nielsen MJ, Watanabe Y, Truc P, Vanhamme L, Nakajima K, et al. (March 2007).

8740:

Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. (August 2010).

8333:

Müller LS, Cosentino RO, Förstner KU, Guizetti J, Wedel C, Kaplan N, et al. (November 2018).

6548:"A current analysis of chemotherapy strategies for the treatment of human African trypanosomiasis" 2130:

relies on a different mechanism of resistance: the serum resistance associated protein (SRA). The

2027:

membrane addressing domain which in turn causes a salt bridge linked hinge to open. This releases

1568:

that possesses two distinct groups that differ in genotype and phenotype. Group 2 is more akin to

9953: 9945: 9890: 3852:

Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character

1534: 1208: 588: 542:, established the basic developmental cycle through which the trypanosome in tsetse fly must pass 221: 9811: 8020:"Antigenic variation in the African trypanosome: molecular mechanisms and phenotypic complexity" 6433:

Burri C, Brun R (June 2003). "Eflornithine for the treatment of human African trypanosomiasis".

5694:"Bottlenecks and the maintenance of minor genotypes during the life cycle of Trypanosoma brucei" 747: 10112: 9979: 8488:"The trypanolytic factor of human serum: many ways to enter the parasite, a single way to kill" 6878: 4798: 4520: 3673: 1808: 1782:

variants H3.V and H4.V. These histones cause changes in the three-dimensional structure of the

1374: 1361: 1154:

undergoes synthesis while a new flagellum extends from the younger, more posterior, basal body.

976: 646: 306: 225: 9796: 8396:

Hajduk SL, Moore DR, Vasudevacharya J, Siqueira H, Torri AF, Tytler EM, Esko JD (March 1989).

7651:

Capewell P, Veitch NJ, Turner CM, Raper J, Berriman M, Hajduk SL, MacLeod A (September 2011).

7558:"Population genomics reveals the origin and asexual evolution of human infective trypanosomes" 7001: 6687:

Bottieau E, Clerinx J (March 2019). "Human African Trypanosomiasis: Progress and Stagnation".

5328: 4064:

Büscher P, Cecchi G, Jamonneau V, Priotto G (November 2017). "Human African trypanosomiasis".

1318:

and the life cycle stages of the parasites. Suramin is used only for first-stage infection of

1056:. The short epimastigote migrate from the proventriculus via the foregut and proboscis to the 846: 840: 595:. Fantham described the parasite's morphology and found that it was a different trypanosome. 10208: 10069: 9934: 9760: 8973:

Madhavan SM, O'Toole JF, Konieczkowski M, Ganesan S, Bruggeman LA, Sedor JR (November 2011).

7138: 5541: 1959: 1946:, the proximal tubular epithelium and the arteriolar endothelium. It has a high affinity for 1775: 1538: 952: 782: 467: 262: 142: 7834:

Jackson AP, Sanders M, Berry A, McQuillan J, Aslett MA, Quail MA, et al. (April 2010).

559:

Forde's colleague Joseph Everett Dutton identified it as a protozoan belonging to the genus

300:

subspecies due to their different means of transmission, clinical presentation, and loss of

10083: 9676: 9394: 9250: 9191: 9136: 8931: 8753: 8644: 8350: 8223: 8115: 7947: 7171: 6472:

Docampo R, Moreno SN (June 2003). "Current chemotherapy of human African trypanosomiasis".

6199: 6140: 6032: 5973: 5873: 4886: 4031: 1357: 811: 759: 618: 10149: 7556:

Weir W, Capewell P, Foth B, Clucas C, Pountain A, Steketee P, et al. (January 2016).

6274: 2753: 8: 9972: 9968: 9930: 9849: 4873:

Koyfman AY, Schmid MF, Gheiratmand L, Fu CJ, Khant HA, Huang D, et al. (July 2011).

2582:"Sir David Bruce's elucidation of the aetiology of nagana--exactly one hundred years ago" 2019:

wherein ApoL1 is activated by a pH mediated conformational change. After fusion with the

1943: 801:

with which it is indistinguishable under microscope. From the basal body arises a single

504: 492: 290: 282: 9680: 9489:"Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders" 9398: 9254: 9195: 9140: 8935: 8757: 8648: 8597: 8572: 8354: 8227: 8119: 7230: 7175: 6203: 6144: 6036: 5977: 5962:"Identification of the meiotic life cycle stage of Trypanosoma brucei in the tsetse fly" 5960:

Peacock L, Ferris V, Sharma R, Sunter J, Bailey M, Carrington M, Gibson W (March 2011).

5877: 5217: 4890: 2685: 2318: 2297: 9938: 9699: 9664: 9645: 9515: 9488: 9464: 9437: 9418: 9362: 9273: 9238: 9214: 9179: 9160: 9099: 9072: 9048: 9023: 8999: 8974: 8955: 8858: 8833: 8774: 8741: 8712: 8687: 8668: 8610: 8518: 8373: 8335:"Genome organization and DNA accessibility control antigenic variation in trypanosomes" 8334: 8267:

Pays E (November 2005). "Regulation of antigen gene expression in Trypanosoma brucei".

