Trypanosoma brucei

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Trypanosoma brucei
Tb brucei.jpg
T. b. brucei TREU667 (Bloodstream form, phase-contrast picture. Black bar indicates 10 µm.)
Scientific classification Red Pencil Icon.png
Domain: Eukaryota
Phylum: Euglenozoa
Class: Kinetoplastea
Order: Trypanosomatida
Family: Trypanosomatidae
Genus: Trypanosoma
Species:
T. brucei
Binomial name
Trypanosoma brucei
Plimmer & Bradford, 1899
Subspecies
  • Trypanosoma brucei brucei
  • Trypanosoma brucei gambiense
  • Trypanosoma brucei rhodesiense

Trypanosoma brucei is a species of parasitic kinetoplastid belonging to the genus Trypanosoma . This parasite is the cause of vector-borne diseases of vertebrate animals, including humans, carried by species of tsetse fly in sub-Saharan Africa. In humans T. brucei causes African trypanosomiasis, or sleeping sickness. In animals it causes animal trypanosomiasis, also called nagana in cattle and horses. [1] T. brucei has traditionally been grouped into three subspecies: T. b. brucei, T. b. gambiense and T. b. rhodesiense. [2] The first is a parasite of non-human vertebrates, while the latter two are known to be parasites of humans. Only rarely can the T. b. brucei infect a human. [3]

Contents

T. brucei is transmitted between mammal hosts by an insect vector belonging to different species of 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 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. [4] 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. [5]

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

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. [9] It was a major infectious diseases in southern and eastern Africa in the 19th century. [10] The Zulu Kingdom (now part of South Africa) was severely struck by the disease, which became known to the British as nagana , [1] a Zulu word for to be low or depressed in spirit. In other parts of Africa, Europeans called it the "fly disease." [11] [12]

A man having sleeping sickness at Buruma Island, Uganda. An inhabitant of Buruma Island, Uganda, suffering from sleep Wellcome V0029100.jpg
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. [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]

The Royal Army Medical Corps appointed David Bruce, who at the time was assistant professor of pathology at the Army Medical School in Netley, in 1894 to investigate the disease in South Africa. 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] He soon discovered protozoan parasites from the blood of infected animals. It was the discovery of Trypanosoma brucei, [17] the name created by British zoologists Henry George Plimmer and John Rose Bradford in 1899 in honour of the discoverer. [18] 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. [19]

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, Gambiaex, in 1901. [20] His report in 1902 indicates that he believed it to be a kind of parasitic worm (helminth). [21] From the same person, Forde's colleague Joseph Everett Dutton identified it as a protozoan belonging to the genus Trypanosoma. 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. [22]

In Uganda, the first case of human infection was reported in 1898. [10] It was followed by an outbreak in 1900. [23] By 1901, it became severe with death toll estimated to about 20,000. [24] More than 250,000 people died in the epidemic that lasted for two decades. [23] The disease commonly popularised as "negro lethargy." [25] [26] It was not known whether the human sleeping sickness and nagana were similar or the two disease were caused by similar parasites. [27] Even the observations of Forde and Dutton did not indicate that the trypanosome was related to sleeping sickness. [28]

The Royal Society constituted a three-member Sleeping Sickness Commission on 10 May 1902 to investigate the epidemic in Uganda. [29] The Commission comprised George Carmichael Low from the London School of Hygiene and Tropical Medicine as the leader, his colleague Aldo Castellani and Cuthbert Christy, a medical officer on duty in Bombay, India. [30] [31] At the time, a debate remained on the etiology, some favoured bacterial infection while some believed as helminth infection. [32] The first investigation focussed on Filaria perstans (later renamed 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. [33] [34] The team was described as an "ill-assorted group" [35] and a "queer lot", [36] and the expedition "a failure." [37] Low, whose conduct was described as "truculent and prone to take offence," left the Commission and Africa after three months. [38]

In February 1902, the British War Office, following a request from the Royal Society, appointed David Bruce to lead the second Sleeping Sickness Commission. [39] With David Nunes Nabarro (from the University College Hospital), Bruce and his wife joined Castellani and Christy on 16 March. [40] 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. [41] 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. [42] By then the Royal Society had already published the report. [43] By August 1903, Bruce and his team established that the disease was transmitted the tsetse fly, Glossina palpalis. [44] However, Bruce did not understand the trypanosoma life cycle and believed that the parasites were simply transmitted from one person to another. [9]

