Trypanosoma brucei

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Trypanosoma brucei
Tb brucei.jpg
Trypanosoma brucei brucei TREU667 (Bloodstream form, phase contrast picture. Black bar indicates 10 µm.)
Scientific classification
Kingdom: Protista
Phylum: Euglenozoa
Class: Kinetoplastea
Order: Trypanosomatida
Genus: Trypanosoma
Species: T. brucei
Binomial name
Trypanosoma brucei
Plimmer & Bradford, 1899
Subspecies

T. b. brucei
T. b. gambiense
T. b. rhodesiense

False colour SEM micrograph of procyclic form Trypanosoma brucei as found in the tsetse fly midgut. The cell body is shown in orange and the flagellum is in red. 84 pixels/μm.

Trypanosoma brucei is a species of salivary trypanosome which causes African trypanosomiasis, known also as sleeping sickness in humans and nagana in animals. T. brucei has traditionally been grouped into three subspecies: T. b. brucei, T. b. gambiense and T. b. rhodesiense. Only rarely can the subspecies T.b.brucei infect a human.[1]

Transmission of T. brucei between mammal hosts is usually by an insect vector, the tsetse fly. T. brucei 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 variant surface glycoprotein (VSG) coats, which undergo remarkable antigenic variation, enabling persistent evasion of host adaptive immunity and chronic infection. T. brucei is one of only a few pathogens that can cross the blood brain barrier.[2] There is an urgent need for the development of new drug therapies as current treatments can prove fatal to the patient.

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.[3]

Infection: Trypanosomiasis[edit]

The insect vector for T. brucei is the tsetse fly (genus Glossina). The initial site of infection is the midgut of the fly (procyclic life cycle stage) and as the infection progresses it migrates via the proventriculus to the salivary glands where it attaches to the salivary gland surface (linked with a differentiation into the epimastigote life cycle stage). In the salivary glands some parasites detach and undergo adaptations (differentiation into the metacyclic life cycle stage) in preparation for injection to the mammalian host with the fly saliva on biting. In the mammal host the parasite lives within the bloodstream (slender bloodstream life cycle stage). Some parasites undergo adaptations (differentiation into the stumpy bloodstream life cycle stage) where it can reinfect the fly vector as it takes a blood meal after biting. 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.

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.[4][5]

There are three different subspecies of T. brucei, which cause different variants of trypanosomiasis.

  • T. brucei gambiense — Causes slow onset chronic trypanosomiasis in humans. Most common in central and western Africa, where humans are thought to be the primary reservoir.[6]
  • T. brucei rhodesiense — Causes fast onset acute trypanosomiasis in humans. Most common in southern and eastern Africa, where game animals and livestock are thought to be the primary reservoir.[6]
  • T. brucei brucei — Causes animal African trypanosomiasis, along with several other species of trypanosoma. T. b. brucei is not human infective due to its susceptibility to lysis by Trypanosome Lytic Factor-1 (TLF-1).[7] However, as it is closely related to, and shares fundamental features with the human infective subspecies, T. b. brucei is used as a model for human infections in laboratory and animal studies.

Genetics of T. brucei subspecies[edit]

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.[8]

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.[9]

In contrast T. b. rhodesiense is dependent upon the expression of a serum resistance associated (SRA) gene.[10] This gene is not found in T. b. gambiense.[11]

Cell structure[edit]

The structure of the cell is fairly typical of eukaryotes (see eukaryotic cell). All major organelles are seen, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus etc. Unusual features include the single large mitochondria with the mitochondrial DNA structure known as the kinetoplast, and its association with the basal body of the flagellum. The cytoskeleton is made up of microtubules. The cell surface of the bloodstream form features a dense coat of variable surface glycoproteins (VSGs) which is replaced by an equally dense coat of procyclins when the parasite differentiates into the procylic in the tsetse fly midgut.

