A co-evolutionary arms race: trypanosomes shaping the human genome, humans shaping the trypanosome genome

<i>Trypanosoma brucei</i> is the causative agent of African sleeping sickness in humans and one of several pathogens that cause the related veterinary disease Nagana. A complex co-evolution has occurred between these parasites and primates that led to the emergence of trypanosome-specific defences and counter-measures. The first line of defence in humans and several other <i>catarrhine</i> primates is the trypanolytic protein apolipoprotein-L1 (APOL1) found within two serum protein complexes, trypanosome lytic factor 1 and 2 (TLF-1 and TLF-2). Two sub-species of <i>T. Brucei</i> have evolved specific mechanisms to overcome this innate resistance, <i>Trypanosoma brucei gambiense</i> and <i>Trypanosoma brucei rhodesiense</i>. In <i>T. b. Rhodesiense</i>, the presence of the serum resistance associated (SRA) gene, a truncated variable surface glycoprotein (VSG), is sufficient to confer resistance to lysis. The resistance mechanism of <i>T. b. Gambiense</i> is more complex, involving multiple components: reduction in binding affinity of a receptor for TLF, increased cysteine protease activity and the presence of the truncated VSG, <i>T. b. Gambiense</i>-specific glycoprotein <i>(TgsGP)</i>. In a striking example of co-evolution, evidence is emerging that primates are responding to challenge by <i>T. b. Gambiense</i> and <i>T. b. Rhodesiense</i>, with several populations of humans and primates displaying resistance to infection by these two sub-species

Genetic exchange in <i>Trypanosoma brucei</i>: evidence for mating prior to metacyclic stage development

It is well established that genetic exchange occurs between Trypanosoma brucei parasites when two stocks are used to infect tsetse flies under laboratory conditions and a number of such crosses have been undertaken. Both cross and self-fertilisation can take place and, with the products of mating being the equivalent of F1 progeny in a Mendelian system and. Recently, analysis of a large collection of independent progeny using a series of polymorphic micro and minisatellite markers, has formally demonstrated that the allelic segregation at loci on each of the 11-megabase chromosomes conforms to ratios predicted for a classical diploid genetic system involving meiosis as well as independent assortment of markers on different chromosomes. Further extensive analysis of these F1 progeny, using a large panel of micro and minisatellite markers, has led to the construction of a genetic map of one parasite stock A. MacLeod, A. Tweedie and S. McLellan et al., The genetic map of Trypanosoma brucei, Nucleic Acids Res 33 (2005), pp. 6688–6693. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (10)

Novel African trypanocidal agents: membrane rigidifying peptides

The bloodstream developmental forms of pathogenic African trypanosomes are uniquely susceptible to killing by small hydrophobic peptides. Trypanocidal activity is conferred by peptide hydrophobicity and charge distribution and results from increased rigidity of the plasma membrane. Structural analysis of lipid-associated peptide suggests a mechanism of phospholipid clamping in which an internal hydrophobic bulge anchors the peptide in the membrane and positively charged moieties at the termini coordinate phosphates of the polar lipid headgroups. This mechanism reveals a necessary phenotype in bloodstream form African trypanosomes, high membrane fluidity, and we suggest that targeting the plasma membrane lipid bilayer as a whole may be a novel strategy for the development of new pharmaceutical agents. Additionally, the peptides we have described may be valuable tools for probing the biosynthetic machinery responsible for the unique composition and characteristics of African trypanosome plasma membranes

Allelic segregation and independent assortment in <i>T. brucei</i> crosses: proof that the genetic system is Mendelian and involves meiosis

The genetic system on Trypanosoma brucei has been analysed by generating large numbers of independent progeny clones from two crosses, one between two cloned isolates of Trypanosoma brucei brucei and one between cloned isolates of T. b. brucei and Trypanosoma brucei gambiense, Type 2. Micro and minisatellite markers (located on each of the 11 megabase housekeeping chromosomes) were identified, that are heterozygous in one or more of the parental strains and the segregation of alleles at each locus was then determined in each of the progeny clones. The results unequivocally show that alleles segregate in the predicted ratios and that alleles at loci on different chromosomes segregate independently. These data provide statistically robust proof that the genetic system is Mendelian and that meiosis occurs. Segregation distortion is observed with the minisatellite locus located on chromosome I of T. b. gambiense Type 2 and neighboring markers, but analysis of markers further along this chromosome did not show distortion leading to the conclusion that this is due to selection acting on one part of this chromosome. The results obtained are discussed in relation to previously proposed models of mating and support the occurrence of meiosis to form haploid gametes that then fuse to form the diploid progeny in a single round of mating

Case of Nigeria-Acquired Human African Trypanosomiasis in United Kingdom, 2016.

