scholarly journals Variant antigen diversity in Trypanosoma vivax is not driven by recombination

2019 ◽  
Author(s):  
Sara Silva Pereira ◽  
Kayo J. G. de Almeida Castilho Neto ◽  
Craig W. Duffy ◽  
Peter Richards ◽  
Harry Noyes ◽  
...  
Keyword(s):  
Gene Conversion ◽  
Immune Evasion ◽  
Antigenic Variation ◽  
Mechanistic Model ◽  
Surface Glycoprotein ◽  
Trypanosoma Vivax ◽  
African Trypanosomiasis ◽  
African Trypanosomes ◽  
Antigenic Diversity ◽  
Transmission Strategy

African trypanosomes are vector-borne haemoparasites that cause African trypanosomiasis in humans and animals. Parasite survival in the bloodstream depends on immune evasion, achieved by antigenic variation of the Variant Surface Glycoprotein (VSG) coating the trypanosome cell surface. Recombination, or rather directed gene conversion, is fundamental in Trypanosoma brucei, as both a mechanism of VSG gene switching and of generating antigenic diversity during infections. Trypanosoma vivax is a related, livestock pathogen also displaying antigenic variation, but whose VSG lack key structures necessary for gene conversion in T. brucei. Thus, this study tests a long-standing prediction that T. vivax has a more restricted antigenic repertoire. Here we show that global VSG repertoire is broadly conserved across diverse T. vivax clinical strains. We use sequence mapping, coalescent approaches and experimental infections to show that recombination plays little, if any, role in diversifying T. vivax VSG sequences. These results explain interspecific differences in disease, such as propensity for self-cure, and indicate that either T. vivax has an alternate mechanism for immune evasion or else a distinct transmission strategy that reduces its reliance on long-term persistence. The lack of recombination driving antigenic diversity in T. vivax has immediate consequences for both the current mechanistic model of antigenic variation in African trypanosomes and species differences in virulence and transmission strategy, requiring us to reconsider the wider epidemiology of animal African trypanosomiasis.

What the genome sequence is revealing about trypanosome antigenic variation

2005 ◽  
Vol 33 (5) ◽  
pp. 986-989 ◽  
Author(s):  
J.D. Barry ◽  
L. Marcello ◽  
L.J. Morrison ◽  
A.F. Read ◽  
K. Lythgoe ◽  
...  
Keyword(s):  
Gene Conversion ◽  
Humoral Immunity ◽  
Antigenic Variation ◽  
Genome Project ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Functional Genes ◽  
Gene Encoding ◽  
African Trypanosomes ◽  
Active Locus

African trypanosomes evade humoral immunity through antigenic variation, whereby they switch expression of the gene encoding their VSG (variant surface glycoprotein) coat. Switching proceeds by duplication of silent VSG genes into a transcriptionally active locus. The genome project has revealed that most of the silent archive consists of hundreds of subtelomeric VSG tandem arrays, and that most of these are not functional genes. Precedent suggests that they can contribute combinatorially to the formation of expressed, functional genes through segmental gene conversion. These findings from the genome project have major implications for evolution of the VSG archive and for transmission of the parasite in the field.

African trypanosomes: the genome and adaptations for immune evasion

2011 ◽  
Vol 51 ◽  
pp. 47-62 ◽  
Author(s):  
Gloria Rudenko
Keyword(s):  
Immune Evasion ◽  
Cell Biology ◽  
Antigenic Variation ◽  
Critical Role ◽  
Sub Saharan Africa ◽  
Surface Glycoprotein ◽  
Tsetse Flies ◽  
African Trypanosomes ◽  
Genes Encoding ◽  
Sub Saharan

The African trypanosome Trypanosoma brucei is a flagellated unicellular parasite transmitted by tsetse flies that causes African sleeping sickness in sub-Saharan Africa. Trypanosomes are highly adapted for life in the hostile environment of the mammalian bloodstream, and have various adaptations to their cell biology that facilitate immune evasion. These include a specialized morphology, with most nutrient uptake occurring in the privileged location of the flagellar pocket. In addition, trypanosomes show extremely high rates of recycling of a protective VSG (variant surface glycoprotein) coat, whereby host antibodies are stripped off of the VSG before it is re-used. VSG recycling therefore functions as a mechanism for cleaning the VSG coat, allowing trypanosomes to survive in low titres of anti-VSG antibodies. Lastly, T. brucei has developed an extremely sophisticated strategy of antigenic variation of its VSG coat allowing it to evade host antibodies. A single trypanosome has more than 1500 VSG genes, most of which are located in extensive silent arrays. Strikingly, most of these silent VSGs are pseudogenes, and we are still in the process of trying to understand how non-intact VSGs are recombined to produce genes encoding functional coats. Only one VSG is expressed at a time from one of approximately 15 telomeric VSG ES (expression site) transcription units. It is becoming increasingly clear that chromatin remodelling must play a critical role in ES control. Hopefully, a better understanding of these unique trypanosome adaptations will eventually allow us to disrupt their ability to multiply in the mammalian bloodstream.

scholarly journals Gene conversions mediating antigenic variation in Trypanosoma brucei can occur in variant surface glycoprotein expression sites lacking 70-base-pair repeat sequences.