8244: 8211: 8187: 8160: 8136: 8103: 8080: 8049: 7934:

Borst P, Sabatini R (2008). "Base J: discovery, biosynthesis, and possible functions".

7862: 7835: 7816: 7733: 7706: 7679: 7652: 7633: 7584: 7557: 7535: 7426: 7399: 7375: 7348: 7280: 7253: 7126: 6977: 6950: 6926: 6901: 6854: 6829: 6805: 6780: 6756: 6731: 6712: 6664: 6639: 6620: 6572: 6547: 6493: 6454: 6415: 6367: 6332: 6313: 6222: 6187: 6163: 6128: 6104: 6077: 6053: 6020: 5996: 5961: 5842: 5790: 5728: 5693: 5674: 5626: 5514: 5479: 5446: 5413: 5226: 5201: 5179: 5131: 5106: 5053: 5040: 5011: 4957: 4909: 4874: 4850: 4821: 4768: 4733: 4709: 4674: 4658: 4625: 4607: 4557: 4448: 4387: 4351: 4324: 4261: 4236: 4212: 4177: 4152: 4117: 4089: 4013: 3704: 3654: 3588: 3486: 3461: 3437: 3312: 3295: 3276: 3198: 3169: 3110: 3085: 2965: 2798: 2773: 2702: 2658: 2631: 2436: 2411: 2331: 2254: 2229: 1916:

has been identified. This glomerulopathy may help to explain the greater prevalence of

1814: 1711:

raised against a specific VSG coat rapidly kills trypanosomes expressing this variant.

1530: 1430: 1252: 940: 727:), which means "borer" or "auger", referring to the corkscrew-like movement; and σῶμα ( 500: 483: 424: 312: 213: 52: 9597: 9580: 8414: 8397: 7983: 7911: 7886: 7079: 7044: 6608: 6301: 5896: 5861: 5389: 5358: 4077: 4001: 3619: 2472: 817: 285:, enabling persistent evasion of host adaptive immunity leading to chronic infection. 10004: 9898: 9842: 9739: 9735: 9704: 9637: 9633: 9602: 9561: 9520: 9469: 9410: 9354: 9319: 9278: 9219: 9164: 9152: 9104: 9053: 9004: 8947: 8904: 8863: 8814: 8779: 8742:"Association of trypanolytic ApoL1 variants with kidney disease in African Americans" 8717: 8660: 8602: 8553: 8549: 8510: 8506: 8468: 8463: 8438: 8419: 8398:"Lysis of Trypanosoma brucei by a toxic subspecies of human high density lipoprotein" 8378: 8284: 8249: 8192: 8141: 8127: 8084: 8041: 8036: 8019: 7997: 7987: 7951: 7916: 7867: 7808: 7773: 7769: 7738: 7684: 7625: 7589: 7527: 7479: 7431: 7380: 7329: 7308:"Targeting the nucleotide metabolism of Trypanosoma brucei and other trypanosomatids" 7285: 7234: 7199: 7194: 7159: 7118: 7083: 7048: 6982: 6931: 6859: 6810: 6761: 6704: 6669: 6612: 6577: 6528: 6485: 6446: 6407: 6372: 6354: 6333:"The unknown risk of vertical transmission in sleeping sickness--a literature review" 6305: 6254: 6227: 6168: 6109: 6058: 6001: 5942: 5901: 5834: 5830: 5782: 5774: 5733: 5715: 5666: 5658: 5618: 5610: 5564: 5519: 5501: 5451: 5433: 5394: 5305: 5273: 5231: 5183: 5171: 5136: 5084: 5045: 4992: 4988: 4949: 4945: 4914: 4855: 4773: 4714: 4696: 4645: 4599: 4561: 4549: 4541: 4497: 4489: 4440: 4432: 4391: 4356: 4305: 4301: 4266: 4217: 4199: 4157: 4139: 4081: 4043: 4005: 3869: 3848:"Further researches on the development of trypanosoma gambiense in glossina palpalis" 3829: 3821: 3696: 3580: 3545: 3518: 3491: 3429: 3394: 3353: 3349: 3317: 3268: 3230: 3150: 3146: 3115: 3064: 3036: 2996: 2930: 2893: 2868: 2841: 2803: 2732: 2707: 2663: 2603: 2598: 2581: 2559: 2555: 2521: 2486: 2441: 2385: 2335: 2323: 2259: 2078: 1947: 1720: 1708: 1655:, an unusual feature unique to the kinetoplastid protozoans. The kinetoplast and the 1526: 1242: 972: 936: 695:

The subspecies lack many of the features commonly considered necessary to constitute

614: 580: 408: 9649: 9296:

Green HP, Del Pilar Molina Portela M, St Jean EN, Lugli EB, Raper J (January 2003).