The six main morphologies of trypanosomatids. The different life cycle stages of Trypanosoma brucei fall into the promastigote 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:

  • Epimastigote — Basal body anterior of nucleus, with a long flagellum attached along the cell body (in the salivary glands).
  • Trypomastigote — Basal body posterior of nucleus, with a long flagellum attached along the cell body (in most other life cycle stages).

These names are derived from the Greek mastig- meaning whip, referring to the trypanosome's whip-like flagellum.

T. brucei is found as a trypomastigote in the slender, stumpy, procyclic and metacyclic forms. The procylic form differentiates to the proliferitive epimastigote form in the salivary glands of the insect. Unlike some other trypanosomatids, the promastigote and amastigote form do not form part of the T. brucei life cycle.

Genome[edit]

The genome of T. brucei is made up of:[12]

  • 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 haploid genome.

Most genes are held on the large chromosomes, with the minichromosomes carrying only VSG genes. The genome has been sequenced and is available online [1].

The mitochondrial genome is found condensed into the kinetoplast, an unusual feature unique to the kinetoplastea class. The kinetoplast and the basal body of the flagellum are strongly associated via a cytoskeletal structure.

VSG surface coat[edit]

Main section: VSG coat

The surface of the trypanosome is covered by a dense coat of Variable Surface Glycoprotein (VSG), which allows persistence of an infecting trypanosome population in the host. See below.

Cytoskeleton[edit]

The cytoskeleton is predominantly made up of microtubules, forming a subpellicular corset. The microtubules lie parallel to each other along the long axis of the cell, with the number of microtubules at any point roughly proportional to the circumference of the cell at that point. As the cell grows (including for mitosis) additional microtubules grow between the existing tubules, leading to semiconservative inheritance of the cytoskeleton. The microtubules are orientated + at the posterior and - at the anterior.

Microfilament and intermediate filaments do not play a role in the cytoskeleton.

Flagellar structure[edit]

Trypanosoma Brucei flagellar structure.

The trypanosome flagellum has two main structures. It is made up of a typical flagellar axoneme which lies parallel to the paraflagellar rod, a lattice structure of proteins unique to the kinetoplastida, euglenoids and dinoflagellates.

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 a 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.

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

VSG coat[edit]

The surface of the trypanosome is covered by a dense coat of ~5 x 106 molecules of Variable Surface Glycoprotein (VSG).[13] This coat enables an infecting T. brucei population to persistently evade the host's immune system, allowing chronic infection. The two properties of the VSG coat that allow immune evasion are:

  • Shielding — the dense nature of the VSG coat prevents the immune system of the mammalian host from accessing the plasma membrane or any other invariant surface epitopes (such as ion channels, transporters, receptors etc.) of the parasite. The coat is uniform, made up of millions of copies of the same molecule; therefore the only parts of the trypanosome the immune system can 'see' are the N-terminal loops of the VSG that make up the coat.[14]
  • Periodic antigenic variation — the VSG coat undergoes frequent stochastic genetic modification — 'switching' — allowing variants expressing a new VSG coat to escape the specific immune response raised against the previous coat.

The cell surface of the bloodstream form features a dense coat of variable surface glycoproteins (VSGs) which is replaced by an equally dense coat of procyclins when the parasite differentiates into the procylic form in the tsetse fly midgut.

Antigenic variation[edit]

VSG is highly immunogenic, and an immune response raised against a specific VSG coat will rapidly kill 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 variant that is being expressed. The frequency of VSG switching has been measured to be approximately 0.1% per division.[15] As T. brucei populations can peak at a size of 1011 within a host [16] this rapid rate of switching ensures that the parasite population is constantly diverse. A diverse range of coats expressed by the trypanosome population means that the immune system is always one step behind: it takes several days for an immune response against a given VSG to develop, giving the population time to diversify as individuals undergo further switching events. Reiteration of this process prevents extinction of the infecting trypanosome population, allowing chronic persistence of parasites in the host, enhancing opportunities for transmission. The clinical effect of this cycle is successive 'waves' of parasitaemia (trypanosomes in the blood).[13]

VSG structure[edit]

VSG genes are hugely variable at the sequence level. However, different VSG variants have strongly conserved structural features, allowing them to perform a similar shielding function.[17] VSGs are made up of a highly variable N terminal domain of around 300 to 350 amino acids, and a more conserved C terminal domain of around 100 amino acids. N-terminal domains dimerise to form a bundle of four alpha helices, around which hang smaller structural features. VSG is anchored to the cell membrane via a glycophosphatidylinositol (GPI) anchor—a covalent linkage from the C-terminus, to approximately four sugars, to a phosphatidylinositol phospholipid acid which lies in the cell membrane.

VSG archive structure[edit]

The source of VSG variability during infection is a large 'archive' of VSG genes present in the T. brucei genome. Some of these are full-length, intact genes; others are pseudogenes) typically with frameshift mutations, premature stop codons, or fragmentation.[18] Expression of an antigenically different VSG can occur by simply switching to a different full-length VSG gene. In addition, chimeric or 'mosaic' VSG genes can be generated by combining segments from more than one silent VSG gene. The formation of mosaic VSGs allows the (partial) expression of pseudogene VSGs, which can constitute the major portion of the VSG archive, and can contribute directly to antigenic variation, vastly increasing the trypanosome's capacity for immune evasion and potentially posing a major problem for vaccine development.[19]

VSG expression[edit]

One major focus in trypanosome research is how all but one of the VSG genes are kept silent at a given time, and how these the active VSG is switched. The expressed VSG is always located in an Expression Site (ES), which are specialised expression loci found at the telomeres of some of the large and intermediate chromosomes. Each ES is a polycistronic unit, containing a number of Expression Site-Associated Genes (ESAGs) all expressed along with the active VSG. While multiple ES exist, only a single one is ever active at one time. A number of mechanisms appear to be involved in this process, but the exact nature of the silencing is still unclear.[20]

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 copies of VSG genes, both on minichromosomes and in repeated sections in the interior of the chromosomes. These are generally 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. Any of these genes can be moved into the active site by recombination for expression. Again, the exact mechanisms that control this are unclear, but the process seems to rely on DNA repair machinery and a process of homologous recombination.[21]

Cell division[edit]

Trypanosome cell cycle (procyclic form).

The mitotic division 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.

Stages of mitosis:

  1. The basal body duplicates and both remain associated with the kinetoplast.
  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.

Killing by human serum and resistance to human serum killing[edit]

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.[22][23] 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.

Trypanolytic factors are found only in a few species including humans, gorillas, mandrills, baboons and sooty mangabeys.[24] This appears to be because haptoglobin related protein and apolipoprotein L-1 are unique to primates.[24] This suggests these gene appeared in the primate genome 25 million years ago-35 million years ago.

Human infective subspecies T. b. gambiense and T. b. rhodesiense have evolved mechanisms of resisting the trypanolytic factors, described below.

ApoL1[edit]

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.[25] ApoL1 has been identified as the toxic component involved in trypanolysis.[26] ApoLs have been subject to recent selective evolution possibly related to resistance to pathogens[27]

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.[28] These benefits are not without their downside as a specific ApoL1 glomeropathy has been identified.[28][29] This glomeropathy may help to explain the greater prevalence of hypertension in African populations.[30]

The gene encodes a protein of 383 residues, including a typical signal peptide of 12 amino acids.[31] 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.[32] 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.[33] It has a high affinity for phosphatidic acid and cardiolipin and can be induced by interferon gamma and tumor necrosis factor alpha.[34]

Hpr[edit]

Hpr is 91% identical to haptoglobin (Hp), an abundant acute phase serum protein, which possesses a high affinity for haemoglobin (Hb). When Hb is released from erythrocytes undergoing intravascular hemolysis Hp forms a complex with the Hb and these are removed from the 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 haemolysis.

