Trypanosome sociology and antigenic variation

Parasitology ◽  
1989 ◽  
Vol 99 (S1) ◽  
pp. S37-S47 ◽  
Author(s):  
K. Vickerman
Keyword(s):  
Trypanosoma Brucei ◽  
Antigenic Variation ◽  
Growth Characteristics ◽  
Tsetse Fly ◽  
Antigenic Specificity ◽  
Surface Coat ◽  
Humoral Immune ◽  
Variable Antigen ◽  
Minority Variants ◽  
Stimulation Of

SUMMARYSurvival of the trypanosome (Trypanosoma brucei) population in the mammalian body depends upon paced stimulation of the host's humoral immune response by different antigenic variants and serial sacrifice of the dominant variant (homotype) so that minority variants (heterotypes) can continue the infection and each become a homotype in its turn. New variants are generated by a spontaneous switch in gene expression so that the trypanosome puts on a surface coat of a glycoprotein differing in antigenic specificity from its predecessor. Homotypes appear in a characteristic order for a given trypanosome clone but what determines this order and the pacing of homotype generation so that the trypanosome does not quickly exhaust its repertoire of variable antigens, is not clear. The tendency of some genes to be expressed more frequently than others may reflect the location within the genome and mode of expression of the genes concerned and may influence homotype succession. Differences in the doubling time of different variants or in the rate at which trypanosomes belonging to a particular variant differentiate into non-dividing (vector infective) stumpy forms have also been invoked to explain how a heterotype's growth characteristics may determine when it becomes a homotype. Recent estimations of the frequency of variable antigen switching in trypanosome populations after transmission through the tsetse fly vector, however, suggest a much higher figure (0·97–2·2 × 10−3switches per cell per generation) than that obtained for syringe-passed infections (10−5–10−7switches per cell per generation) and it seems probable that most of the variable antigen genes are expressed as minority variable antigen types very early in the infection. Instability of expression is a feature of trypanosome clones derived from infective tsetse salivary gland (metacyclic) trypanosomes and it is suggested that high switching rates in tsetse-transmitted infections may delay the growth of certain variants to homotype status until later in the infection.

Antigenic variation in Trypanosoma brucei infections: an holistic view

1999 ◽  
Vol 112 (19) ◽  
pp. 3187-3192
Author(s):  
C.M. Turner
Keyword(s):  
Immune Responses ◽  
Trypanosoma Brucei ◽  
Antigenic Variation ◽  
Tsetse Fly ◽  
High Rate ◽  
T Helper 1 ◽  
Holistic View ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Variable Antigen

Trypanosoma brucei parasites undergo clonal phenotypic (antigenic) variation to promote their transmission between mammals and tsetse-fly vectors. This process is classically considered to be a mechanism for evading humoral immune responses, but such an explanation cannot account for the high rate of switching between variable antigens or for their hierarchical (i.e. non-random) expression. I suggest that these anomalies can be explained by a new model: that antigenic variation has evolved as a bifunctional, rather than as a unifunctional, strategy that not only evades humoral immune responses but also enables competition between parasite strains in concomitantly infected hosts. This competition causes a depression of cellular responses. My proposal gives rise to a number of testable predictions. First, low numbers of trypanosomes should express some variable antigen types (VATs) in infections several weeks before these VATs are detectable. Second, as an infection progresses, the number of VATs expressed simultaneously in the population should decrease. Third, immunisation to generate a T helper 1 response against those VATs that are expressed most frequently should lower parasitaemias and reduce virulence.

Differentiation in Trypanosoma brucei: host-parasite cell junctions and their persistence during acquisition of the variable antigen coat

1985 ◽  
Vol 74 (1) ◽  
pp. 1-19 ◽  
Author(s):  
L. Tetley ◽  
K. Vickerman
Keyword(s):  
Electron Microscopy ◽  
Trypanosoma Brucei ◽  
Morphological Changes ◽  
Freeze Fracture ◽  
Tsetse Fly ◽  
Cell Junctions ◽  
Surface Coat ◽  
Thin Sections ◽  
Variable Antigen ◽  
Host Parasite