8959: 8614: 8454: 8053: 7637: 7539: 7130: 6716: 6497: 6458: 6419: 5678: 4961: 4611: 3708: 3658: 3441: 3389: 3372: 3280: 2969: 2015:

membranes. After ingestion by the parasite, the TLF-1 particle is trafficked to the

987:

aids in increasing the total transmitting duration of any particular infested host.

832:

show several different classes of cellular organisation of which two are adopted by

9926: 9731: 9694: 9684: 9629: 9592: 9551: 9510: 9500: 9459: 9449: 9422: 9402: 9366: 9346: 9309: 9268: 9258: 9209: 9199: 9144: 9094: 9084: 9043: 9035: 8994: 8986: 8939: 8894: 8853: 8845: 8806: 8769: 8761: 8707: 8699: 8672: 8652: 8592: 8584: 8545: 8522: 8502: 8458: 8450: 8409: 8368: 8358: 8313: 8276: 8239: 8231: 8182: 8172: 8131: 8123: 8076: 8031: 7979: 7943: 7906: 7898: 7857: 7847: 7820: 7800: 7765: 7728: 7718: 7674: 7664: 7617: 7579: 7569: 7517: 7471: 7421: 7411: 7370: 7360: 7319: 7275: 7265: 7226: 7189: 7179: 7110: 7075: 7040: 7013: 6972: 6962: 6921: 6913: 6849: 6841: 6800: 6792: 6751: 6743: 6696: 6659: 6655: 6651: 6624: 6604: 6567: 6563: 6559: 6520: 6477: 6438: 6399: 6362: 6344: 6317: 6297: 6217: 6207: 6158: 6148: 6099: 6089: 6048: 6040: 5991: 5981: 5932: 5891: 5881: 5846: 5826: 5822: 5794: 5764: 5723: 5705: 5650: 5630: 5602: 5556: 5509: 5491: 5441: 5425: 5384: 5374: 5265: 5221: 5213: 5163: 5126: 5118: 5076: 5057: 5035: 5027: 4984: 4941: 4904: 4894: 4845: 4837: 4763: 4753: 4704: 4686: 4653: 4637: 4591: 4533: 4479: 4452: 4422: 4383: 4346: 4336: 4297: 4256: 4248: 4207: 4189: 4147: 4129: 4093: 4073: 4017: 3997: 3971: 3967: 3930: 3859: 3811: 3778: 3739: 3688: 3646: 3615: 3572: 3481: 3473: 3421: 3384: 3345: 3307: 3260: 3222: 3193: 3185: 3142: 3105: 3097: 3026: 2992: 2957: 2922: 2833: 2793: 2785: 2697: 2653: 2643: 2593: 2551: 2513: 2504:

Gibson W (July 2007). "Resolution of the species problem in African trypanosomes".

2476: 2468: 2431: 2423: 2375: 2313: 2249: 2241: 1471: 1380: 964: 547: 479: 8318: 8303: 6546:

Babokhov P, Sanyaolu AO, Oyibo WA, Fagbenro-Beyioku AF, Iriemenam NC (July 2013).

5937: 5920: 4734:"Characterization of the novel mitochondrial genome replication factor MiRF172 in 2926: 2859:

Ormerod WE (October 1991). "Hypothesis: the significance of Winterbottom's sign".

2380: 2363: 2007:

is the main lethal factor in the TLFs and kills trypanosomes after insertion into

1112:

vectors' head proteomes under infection by other eukaryotic parasites of mammals.

853: 10089: 10044: 9875: 9866: 9556: 9539: 9454: 9089: 8346: 8308: 8177: 7852: 7723: 7669: 7398:

Ranjbarian F, Vodnala M, Alzahrani KJ, Ebiloma GU, de Koning HP, Hofer A (2016).

6349: 6246: 6212: 5710: 5560: 5299: 5269: 4341: 4194: 3058: 2726: 2517: 1974:(Hp), an abundant acute phase serum protein, which possesses a high affinity for 1553: 829: 821:

The six main morphologies of trypanosomatids. The different life cycle stages of

797:, which is a complex of thousands of mitochondria. The kinetoplast lies near the 786: 770: 626: 475: 396: 233: 109: 99: 9237:

Higgins MK, Tkachenko O, Brown A, Reed J, Raper J, Carrington M (January 2013).

6949:

Kasozi KI, MacLeod ET, Waiswa C, Mahero M, Ntulume I, Welburn SC (August 2022).

6830:"Action of the Colours of Benzidine on Mice Infected with Trypanosoma dimorphon" 6127:

Hampl V, Hug L, Leigh JW, Dacks JB, Lang BF, Simpson AG, Roger AJ (March 2009).

3888: 2684:

Berrang-Ford L, Odiit M, Maiso F, Waltner-Toews D, McDermott J (December 2006).

1879:

have evolved mechanisms of resisting the trypanolytic factors, described below.

916: 435:

was already introduced by Hungarian physician David Gruby in his description of

10075: 10060: 9995: 9904: 9669: