Trypanosoma brucei
Trypanosoma brucei | |
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T. b. brucei TREU667 (Bloodstream form, phase-contrast picture. Black bar indicates 10 µm.)
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Scientific classification | |
Domain: | Eukaryota |
Phylum: | Euglenozoa |
Class: | Kinetoplastea |
Order: | Trypanosomatida |
Family: | Trypanosomatidae |
Genus: | Trypanosoma |
Species: | T. brucei
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Binomial name | |
Trypanosoma brucei Plimmer & Bradford, 1899
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Subspecies | |
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Trypanosoma brucei is a species of parasitic
T. brucei is transmitted between mammal hosts by an
Whilst not historically regarded as T. brucei subspecies due to their different means of transmission, clinical presentation, and loss of kinetoplast DNA, genetic analyses reveal that T. equiperdum and T. evansi are evolved from parasites very similar to T. b. brucei, and are thought to be members of the brucei clade.[6]
The parasite was discovered in 1894 by Sir David Bruce, after whom the scientific name was given in 1899.[7][8]
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.
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.[13] Another English physician Thomas Masterman Winterbottom gave clearer description of the symptoms from Sierra Leone in 1803.[14] 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.[13] The symptom is eponymously known as "Winterbottom's sign."[15]
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.[3] On 27 October 1894, Bruce and his microbiologist-wife Mary Elizabeth Bruce (née Steele) moved to Ubombo Hill, where the disease was most prevalent.[16]
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 .
Outbreaks
In Uganda, the first case of human infection was reported in 1898.[10] It was followed by an outbreak in 1900.[20] By 1901, it became severe with death toll estimated to about 20,000.[21] More than 250,000 people died in the epidemic that lasted for two decades.[20] The disease commonly popularised as "negro lethargy."[22][23] It was not known whether the human sleeping sickness and nagana were similar or the two disease were caused by similar parasites.[24] Even the observations of Forde and Dutton did not indicate that the trypanosome was related to sleeping sickness.[25]
Sleeping Sickness Commission
The
In February 1902, the
Around the same time, Germany sent an expeditionary team led by 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.[9] 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.[38][39] An open question, noted by Bruce at this stage, was how the trypanosome finds its way to the salivary glands. Muriel Robertson,[40][41] 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.[9] His report in 1902 indicates that he believed it to be a kind of filarial worm.[14] From the same person, Forde's colleague Joseph Everett Dutton identified it as a protozoan belonging to the genus Trypanosoma.[3] Knowing the distinct features, Dutton proposed a new species name in 1902:
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.[42]
Another human trypanosome (now called T. brucei rhodesiense) was discovered by British parasitologists John William Watson Stephens and Harold Benjamin Fantham.[9] 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 Ronald Ross.[3] Fantham described the parasite's morphology and found that it was a different trypanosome.[43][44]
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
- 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.[45][48]
- T. brucei brucei which causes animal trypanosomiasis, along with several other species of Trypanosoma. T. b. brucei is not infective to humans due to its susceptibility to lysis by trypanosome lytic factor-1 (TLF-1).[50][51] However, it is closely related to, and shares fundamental features with the human-infective subspecies.[52] Only rarely can the T. b. brucei infect a human.[53]
The subspecies cannot be distinguished from their structure as they are all identical under microscopes. Geographical location is the main distinction.[48] Molecular markers have been developed for individual identification. Serum resistance-associated (SRA) gene is used to differentiate T. b. rhodesiense from other subspecies.[54] TgsGP gene, found only in type 1 T. b. gambiense is also a specific distinction between T. b. gambiense strains.[55]
The subspecies lack many of the features commonly considered necessary to constitute monophyly.[56] As such Lukeš et al., 2022 proposes a new polyphyly by ecotype.[56]
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;[57] and σῶμα (sôma), meaning "body."[58][59] The specific name is after David Bruce, who discovered the parasites in 1894.[7][8] 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.[3]
Structure
Trypanosomatids show several different classes of cellular organisation of which two are adopted by T. brucei at different stages of the life cycle:[61]
- 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.
- 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.
These names are derived from the
The microtubules of the flagellar 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.[66][67]
The flagellar function is twofold — locomotion via oscillations along the attached flagellum and cell body in human blood stream and tsetse fly gut,[68][69] and attachment to the salivary gland epithelium of the fly during the epimastigote stage.[57][70] 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.[57] 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.[70]
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
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
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.[72] 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 – controlling parasitemia aids in increasing the total transmitting duration of any particular infested host.[74][2]
In tsetse fly
Unlike
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.[76] The epimastigotes divide asymmetrically to produce long and short epimastigotes. The long epimastigote cannot move to other places and simply die off by apoptosis.[78][79] 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.[57] 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.[76][80]
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.[76] 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.[81] 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.[48] Complete development in the fly takes about 20 days.[72][73] They are injected into the mammalian host along with the saliva on biting, and are known as salivarian.[76]
In the case of T. b. brucei infecting Glossina palpalis gambiensis, the parasite changes the 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 glucose metabolism that causes a perceived need for more calories. (The metabolic change, in turn, being due to complete absence of glucose-6-phosphate 1-dehydrogenase in infected flies.) Monoamine neurotransmitter synthesis is also altered: production of aromatic L-amino acid decarboxylase involved in dopamine and serotonin synthesis, and α-methyldopa hypersensitive protein was induced. This is similar to the alterations in other dipteran vectors' head proteomes under infection by other eukaryotic parasites of mammals.[82]
Reproduction
Binary fission
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 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:[61]
- 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.
- Nuclear DNA undergoes synthesis while a new flagellum extends from the younger, more posterior, basal body.
- The nucleus undergoes mitosis.
- Cytokinesis progresses from the anterior to posterior.
- Division completes with 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 meiosis, i.e., a sexual reproduction stage.[83] But it is not always necessary for a complete life cycle.[84] The existence of meiosis-specific proteins was reported in 2011.[85] 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).[86][87] Thus, in addition to binary fission, T. brucei can multiply by sexual reproduction. Trypanosomes belong to the supergroup Excavata and are one of the earliest diverging lineages among eukaryotes.[88] The discovery of sexual reproduction in T. brucei supports the hypothesis that meiosis and sexual reproduction are ancestral and ubiquitous features of eukaryotes.[89]
Infection and pathogenicity
The insect vectors for T. brucei are different species of tsetse fly (genus Glossina). The major vectors of T. b. gambiense, causing West African sleeping sickness, are G. palpalis, G. tachinoides, and G. fuscipes. While the principal vectors of T. b. rhodesiense, causing East African sleeping sickness, are G. morsitans, G. pallidipes, and G. swynnertoni. Animal trypanosomiasis is transmitted by a dozen species of Glossina.[90]
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.[72]
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.[91][92] Newborn babies can be infected (vertical or congenital transmission) from infected mothers.[93]
Chemotherapy
There are four drugs generally recommended for the first-line treatment of African trypanosomiasis: suramin developed in 1921, pentamidine developed in 1941, melarsoprol developed in 1949 and eflornithine developed in 1990.[94][95] These drugs are not fully effective and are toxic to humans.[96] In addition, drug resistance has developed in the parasites against all the drugs.[97] 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,[98] but is highly toxic, such that 5% of treated individuals die of brain damage (reactive encephalopathy).[99] Another drug, nifurtimox, recommended for 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.[100][101]
Historically, arsenic and mercuric compounds were introduced in the early 20th century, with success particularly in animal infections.[102][103] German physician 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.[104] These chemical preparations were effective only at high and toxic dosages, and were not suitable for clinical use.[105]
Animal trypanosomiasis is treated with six drugs:
Alternative therapy
Some phytochemicals have shown research promise against the T. b. brucei strain.[115] Aderbauer et al., 2008 and Umar et al., 2010 find Khaya senegalensis is effective in vitro and Ibrahim et al., 2013 and 2008 in vivo (in rats).[115] Ibrahim et al., 2013 find a lower dose reduces parasitemia by this subspecies and a higher dose is curative and prevents injury.[115]
Distribution
T. brucei is found where its tsetse fly vectors are prevalent in continental Africa. That is to say, tropical rainforest (Af), tropical monsoon (Am), and tropical savannah (Aw) areas of continental Africa.[61] 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
Evolution
Trypanosoma brucei gambiense evolved from a single progenitor ~10,000 years ago.
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.[118]
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.[119]
In contrast, resistance in T. b. rhodesiense is dependent upon the expression of a serum resistance associated (SRA) gene.[120] This gene is not found in T. b. gambiense.[121]
Genome
The genome of T. brucei is made up of:[122]
- 11 pairs of large chromosomes 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 haploidgenome.
Most
The mitochondrial genome is found condensed into the kinetoplast, an unusual feature unique to the kinetoplastid protozoans. The kinetoplast and the basal body of the flagellum are strongly associated via a cytoskeletal structure[124]
In 1993, a new base, ß-d-glucopyranosyloxymethyluracil (base J), was identified in the nuclear DNA of T. brucei.[125]
VSG coat
The surface of T. brucei and other species of trypanosomes is covered by a dense external coat called variant surface glycoprotein (VSG).[126] VSGs are 60-kDa proteins which are densely packed (~5 x 106 molecules) to form a 12–15 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.[126][127]
This VSG coat enables an infecting T. brucei population to persistently evade the host's
Expression of VSG genes occurs through a number of mechanisms yet to be fully understood.
Killing by human serum and resistance to human serum killing
Trypanosoma brucei brucei (as well as related species
Trypanolytic factors are found only in a few species, including humans, gorillas, mandrills, baboons and sooty mangabeys. 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 25 million years ago-35 million years ago.[138]
Human infective subspecies T. b. gambiense and T. b. rhodesiense have evolved mechanisms of resisting the trypanolytic factors, described below.
ApoL1
The gene encoding
The gene encodes a protein of 383 residues, including a typical signal peptide of 12 amino acids. This domain is flanked by the membrane addressing domain and both these domains are required for parasite killing.
Within the kidney,
Hpr
Hpr is 91% identical to haptoglobin (Hp), an abundant acute phase serum protein, which possesses a high affinity for 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 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.[149]
Killing mechanism
The association of HPR with hemoglobin allows TLF-1 binding and uptake via the trypanosome haptoglobin-hemoglobin receptor (TbHpHbR).[150] TLF-2 enters trypanosomes independently of TbHpHbR.[150] 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.[151]
The trypanosome haptoglobin-hemoglobin receptor is an elongated three a-helical bundle with a small membrane distal head.[152] 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.
Resistance mechanisms: T. b. gambiense
Trypanosoma brucei gambiense causes 97% of human cases of sleeping sickness. Resistance to
These mutations may have evolved due to the coexistence of
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.
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.[161] Experimental mutations allowing ApoL1 to be protected from neutralization by SRA have been shown capable of conferring trypanolytic activity on T. b. rhodesiense.[120] 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.[142]
See also
- List of parasites (human)
- Queen Mary, University of London, researches various forms of mass spectrometryto determine the quantity and longevity of these proteins.
- Tryptophol, a chemical compound produced by the T. brucei which induces sleep in humans[162]
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External links
- "Trypanosomiasis, African (Trypanosoma brucei gambiense) (Trypanosoma brucei rhodesiense)". DPDx—Laboratory Identification of Parasitic Diseases of Public Health Concern. Centers for Disease Control and Prevention. 29 November 2013.
- "Trypanosoma brucei". NCBI Taxonomy Browser. 5691.
- "Parasites – African Trypanosomiasis (also known as Sleeping Sickness)". Centers for Disease Control and Prevention. 8 June 2018.