Acquisition of the variable antigen-containing surface coat of Trypanosoma brucei occurs at the metacyclic stage in the salivary glands of the tsetse fly vector. The differentiation of the metacyclic trypanosome in the gland has been studied by scanning electron microscopy and by transmission electron microscopy of thin sections and freeze-fracture replicas. The uncoated epimastigote trypanosomes (with a prenuclear kinetoplast) divide while attached to the salivary gland epithelium brush border by elaborate branched flagellar outgrowths, which ramify between the host cell microvilli and form punctate hemidesmosome-like attachment plaques where they are indented by the microvilli. These outgrowths become reduced as the epimastigotes transform to uncoated trypomastigotes (with postnuclear kinetoplast), which remain attached and capable of binary fission. The flagellar outgrowths disappear but the attachment plaques persist as the uncoated trypomastigotes (premetacyclics) stop dividing and acquire the surface coat to become ‘nascent metacyclics’. Coat acquisition therefore occurs in the attached trypanosome and not, as previously believed, after detachment. Coating is accompanied by morphological changes in the glycosomes and mitochondrion of the parasite. Freeze-fracture replicas of the host-parasite junctional complexes show membrane particle aggregates on the host membrane but not on the parasite membrane. It is suggested that disruption of the complex occurs when maximum packing of the glycoprotein molecules has been achieved in the trypanosome surface coat, releasing the metacyclic trypanosome into the lumen of the gland.

scholarly journals Keith Vickerman. 21 March 1933—28 June 2016

2021 ◽  
Author(s):  
Francis Cox ◽  
Keith Gull
Keyword(s):  
Antigenic Variation ◽  
Morphological Changes ◽  
Tsetse Fly ◽  
Mammalian Host ◽  
Surface Coat ◽  
African Trypanosomes ◽  
Causative Agents ◽  
University College London ◽  
Variable Antigen ◽  
Commercially Important

Keith Vickerman was a parasitologist and protozoologist who made major contributions to our understanding of the biology of African trypanosomes, the causative agents of human sleeping sickness and nagana in cattle. His first academic post was at University College London, where he quickly mastered the techniques of electron microscopy (EM) and produced some of the best electron micrographs of parasitic protozoa at that time. He was a great believer in observation and deduction, and what began as an exercise in EM led him to investigate two of the then outstanding problems of trypanosome biology: how the parasites manage the transition from the tsetse fly vector to its mammalian host, and how they evade the host's immune response. Morphological changes, he found, were correlated with changes in the single mitochondrion and ensuring biochemical changes during the transition from a glucose-rich environment in mammalian blood to the glucose-poor tsetse gut. It was while comparing bloodstream and tsetse forms that he observed that the trypanosomes possessed a thick surface coat in the blood, which he subsequently identified as the variable antigen that was repeatedly formed and reformed and that this was the basis of antigenic variation—findings that stimulated a vast amount of interest among immunologists, biochemists and geneticists. In his later career a new problem emerged, and he found that a disease devastating stocks of the commercially important Norway lobster, Nephrops norvegicus , thought to be caused by a virus was actually caused by a protozoan, Hematodinium . Keith will always be remembered as one of the founders of modern parasitology.

Parasite development and host responses during the establishment of Trypanosoma brucei infection transmitted by tsetse fly

Parasitology ◽  
1984 ◽  
Vol 88 (1) ◽  
pp. 67-84 ◽  
Author(s):  
J. D. Barry ◽  
D. L. Emery
Keyword(s):  
Trypanosoma Brucei ◽  
Antigenic Variation ◽  
Tsetse Fly ◽  
Host Responses ◽  
Parasite Development ◽  
Large Mammals ◽  
Local Skin ◽  
Sequence Of Events ◽  
Draining Lymph Node ◽  
Variable Antigen

SUMMARYFollowing inoculation of Trypanosoma brucei into large mammals by the tsetse fly a local skin reaction, the ‘chancre’, develops due to trypanosome proliferation. We have cannulated the afferent and efferent lymphatics of the draining lymph node in goats and examined the onset of a cellular reaction, the emigration of the parasite from the chancre and the development of both antigenic variation and the specific immune response. The chancre first became detectable by day 3 post-infection, peaked by day 6 and then subsided. Lymphocyte output increased 6- to 8-fold by day 10 and the number of lymphoblasts increased 50-fold in this period. Both then declined. Trypanosomes were detected in lymph 1–2 days before the chancre, peaked by days 5–6, declined during development of the chancre and then peaked again. The bloodstream population appeared by days 4–5 and displayed different kinetics from that in lymph. Recirculation of parasites through the lymphatics ensued. Lymph-borne trypanosome populations were highly pleomorphic. Parasites in lymph expressed firstly a mixture of the Variable Antigen Types (VATs) which are found characteristically in the tsetse fly, this being followed by a mixture of other VATs. The two groups overlapped in appearance. In the bloodstream the same sequence of events occurred although 2 or 3 days later. The specific antibody response, as measured by radioimmunoassay and agglutination, arose within a few days of the first detection of each VAT. Activities appeared first in the lymph and then in plasma.