Around the same time, Germany sent a 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. [45] Bruce, in the third Sleeping Sickness Commission (1908–1912) that included Albert Ernest Hamerton, H.R. Bateman and Frederick Percival Mackie, established the complete developmental stages of the trypanosome in tsetse fly. [46] [47]

Another human trypanosome (now called T. brucei rhodesiense) was discovered by British parasitologists John William Watson Stephens and Harold Benjamin Fantham. [45] In 1910, Stephens noted in his experimental infection in rats that the trypanosome, obtained from an individual from Rhodesia, was not the same as T. gambiense. Fantham described the morphology and found that it was a different trypanosome. [48] [49]

Species

T. brucei is a species complex that includes:

Structure

False colour SEM micrograph of the procyclic form of T. brucei as found in the tsetse fly midgut. The cell body is shown in orange and the flagellum is in red. 84 pixels/mm. TrypanosomaBrucei ProcyclicTrypomastigote SEM.jpg
False colour SEM micrograph of the procyclic form of T. brucei 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. [56] The kinetoplast lies near the basal body with which it is indistinguishable under microscope. From the basal body arises a single 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. [57] 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. [58]

The six main morphologies of trypanosomatids. The different life cycle stages of T brucei fall into the trypomastigote and epimastigote morphological categories. TrypanosomatidMorphologies PlainSVG.svg
The six main morphologies of trypanosomatids. The different life cycle stages of T brucei fall into the trypomastigote and epimastigote morphological categories.

Trypanosomatids show several different classes of cellular organisation of which two are adopted by Trypanosoma brucei at different stages of the life cycle: [57]

T. brucei flagellar structure Trypanosome Flagellum Structure.png
T. brucei flagellar structure

These names are derived from the 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, [59] a lattice structure of proteins unique to the kinetoplastids, euglenoids and dinoflagellates. [60] [61]

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. [62] [63]

The flagellar function is twofold — locomotion via oscillations along the attached flagellum and cell body, [64] [65] and attachment to the fly gut during the procyclic phase.[ citation needed ]

Life cycle

Life cycle Trypanosoma brucei Life Cycle.svg
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 exosomes containing the spliced leader RNA and uses the endosomal sorting complexes required for transport (ESCRT) system to secrete them as extracellular vesicles. [66] When absorbed by other trypanosomes these EVs cause repulsive movement away from the area and so away from bad environments. [66]

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 lymphatic system and into the bloodstream. The initial trypomastigotes are short and stumpy (SS). Once inside the bloodstream, they grow into long and slender forms (LS). Then, they multiply by binary fission. Some of the daughter cells then become short and stumpy again. [67] [68] [69] [1] The long slender forms are able to penetrate the blood vessel endothelium and invade extravascular tissues, including the central nervous system (CNS). [64]

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. [67] 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. [69] [1]

In tsetse fly

The short and stumpy trypomastigotes (SS) are taken up by tsetse flies during a blood meal. [69] [1] Survival in the tsetse midgut is one reason for the particular adaptations of the SS stage. [69] [1] The trypomastigotes enter the midgut of the fly where they become procyclic trypomastigotes. Because the fly faces digestive damage from immune factors in the bloodmeal, it produces serpins to suppress them - and Ooi et al 2015 found T. brucei in turn hijacks these serpins. T. brucei hijacks GmmSRPN3 , GmmSRPN5 , GmmSRPN9 , and especially GmmSRPN10 to aid its own midgut infection, using them to inactivate bloodmeal trypanolytic factors which would otherwise make the fly host inhospitable. [70] :346 These rapidly divide to become epimastigotes. The epimastigotes migrate from the gut via the proventriculus to the salivary glands where they get attached to the salivary gland epithelium. In the salivary glands, some parasites detach and undergo transformation into short and stumpy trypomastigotes. These become the infective metacyclic trypomastigotes. They are injected into the mammalian host along with the saliva on biting. Complete development in the fly takes about 20 days. [67] [68]

In the case of T. b. brucei infecting G. p. gambiensis, during this time the parasite changes the proteome contents of the fly's head. This may be the reason/a reason for the behavioral changes seen, especially the unnecessarily increased feeding frequency, which increases transmission opportunities. This may be due in part to the altered glucose metabolism observed, causing 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 very similar to the alterations in other dipteran vectors' head proteomes under infection by other eukaryotic parasites of mammals, found in another study by the same team in the same year. [71]