Human African trypanosomiasis has not been reported in Nigeria since 2012. Nevertheless, limitations of current surveillance programs mean that undetected infections may persist. We report a recent case of stage 2 trypanosomiasis caused by Trypanosoma brucei gambiense acquired in Nigeria and imported into the United Kingdom

Spatially and genetically distinct African trypanosome virulence variants defined by host interferon-g response

We describe 2 spatially distinct foci of human African trypansomiasis in eastern Uganda. The Tororo and Soroti foci of &lt;i&gt;Trypanosoma brucei rhodesiense&lt;/i&gt; infection were genetically distinct as characterized by 6 microsatellite and 1 minisatellite polymorphic markers and were characterized by differences in disease progression and host-immune response. In particular, infections with the Tororo genotype exhibited an increased frequency of progression to and severity of the meningoencephalitic stage and higher plasma interferon (IFN)–γ concentration, compared with those with the Soroti genotype. We propose that the magnitude of the systemic IFN-γ response determines the time at which infected individuals develop central nervous system infection and that this is consistent with the recently described role of IFN-γ in facilitating blood-brain barrier transmigration of trypanosomes in an experimental model of infection. The identification of trypanosome isolates with differing disease progression phenotypes provides the first field-based genetic evidence for virulence variants in T. &lt;i&gt;brucei rhodesiense&lt;/i&gt;

Population genetics of trypanosoma brucei rhodesiense: clonality and diversity within and between foci

African trypanosomes are unusual among pathogenic protozoa in that they can undergo their complete morphological life cycle in the tsetse fly vector with mating as a non-obligatory part of this development. Trypanosoma brucei rhodesiense, which infects humans and livestock in East and Southern Africa, has classically been described as a host-range variant of the non-human infective Trypanosoma brucei that occurs as stable clonal lineages. We have examined T. b. rhodesiense populations from East (Uganda) and Southern (Malawi) Africa using a panel of microsatellite markers, incorporating both spatial and temporal analyses. Our data demonstrate that Ugandan T. b. rhodesiense existed as clonal populations, with a small number of highly related genotypes and substantial linkage disequilibrium between pairs of loci. However, these populations were not stable as the dominant genotypes changed and the genetic diversity also reduced over time. Thus these populations do not conform to one of the criteria for strict clonality, namely stability of predominant genotypes over time, and our results show that, in a period in the mid 1990s, the previously predominant genotypes were not detected but were replaced by a novel clonal population with limited genetic relationship to the original population present between 1970 and 1990. In contrast, the Malawi T. b. rhodesiense population demonstrated significantly greater diversity and evidence for frequent genetic exchange. Therefore, the population genetics of T. b. rhodesiense is more complex than previously described. This has important implications for the spread of the single copy T. b. rhodesiense gene that allows human infectivity, and therefore the epidemiology of the human disease, as well as suggesting that these parasites represent an important organism to study the influence of optional recombination upon population genetic dynamics

Genetic analysis of Trypanosoma brucei

Analysis of trypanosomes derived from laboratory crosses showed that minisatellite inheritance is in agreement with a Mendelian system and that such markers are particularly useful for the detection of cross and self-fertilization. Examination of the F1 hybrids from these crosses has identified some hybrids as being trisomic, but that, contrary to previous reports, triploidy is rare. The rate of recombination between homologous chromosomes was also examined and used to estimate the physical distance per centiMorgan (4.9-25kb/cM).Although sexual recombination has been demonstrated to occur in laboratory experiments the extent of genetic exchange in natural populations remained to be elucidated. Analysis of a series of field samples isolated from tsetse flies indicated that a high proportion of tsetse flies harboured mixed T. brucei infections, a prerequisite for genetic exchange to occur in the field.Minisatellite variant repeat PCR (MVR-PCR) was employed, to map the interspersion patterns of variant repeat units within a minisatellite locus, a ternary code for a number of different alleles was generated and from this the underlying mechanism of mutation for one minisatellite (MS42) were inferred. This method of allele mapping was applied to a collection of field samples to study the relationship between T. b. brucei and T. b. rhodesiense populations and the extent of sexual recombination in natural populations in each sub-species. The analysis revealed that there is considerable sub-structuring in T. brucei populations, due to geographical barriers and host specificities. T. b. rhodesiense populations are distinct from T. b. brucei and a T. b. rhodesiense-specific marker has been identified for the Busoga (Uganda) focus