Killing mechanism[edit]

The association HPR with haemoglobin allows TLF-1 binding and uptake via the trypanosome haptoglobin-hemoglobin receptor (TbHpHbR).[35] TLF-2 enters trypanosomes independently of TbHpHbR.[35] TLF-1 uptake is enhanced in the low levels of haptoglobin which competes with haptoglobin related protein to bind free haemoglobin in the serum. However the complete absence of haptoglobin is associated with a decreased killing rate by serum.[36]

The trypanosome haptoglobin-hemoglobin receptor is an elongated three a-helical bundle with a small membrane distal head.[37] 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.[35][38] 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.[26] After ingestion by the parasite, the TLF-1 particle is trafficked to the lysosome wherein Apo1 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.[39]

Resistance mechanisms: T. b. gambiense[edit]

Trypanosoma brucei gambiense causes 97% of human cases of sleeping sickness. Resistance to ApoL1 is principally mediated by the hydrophobic ß-sheet of the T. b. gambiense specific glycoprotein.[40] 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.[40][41] This is due to a thymidine to cytosine mutation at the second codon position.

These mutations may have evolved due to the coexistence of malaria where this parasite is found.[40] Haptoglobin levels are low in malaria because of the haemolysis 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.

Resistance mechanisms: T. b. rhodesiense[edit]

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.[42] It has a low sequence homology with the VSGc (<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.[43] 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 remain on its presence in the lysosome.[26][44] SRA binds to ApoL1 using a coiled–coiled interaction at the ApoL1 SRA interacting domain while within the trypanosome lysosome.[26] 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.[45] Experimental mutations allowing ApoL1 to be protected from neutralization by SRA have been shown capable of conferring trypanolytic activity on T. b. rhodesiense.[10] 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 .[28]

See also[edit]

References[edit]