1997 ◽  
Vol 17 (2) ◽  
pp. 833-843 ◽  
Author(s):  
R McCulloch ◽  
G Rudenko ◽  
P Borst
Keyword(s):  
Gene Conversion ◽  
Antigenic Variation ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Mammalian Host ◽  
Recognition Sequence ◽  
African Trypanosomes ◽  
Repeat Sequences ◽  
Active Expression ◽  
Expression Site

African trypanosomes undergo antigenic variation of their variant surface glycoprotein (VSG) coat to avoid immune system-mediated killing by their mammalian host. An important mechanism for switching the expressed VSG gene is the duplicative transposition of a silent VSG gene into one of the telomeric VSG expression sites of the trypanosome, resulting in the replacement of the previously expressed VSG gene. This process appears to be a gene conversion reaction, and it has been postulated that sequences within the expression site may act to initiate and direct the reaction. All bloodstream form expression sites contain huge arrays (many kilobase pairs) of 70-bp repeat sequences that act as the 5' boundary of gene conversion reactions involving most silent VSG genes. For this reason, the 70-bp repeats seemed a likely candidate to be involved in the initiation of switching. Here, we show that deletion of the 70-bp repeats from the active expression site does not affect duplicative transposition of VSG genes from silent expression sites. We conclude that the 70-bp repeats do not appear to function as indispensable initiation sites for duplicative transposition and are unlikely to be the recognition sequence for a sequence-specific enzyme which initiates recombination-based VSG switching.

scholarly journals Targeting the Variable Surface of African Trypanosomes with Variant Surface Glycoprotein-Specific, Serum-Stable RNA Aptamers

2003 ◽  
Vol 2 (1) ◽  
pp. 84-94 ◽  
Author(s):  
Mihaela Lorger ◽  
Markus Engstler ◽  
Matthias Homann ◽  
H. Ulrich Göringer
Keyword(s):  
Antigenic Variation ◽  
Sleeping Sickness ◽  
Rna Aptamers ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Parasite Protein ◽  
African Trypanosomes ◽  
Variable Surface ◽  
New Strategy

ABSTRACT African trypanosomes cause sleeping sickness in humans and Nagana in cattle. The parasites multiply in the blood and escape the immune response of the infected host by antigenic variation. Antigenic variation is characterized by a periodic change of the parasite protein surface, which consists of a variant glycoprotein known as variant surface glycoprotein (VSG). Using a SELEX (systematic evolution of ligands by exponential enrichment) approach, we report the selection of small, serum-stable RNAs, so-called aptamers, that bind to VSGs with subnanomolar affinity. The RNAs are able to recognize different VSG variants and bind to the surface of live trypanosomes. Aptamers tethered to an antigenic side group are capable of directing antibodies to the surface of the parasite in vitro. In this manner, the RNAs might provide a new strategy for a therapeutic intervention to fight sleeping sickness.

DNA rearrangements and antigenic variation in Trypanosoma equiperdum: multiple expression-linked sites in independent isolates of trypanosomes expressing the same antigen

1983 ◽  
Vol 3 (3) ◽  
pp. 399-409
Author(s):  
S Longacre ◽  
U Hibner ◽  
A Raibaud ◽  
H Eisen ◽  
T Baltz ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanism ◽  
Antigenic Variation ◽  
Cdna Probe ◽  
Surface Glycoprotein ◽  
Dna Rearrangements ◽  
African Trypanosomes ◽  
Trypanosoma Equiperdum ◽  
Variant Surface Glycoproteins ◽  
Multiple Expression

African trypanosomes resist the immune response of their mammalian hosts by varying the surface glycoprotein which constitutes their antigenic identity. The molecular mechanism of this antigenic variation involves the successive activation of a series of genes which code for different variant surface glycoproteins (VSGs). We have studied the expression of two VSG genes (those of VSG-1 and VSG-28) in Trypanosoma equiperdum, and we report the following findings. (i) The expression of both VSG genes is associated with the duplication and transposition of corresponding basic copy genes. (ii) The duplicated transposed copy appears to be the expressed copy. (iii) Although there are multiple genes which cross-hybridize with the VSG-1 cDNA probe, only one of these appears to be used as a template for the expression-linked copy in four independent BoTat-1 clones. (iv) Analysis of the genomic environments of the expressed VSG-1 genes from each of four independently derived BoTat-1 trypanosome clones revealed that there are at least three different sites into which the expression-linked copy can be inserted.

scholarly journals Escaping the immune system by DNA repair and recombination in African trypanosomes

Open Biology ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 190182 ◽  
Author(s):  
Núria Sima ◽  
Emilia Jane McLaughlin ◽  
Sebastian Hutchinson ◽  
Lucy Glover
Keyword(s):  
Immune Response ◽  
Dna Repair ◽  
Trypanosoma Brucei ◽  
Antigenic Variation ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Surface Coat ◽  
African Trypanosomes ◽  
Active Expression ◽  
Expression Site