Reproduction

Binary fission

Trypanosome cell cycle (procyclic form) Trypanosome Cell Cycle.png
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 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: [57]

  1. The basal body duplicates and both remain associated with the kinetoplast. Each basal body forms a separate flagellum.
  2. Kinetoplast DNA undergoes synthesis then the kinetoplast divides coupled with separation of the two basal bodies.
  3. Nuclear DNA undergoes synthesis while a new flagellum extends from the younger, more posterior, basal body.
  4. The nucleus undergoes mitosis.
  5. Cytokinesis progresses from the anterior to posterior.
  6. 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. [72] But it is not always necessary for a complete life cycle. [73] The existence of meiosis-specific proteins was reported in 2011. [74] 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). [75] [76] 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. [77] The discovery of sexual reproduction in T. brucei supports the hypothesis that meiosis and sexual reproduction are ancestral and ubiquitous features of eukaryotes. [78]

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. [79]

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. [67]

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. [80] [81]

Chemotherapy

Some phytochemicals have shown research promise against the T. b. brucei strain. [82] 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). [82] Ibrahim et al., 2013 find a lower dose reduces parasitemia by this subspecies and a higher dose is curative and prevents injury. [82]

Distribution

Koppen-Geiger Map Africa present.svg
T. brucei is only found in the blue areas

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. [57] 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 sub-Saharan Africa. [1] [83] It is thus of tremendous veterinary concern and one of the greatest limitations on agriculture in Africa and the economic life of sub-Saharan Africa. [1] [83]

Evolution

Trypanosoma brucei gambiense evolved from a single progenitor ~10,000 years ago. [84] It is evolving asexually and its genome shows the Meselson effect. [84]

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. [85]

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. [86]

In contrast, resistance in T. b. rhodesiense is dependent upon the expression of a serum resistance associated (SRA) gene. [87] This gene is not found in T. b. gambiense. [88]

Genome

The genome of T. brucei is made up of: [89]

Most genes are held on the large chromosomes, with the minichromosomes carrying only VSG genes. The genome has been sequenced and is available on GeneDB. [90]

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 [91]

In 1993, a new base, ß-d-glucopyranosyloxymethyluracil (base J), was identified in the nuclear DNA of T. brucei. [92]

VSG coat

The surface of T. brucei and other species of trypanosomes is covered by a dense external coat called variant surface glycoprotein (VSG). [93] 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. [94] [95]

This VSG coat enables an infecting T. brucei population to persistently evade the host's 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. Antibody-mediated trypanosome killing can also be observed in vitro by a complement-mediated lysis assay. However, with each cell division there is a possibility that one or both of the 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. [96] As T. brucei populations can peak at a size of 1011 within a host [97] this rapid rate of switching ensures that the parasite population is typically highly diverse. [98] [99] 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 parasitemia (trypanosomes in the blood). [93]

Expression of VSG genes occurs through a number of mechanisms yet to be fully understood. [100] 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 pseudogenes. It is thought that any of these genes can be moved into the active site by recombination for expression. [95] VSG silencing is largely due to the effects of 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. [101] [102] It remains unproven whether the regulation of VSG switching is purely stochastic or whether environmental stimuli affect switching frequency. Lythgoe et al 2007 presents the best fitting known model, attributing switching to only 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. [70] As of 2021 it also remains unexplained how this transition is timed and how the next surface protein gene is chosen. [1] These questions of antigenic variation in T. brucei and other parasites are among the most interesting in the field of infection. [1]

Killing by human serum and resistance to human serum killing

Trypanosoma brucei brucei (as well as related species T. equiperdum and 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 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. [103] [104] 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. [105]

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. [106]

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. [107] ApoL1 has been identified as the toxic component involved in trypanolysis. [108] ApoLs have been subject to recent selective evolution possibly related to resistance to pathogens. [109]

The gene encoding ApoL1 is found on the long arm of chromosome 22 (22q12.3). Variants of this gene, termed G1 and G2, provide protection against T. b. rhodesiense. [110] These benefits are not without their downside as a specific ApoL1 glomerulopathy has been identified. [110] [111] This glomerulopathy may help to explain the greater prevalence of hypertension in African populations. [112]

The gene encodes a protein of 383 residues, including a typical signal peptide of 12 amino acids. [113] 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 colicins. [114] 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 podocytes in the glomeruli, the proximal tubular epithelium and the arteriolar endothelium. [115] It has a high affinity for phosphatidic acid and cardiolipin and can be induced by interferon gamma and tumor necrosis factor alpha. [116]