  1. ^ Deborggraeve S, Koffi M, Jamonneau V, et al. (August 2008). "Molecular analysis of archived blood slides reveals an atypical human Trypanosoma infection". Diagn. Microbiol. Infect. Dis. 61 (4): 428–33. doi:10.1016/j.diagmicrobio.2008.03.006. PMID 18455900. 
  2. ^ Masocha W, Kristensson K (2012). "Passage of parasites across the blood-brain barrier". Virulence 3 (2): 202–12. doi:10.4161/viru.19178. PMC 3396699. PMID 22460639. 
  3. ^ Gibson, W. C. (2007). "Resolution of the species problem in African trypanosomes". Int J Parasitol 37 (8–9): 829–838. doi:10.1016/j.ijpara.2007.03.002. PMID 17451719. 
  4. ^ "African Trypanosomes: epidemiology and risk factors". Centers for Disease Control. 
  5. ^ Rocha, G; Martins, A; Gama, G; Brandão, F; Atouguia, J (2004). "Possible cases of sexual and congenital transmission of sleeping sickness". The Lancet 363 (9404): 247. doi:10.1016/S0140-6736(03)15345-7. PMID 14738812. 
  6. ^ a b Barrett MP, Burchmore RJ, Stich A, et al. (November 2003). "The trypanosomiases". Lancet 362 (9394): 1469–80. doi:10.1016/S0140-6736(03)14694-6. PMID 14602444. 
  7. ^ Stephens NA, Kieft R, Macleod A, Hajduk SL (December 2012). "Trypanosome resistance to human innate immunity: targeting Achilles' heel". Trends Parasitol. 28 (12): 539–45. doi:10.1016/j.pt.2012.09.002. PMID 23059119. 
  8. ^ Paindavoine P, Pays E, Laurent M, et al. (February 1986). "The use of DNA hybridization and numerical taxonomy in determining relationships between Trypanosoma brucei stocks and subspecies". Parasitology 92 (Pt 1): 31–50. doi:10.1017/S0031182000063435. PMID 3960593. 
  9. ^ Capewell P, Veitch NJ, Turner CM, et al. (September 2011). "Differences between Trypanosoma brucei gambiense groups 1 and 2 in their resistance to killing by trypanolytic factor 1". PLoS Negl Trop Dis 5 (9): e1287. doi:10.1371/journal.pntd.0001287. PMC 3167774. PMID 21909441. 
  10. ^ a b Lecordier L, Vanhollebeke B, Poelvoorde P, Tebabi P, Andris F, Lins L and Pays E (2009). "C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense". In Mansfield, John M. PLoS Pathog 5 (12): e1000685. doi:10.1371/journal.ppat.1000685. PMC 2778949. PMID 19997494. 
  11. ^ 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". Mol. Biochem. Parasitol. 36 (2): 169–76. doi:10.1016/0166-6851(89)90189-8. PMID 2528066. 
  12. ^ Ogbadoyi E, Ersfeld K, Robinson D, Sherwin T, Gull K (March 2000). "Architecture of the Trypanosoma brucei nucleus during interphase and mitosis". Chromosoma 108 (8): 501–13. doi:10.1007/s004120050402. PMID 10794572. 
  13. ^ a b Barry JD, McCulloch R (2001). "Antigenic variation in trypanosomes: enhanced phenotypic variation in a eukaryotic parasite". Adv Parasitol. Advances in Parasitology 49: 1–70. doi:10.1016/S0065-308X(01)49037-3. ISBN 978-0-12-031749-3. PMID 11461029. 
  14. ^ Overath P, Chaudhri M, Steverding D, Ziegelbauer K (February 1994). "Invariant surface proteins in bloodstream forms of Trypanosoma brucei". Parasitol. Today (Regul. Ed.) 10 (2): 53–8. doi:10.1016/0169-4758(94)90393-X. PMID 15275499. 
  15. ^ Turner CM (August 1997). "The rate of antigenic variation in fly-transmitted and syringe-passaged infections of Trypanosoma brucei". FEMS Microbiol Lett. 153 (1): 227–31. doi:10.1111/j.1574-6968.1997.tb10486.x. PMID 9252591. 
  16. ^ Barry, J. D.; Hall, Plenderleith (2012). "Genome hyperevolution and the success of a parasite". Ann N Y Acad Sci 1267 (1): 11–17. doi:10.1111/j.1749-6632.2012.06654.x. PMC 3467770. PMID 22954210. 
  17. ^ Blum, Michael L.; Down, James A.; Gurnett, Anne M.; Carrington, Mark; Turner, Mervyn J.; Wiley, Don C. (1993). "A structural motif in the variant surface glycoproteins of Trypanosoma brucei". Nature 362 (6421): 603–9. doi:10.1038/362603a0. PMID 8464512. 