African trypanosomes escape the mammalian immune response by antigenic variation—the periodic exchange of one surface coat protein, in Trypanosoma brucei the variant surface glycoprotein (VSG), for an immunologically distinct one. VSG transcription is monoallelic, with only one VSG being expressed at a time from a specialized locus, known as an expression site. VSG switching is a predominantly recombination-driven process that allows VSG sequences to be recombined into the active expression site either replacing the currently active VSG or generating a ‘new’ VSG by segmental gene conversion. In this review, we describe what is known about the factors that influence this process, focusing specifically on DNA repair and recombination.

scholarly journals Nuclear Phosphatidylinositol 5-Phosphatase Is Essential for Allelic Exclusion of Variant Surface Glycoprotein Genes in Trypanosomes

2018 ◽  
Vol 39 (3) ◽  
Author(s):  
Igor Cestari ◽  
Hilary McLeland-Wieser ◽  
Kenneth Stuart
Keyword(s):  
Antibody Response ◽  
Antigenic Variation ◽  
Chromatin Organization ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Allelic Exclusion ◽  
Activator Protein 1 ◽  
Multiprotein Complex ◽  
African Trypanosomes ◽  
Activator Protein

ABSTRACT Allelic exclusion of variant surface glycoprotein (VSG) genes is essential for African trypanosomes to evade the host antibody response by antigenic variation. The mechanisms by which this parasite expresses only one of its ∼2,000 VSG genes at a time are unknown. We show that nuclear phosphatidylinositol 5-phosphatase (PIP5Pase) interacts with repressor activator protein 1 (RAP1) in a multiprotein complex and functions in the control of VSG allelic exclusion. RAP1 binds PIP5Pase substrate phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], and catalytic mutation of PIP5Pase that inhibits PI(3,4,5)P3 dephosphorylation results in simultaneous transcription of VSGs from all telomeric expression sites (ESs) and from silent subtelomeric VSG arrays. PIP5Pase and RAP1 bind to telomeric ESs, especially at 70-bp repeats and telomeres, and their binding is altered by PIP5Pase inactivation or knockdown, implying changes in ES chromatin organization. Our data suggest a model whereby PIP5Pase controls PI(3,4,5)P3 binding by RAP1 and, thus, RAP1 silencing of telomeric and subtelomeric VSG genes. Hence, allelic exclusion of VSG genes may entail control of nuclear phosphoinositides.

scholarly journals RibonucleaseH1-targeted R-loops in surface antigen gene expression sites can direct trypanosome immune evasion

2018 ◽  
Author(s):  
Emma Briggs ◽  
Kathryn Crouch ◽  
Leandro Lemgruber ◽  
Craig Lapsley ◽  
Richard McCulloch
Keyword(s):  
Immune Evasion ◽  
Protein Gene ◽  
Antigenic Variation ◽  
Surface Protein ◽  
Surface Glycoprotein ◽  
Surface Coat ◽  
Loop Formation ◽  
New Host ◽  
Genome Damage ◽  
Surface Protein Gene

AbstractSwitching of the Variant Surface Glycoprotein (VSG) inTrypanosoma bruceiprovides a crucial host immune evasion strategy that is catalysed both by transcription and recombination reactions, each operating within specialised telomeric VSG expression sites (ES). VSG switching is likely triggered by events focused on the single actively transcribed ES, from a repertoire of around 15, but the nature of such events is unclear. Here we show that RNA-DNA hybrids, called R-loops, form preferentially within sequences termed the 70 bp repeats in the actively transcribed ES, but spread throughout the active and inactive ES in the absence of RNase H1, which degrades R-loops. Loss of RNase H1 also leads to increased levels of VSG coat switching and replication-associated genome damage, some of which accumulates within the active ES. This work indicates VSG ES architecture elicits R-loop formation, and that these RNA-DNA hybrids connectT. bruceiimmune evasion by transcription and recombination.Author summaryAll pathogens must survive eradication by the host immune response in order to continue infections and be passed on to a new host. Changes in the proteins expressed on the surface of the pathogen, or on the surface of the cells the pathogen infects, is a widely used strategy to escape immune elimination. Understanding how this survival strategy, termed antigenic variation, operates in any pathogen is critical, both to understand interaction between the pathogen and host and disease progression. A key event in antigenic variation is the initiation of the change in expression of the surface protein gene, though how this occurs has been detailed in very few pathogens. Here we examine how changes in expression of the surface coat of the African trypanosome, which causes sleeping sickness disease, are initiated. We reveal that specialised nucleic acid structures, termed R-loops, form around the expressed trypanosome surface protein gene and increase in abundance after mutation of an enzyme that removes them, leading to increased changes in the surface coat in trypanosome cells that are dividing. We therefore shed light on the earliest acting events in trypanosome antigenic variation.

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