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. [117]

Killing mechanism

The association of HPR with hemoglobin allows TLF-1 binding and uptake via the trypanosome haptoglobin-hemoglobin receptor (TbHpHbR). [118] TLF-2 enters trypanosomes independently of TbHpHbR. [118] 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. [119]

The trypanosome haptoglobin-hemoglobin receptor is an elongated three a-helical bundle with a small membrane distal head. [120] 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. [118] [121] The bound TLF is endocytosed via coated vesicles and then trafficked to the parasite lysosomes. ApoL1 is the main lethal factor in the TLFs and kills trypanosomes after insertion into endosomal / lysosomal membranes. [108] After ingestion by the parasite, the TLF-1 particle is trafficked to the lysosome wherein ApoL1 is activated by a pH mediated conformational change. After fusion with the 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 chloride and subsequent osmotic swelling of the lysosome. This influx in its turn leads to rupture of the lysosome and the subsequent death of the parasite. [122]

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 glycoprotein. [123] Other factors involved in resistance appear to be a change in the cysteine protease activity and TbHpHbR inactivation due to a leucine to serine substitution (L210S) at codon 210. [123] This is due to a thymidine to cytosine mutation at the second codon position. [124]

These mutations may have evolved due to the coexistence of malaria where this parasite is found. [123] 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 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 reticuloendothelial system. [125]

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. [126] 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. [127] 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 endosomes while some dispute remains as to its presence in the lysosome. [108] [128] SRA binds to ApoL1 using a coiled–coiled interaction at the ApoL1 SRA interacting domain while within the trypanosome lysosome. [108] 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 Trypanosoma brucei 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. [129] Experimental mutations allowing ApoL1 to be protected from neutralization by SRA have been shown capable of conferring trypanolytic activity on T. b. rhodesiense. [87] 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. [110]

See also

Related Research Articles

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African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species Trypanosoma brucei. Humans are infected by two types, Trypanosoma brucei gambiense (TbG) and Trypanosoma brucei rhodesiense (TbR). TbG causes over 98% of reported cases. Both are usually transmitted by the bite of an infected tsetse fly and are most common in rural areas.

Trypanosomatida Order of flagellate protists in the kinetoplastid excavates

Trypanosomatida is a group of kinetoplastid excavates distinguished by having only a single flagellum. The name is derived from the Greek trypano (borer) and soma (body) because of the corkscrew-like motion of some trypanosomatid species. All members are exclusively parasitic, found primarily in insects. A few genera have life-cycles involving a secondary host, which may be a vertebrate, invertebrate or plant. These include several species that cause major diseases in humans. Trypanosomatida are intracellular parasites.

Tsetse fly Genus of disease-spreading insects

Tsetse, sometimes spelled tzetze and also known as tik-tik flies, are large biting flies that inhabit much of tropical Africa. Tsetse flies include all the species in the genus Glossina, which are placed in their own family, Glossinidae. The tsetse are obligate parasites that live by feeding on the blood of vertebrate animals. Tsetse have been extensively studied because of their role in transmitting disease. They have a prominent economic impact in sub-Saharan Africa as the biological vectors of trypanosomes, which cause human sleeping sickness and animal trypanosomiasis. Tsetse are multivoltine and long-lived, typically producing about four broods per year, and up to 31 broods over their lifespans.

Trypanosomiasis Medical condition

Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. In humans this includes African trypanosomiasis and Chagas disease. A number of other diseases occur in other animals.

Suramin Medical drug

Suramin is a medication used to treat African sleeping sickness and river blindness. It is the treatment of choice for sleeping sickness without central nervous system involvement. It is given by injection into a vein.

<i>Trypanosoma</i> Genus of parasitic flagellate protist in the Kinetoplastea class

Trypanosoma is a genus of kinetoplastids, a monophyletic group of unicellular parasitic flagellate protozoa. Trypanosoma is part of the phylum Sarcomastigophora. The name is derived from the Greek trypano- (borer) and soma (body) because of their corkscrew-like motion. Most trypanosomes are heteroxenous and most are transmitted via a vector. The majority of species are transmitted by blood-feeding invertebrates, but there are different mechanisms among the varying species. Some, such as Trypanosoma equiperdum, are spread by direct contact. In an invertebrate host they are generally found in the intestine, but normally occupy the bloodstream or an intracellular environment in the vertebrate host.