  18. ^ Marcello L, Barry JD (September 2007). "Analysis of the VSG gene silent archive in Trypanosoma brucei reveals that mosaic gene expression is prominent in antigenic variation and is favored by archive substructure". Genome Res. 17 (9): 1344–52. doi:10.1101/gr.6421207. PMC 1950903. PMID 17652423. 
  19. ^ Barbour AG, Restrepo BI (2000). "Antigenic variation in vector-borne pathogens". Emerging Infect Dis. 6 (5): 449–57. doi:10.3201/eid0605.000502. PMC 2627965. PMID 10998374. 
  20. ^ Pays E (November 2005). "Regulation of antigen gene expression in Trypanosoma brucei". Trends Parasitol. 21 (11): 517–20. doi:10.1016/j.pt.2005.08.016. PMID 16126458. 
  21. ^ Morrison, Liam J.; Marcello, Lucio; McCulloch, Richard (1 December 2009). "Antigenic variation in the African trypanosome: molecular mechanisms and phenotypic complexity". Cellular Microbiology 11 (12): 1724–1734. doi:10.1111/j.1462-5822.2009.01383.x. PMID 19751359. 
  22. ^ Hajduk SL, Moore DR, Vasudevacharya J, et al. (March 1989). "Lysis of Trypanosoma brucei by a toxic subspecies of human high density lipoprotein". J. Biol. Chem. 264 (9): 5210–7. PMID 2494183. 
  23. ^ Raper J, Fung R, Ghiso J, Nussenzweig V, Tomlinson S (April 1999). "Characterization of a novel trypanosome lytic factor from human serum". Infect. Immun. 67 (4): 1910–6. PMC 96545. PMID 10085035. 
  24. ^ a b Lugli EB, Pouliot M, Portela Mdel P, Loomis MR, Raper J (November 2004). "Characterization of primate trypanosome lytic factors". Mol. Biochem. Parasitol. 138 (1): 9–20. doi:10.1016/j.molbiopara.2004.07.004. PMID 15500911. 
  25. ^ Vanhollebeke B, Pays E (2006). "The function of apolipoproteins L". Cell. Mol. Life Sci. 63 (17): 1937–1944. doi:10.1007/s00018-006-6091-x. PMID 16847577. 
  26. ^ a b c d Vanhamme L, Paturiaux-Hanocq F, Poelvoorde P, Nolan DP, Lins L, Van den Abbeele J, Pays A, Tebabi P, Xong HV, Jacquet A, Moguilevsky N, Dieu M, Kane JP, De Baetselier P, Brasseur R, and Pays E (2003). "Apolipoprotein L-I is the trypanosome lytic factor of human serum". Nature 422 (6927): 83–87. Bibcode:2003Natur.422...83V. doi:10.1038/nature01461. PMID 12621437. 
  27. ^ Smith EE, Malik HS (May 2009). "The apolipoprotein L family of programmed cell death and immunity genes rapidly evolved in primates at discrete sites of host-pathogen interactions". Genome Res. 19 (5): 850–8. doi:10.1101/gr.085647.108. PMC 2675973. PMID 19299565. 
  28. ^ a b c Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Knob AU, Bernhardy A, Hicks PJ, Appel GB, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E and Pollak MR (2010). "Association of trypanolytic ApoL1 variants with kidney disease in African-Americans". Science 329 (5993): 841–845. doi:10.1126/science.1193032. PMC 2980843. PMID 20647424. 
  29. ^ Wasser WG, Tzur S, Wolday D, et al. (2012). "Population genetics of chronic kidney disease: the evolving story of APOL1". J. Nephrol. 25 (5): 603–18. doi:10.5301/jn.5000179. PMID 22878977. 
  30. ^ Lipkowitz MS, Freedman BI, Langefeld CD, et al. (January 2013). "Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans". Kidney Int. 83 (1): 114–20. doi:10.1038/ki.2012.263. PMC 3484228. PMID 22832513. 
  31. ^ Duchateau PN, Pullinger CR, Orellana RE, et al. (October 1997). "Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L". J. Biol. Chem. 272 (41): 25576–82. PMID 9325276. 
  32. ^ Pérez-Morga D, Vanhollebeke B, Paturiaux-Hanocq F, et al. (July 2005). "Apolipoprotein L-I promotes trypanosome lysis by forming pores in lysosomal membranes". Science 309 (5733): 469–72. doi:10.1126/science.1114566. PMID 16020735. 
  33. ^ Madhavan SM, O'Toole JF, Konieczkowski M, Ganesan S, Bruggeman LA, Sedor JR (November 2011). "APOL1 localization in normal kidney and nondiabetic kidney disease". J. Am. Soc. Nephrol. 22 (11): 2119–28. doi:10.1681/ASN.2011010069. PMC 3231786. PMID 21997392. 
  34. ^ Zhaorigetu S, Wan G, Kaini R, Jiang Z, Hu CA (November 2008). "ApoL1, a BH3-only lipid-binding protein, induces autophagic cell death". Autophagy 4 (8): 1079–82. PMC 2659410. PMID 18927493. 
  35. ^ a b c Vanhollebeke B, Demuylder G, Nielsen MJ, Pays A, Tebabi P, Dieu M, Raes M, Moestrup SK, and Pays E (2008). "A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans". Science 320 (5876): 677–681. doi:10.1126/science.1156296. PMID 18451305. 
  36. ^ Vanhollebeke B, Nielsen MJ, Watanabe Y, et al. (March 2007). "Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum". Proc. Natl. Acad. Sci. U.S.A. 104 (10): 4118–23. doi:10.1073/pnas.0609902104. PMC 1820718. PMID 17360487. 
  37. ^ Higgins MK, Tkachenko O, Brown A, Reed J, Raper J, Carrington M (January 2013). "Structure of the trypanosome haptoglobin-hemoglobin receptor and implications for nutrient uptake and innate immunity". Proc. Natl. Acad. Sci. U.S.A. 110 (5): 1905–10. doi:10.1073/pnas.1214943110. PMC 3562850. PMID 23319650. 
  38. ^ Green HP, Del Pilar Molina Portela M, St Jean EN, Lugli EB, Raper J (January 2003). "Evidence for a Trypanosoma brucei lipoprotein scavenger receptor". J. Biol. Chem. 278 (1): 422–7. doi:10.1074/jbc.M207215200. PMID 12401813. 
  39. ^ Pays E, Vanhollebeke B, Vanhamme L, Paturiaux-Hanocq F, Nolan DP, and Pérez-Morga D (2006). "The trypanolytic factor of human serum". Nature Reviews Microbiology 4 (6): 477–486. doi:10.1038/nrmicro1428. PMID 16710327. 
  40. ^ a b c Uzureau P, Uzureau S, Lecordier L, Fontaine F, Tebabi P, Homblé F, Grélard A, Zhendre V, Nolan D, Lins L, Crowet JM, Pays A, Felu C, Poelvoorde P, Vanhollebeke B, Moestrup SK, Lyngsø J, Pedersen JS, Mottram J, Dufourc EJ,Pérez-Morga D and Pays E (2013). "Mechanism of Trypanosoma gambiense resistance to human serum". Nature 501 (7467): 430–4. doi:10.1038/nature12516. PMID 23965626. 
  41. ^ DeJesus E, Kieft R, Albright B, Stephens NA, Hajduk SL (2013). "A single amino acid substitution in the group 1 Trypanosoma brucei gambiense haptoglobin-hemoglobin receptor abolishes TLF-1 binding". PLoS Pathog. 9 (4): e1003317. doi:10.1371/journal.ppat.1003317. PMC 3630162. PMID 23637606. 
  42. ^ Pays E, Vanhollebeke B (July 2008). "Mutual self-defence: the trypanolytic factor story". Microbes Infect. 10 (9): 985–9. doi:10.1016/j.micinf.2008.07.020. PMID 18675374. 
  43. ^ Xong HV, Vanhamme L, Chamekh M, et al. (December 1998). "A VSG expression site-associated gene confers resistance to human serum in Trypanosoma rhodesiense". Cell 95 (6): 839–46. PMID 9865701. 
  44. ^ Shiflett AM, Faulkner SD, Cotlin LF, Widener J, Stephens N, Hajduk SL (2007). "African trypanosomes: intracellular trafficking of host defense molecules". J. Eukaryot. Microbiol. 54 (1): 18–21. doi:10.1111/j.1550-7408.2006.00228.x. PMID 17300512. 
  45. ^ Thomson R, Molina-Portela P, Mott H, Carrington M, Raper J (November 2009). "Hydrodynamic gene delivery of baboon trypanosome lytic factor eliminates both animal and human-infective African trypanosomes". Proc. Natl. Acad. Sci. U.S.A. 106 (46): 19509–14. doi:10.1073/pnas.0905669106. PMC 2780755. PMID 19858474. 
  46. ^ Richard Seed, J.; Seed, T. M.; Sechelski, J. (1978). "The biological effects of tryptophol (indole-3-ethanol): Hemolytic, biochemical and behavior modifying activity". Comparative Biochemistry and Physiology Part C: Comparative Pharmacology 60 (2): 175. doi:10.1016/0306-4492(78)90091-6.  edit

External links[edit]