Melarsoprol

Melarsoprol is an arsenic-containing medication used for the treatment of sleeping sickness. It is specifically used for second-stage disease caused by Trypanosoma brucei rhodesiense when the central nervous system is involved. For Trypanosoma brucei gambiense, eflornithine or fexinidazole is usually preferred. It is effective in about 95% of people. It is given by injection into a vein.

Eflornithine

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis and excessive hair growth on the face in women. Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is used by injection or applied to the skin.

David Bruce (microbiologist) British pathologist

Major-General Sir David Bruce was an Australian-born British pathologist and microbiologist who made some of the key contributions in tropical medicine. In 1887, he discovered a bacterium, now called Brucella, that caused what was known as Malta fever. In 1894, he discovered a protozoan parasite, named Trypanosoma brucei, as the causative pathogen of nagana.

Animal trypanosomiasis

Animal trypanosomiasis, also known as nagana and nagana pest, or sleeping sickness, is a disease of vertebrates. The disease is caused by trypanosomes of several species in the genus Trypanosoma such as Trypanosoma brucei. Trypanosoma vivax causes nagana mainly in West Africa, although it has spread to South America. The trypanosomes infect the blood of the vertebrate host, causing fever, weakness, and lethargy, which lead to weight loss and anemia; in some animals the disease is fatal unless treated. The trypanosomes are transmitted by tsetse flies.

Winterbottom's sign is a swelling of lymph nodes (lymphadenopathy) along the posterior cervical lymph node chain, associated with the early phase of African trypanosomiasis, a disease caused by the parasites Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. It may be suggestive of cerebral infection. Winterbottom reported about the slave traders who, apparently aware of the ominous sign of swollen cervical lymph glands, used to palpate the necks of the slaves before buying them.

Apolipoprotein L1

Apolipoprotein L1 is a protein that in humans is encoded by the APOL1 gene. Two transcript variants encoding two different isoforms have been found for this gene.

<i>Trypanosoma congolense</i>

Trypanosoma congolense is a species of trypanosomes and is the major pathogen responsible for the disease nagana in cattle and other animals including sheep, pigs, goats, horses and camels, dogs, as well as laboratory mice. It is the most common cause of nagana in east Africa, but is also a major cause of nagana in west Africa. This parasite is spread by tsetse flies. In its mammalian host, Trypanosoma congolense only lives in blood vessels, and causes in particular anaemia.

Wendy Gibson is Professor of Protozoology at University of Bristol, specialising in trypanosomes and molecular parasitology.

Fexinidazole is a medication used to treat African trypanosomiasis caused by Trypanosoma brucei gambiense. It is effective against both first and second stage disease. Some evidence also supports its use in Chagas disease. It is taken by mouth.

Variant surface glycoprotein

Variant surface glycoprotein (VSG) is a ~60kDa protein which densely packs the cell surface of protozoan parasites belonging to the genus Trypanosoma. This genus is notable for their cell surface proteins. They were first isolated from Trypanosoma brucei in 1975 by George Cross. VSG allows the trypanosomatid parasites to evade the mammalian host's immune system by extensive antigenic variation. They form a 12–15 nm surface coat. VSG dimers, ~90% of all cell surface protein. It also makes 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. VSG has no prescribed biochemical activity.

John William Watson Stephens

John William Watson Stephens FRS (1865–1946) was a British parasitologist and expert on tropical diseases.

Robert Michael Forde

Robert Michael Forde was Colonial Surgeon in The Gambia when in 1901, he made the first definitive observation of trypanosomes in a human being when he found them in the blood of a steamboat master on the Gambia River. In 1907 he became principal medical officer of Sierra Leone.

The Sleeping Sickness Commission was a medical project established by the British Royal Society to investigate the outbreak of African sleeping sickness or African trypanosomiasis in Africa at the turn of the 20th century. The outbreak of the disease started in 1900 in Uganda, which was at the time a protectorate of the British Empire. The initial team in 1902 consisted of Aldo Castellani and George Carmichael Low, both from the London School of Hygiene and Tropical Medicine, and Cuthbert Christy, a medical officer on duty in Bombay, India. From 1903, David Bruce of the Royal Army Medical Corps and David Nunes Nabarro of the University College Hospital took over the leadership. The commission established that species of blood protozoan called Trypanosoma brucei, named after Bruce, was the causative parasite of sleeping sickness.

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