Analysis of trypanosome variable antigen types in cultures of metacyclic and mammalian forms of Trypanosoma congolense

Parasitology ◽  
1986 ◽  
Vol 93 (1) ◽  
pp. 99-109 ◽  
Author(s):  
A. G. Luckins ◽  
I. A. Frame ◽  
M. A. Gray ◽  
J. S. Crowe ◽  
C. A. Ross
Keyword(s):  
Antigenic Variation ◽  
Antigen Expression ◽  
Trypanosoma Congolense ◽  
Tsetse Fly ◽  
The Other ◽  
Surface Coat ◽  
Differentiation Process ◽  
Variable Antigen

SUMMARYCultured metacyclic forms of Trypanosoma congolense display a characteristic repertoire of metacyclic variable antigen types (M-VATs) similar to that exhibited in vitro in the tsetse fly. There appeared to be no change in expression of M-VATs in cultures of two stocks of T. congolense even after several passages, cryopreservation or long-term cultivation in vitro. Metacyclic forms transformed into mammalian forms when transferred to cultures of bovine aorta endothelial cells and whilst one stock retained expression of M-VATs without change even after 4 months, the other stock underwent antigenic variation within 14 days of transfer. Analysis of the M-VAT composition of mammalian forms of this stock using monoclonal antibodies showed that although the proportion of mammalian forms expressing certain M-VATs declined considerably, trypanosomes expressing one M-VAT increased proportionally to comprise 50 % of the population. In contrast, only small changes were seen in antigen expression in cultures of metacyclic trypanosomes from which mammalian-form cultures were derived. It was possible to produce in vitro, loss and reacquisition of variable antigen surface coat, similar to the differentiation process occurring when bloodstream trypanosomes are ingested by the tsetse fly and eventually develop into metacyclic forms.

Capping of variable antigen on Trypanosoma brucei, and its immunological and biological significance

1979 ◽  
Vol 37 (1) ◽  
pp. 287-302
Author(s):  
J.D. Barry
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Trypanosoma Brucei ◽  
Surface Antigen ◽  
Mammalian Cells ◽  
Antigenic Variation ◽  
Surface Coat ◽  
Antibody Molecule ◽  
Variable Antigen

Pathogenic trypanosomes undergo antigenic variation, whereby the glycoprotein molecules constituting the cell coat are changed, the parasite thus evading the host's immune response. On application of homologous antiserum in indirect immunofluorescence to a given variable antigen type of Trypanosoma brucei, the surface variable antigen moves to the flagellar pocket region, which overlies the Golgi apparatus. This redistribution, or capping, is temperature-dependent, occurring at 37 degrees C but not at 0-4 degree C. Patching does not occur at either temperature. Immediately after capping no homologous or heterologous variable antigen, or host plasma or blood cell antigens, can be detected by immunofluorescence on the cell surface outside the cap; only trypanosome membrane common antigens can be found. It seems unlikely for two reasons that this antibody-induced redistribution is relevant to antigenic variation. Capping of the coat requires the indirect, rather than the direct, immunofluorescent method; a single layer of antibody, in nature, would appear to be ineffective. Also, capping of variable antigen of one type is followed within 3 h by appearance of antigen of the same, and not another, type. The necessity for 2 antibody layers is usually thought of as meaning that the individual molecules of the cell surface antigen are spaced further apart than the binding sites of an individual antibody molecule, so that the necessary cross-linked lattice cannot be formed, but on T. brucei the surface variable antigen molecules are very closely packed. It is proposed that one layer of antibody is ineffective for steric reasons; the dimensions of the exposed face of each variable antigen molecule may not permit the binding of more than one molecule of immunoglobulin, or perhaps the antigen molecules are so closely packed that most of the antigenic determinants are hidden from antibodies. To test this hypothesis, an attempt was made to cap variable antigen on trypanosomes transforming in vitro from the bloodstream to the procyclic (insect midgut) stage; such forms have a much less densely packed surface coat. Patching was observed, indicative of lattice formation, but these trypanosomes did not survive the in vitro manipulation long enough to permit any possible capping. T. brucei differs structurally from most other eukaryotic cells. It has no detectable microfilaments under the plasma membrane, except at the desmosomes in the region of flagellar binding, and it also has a pellicular cortex of microtubules. Capping of its surface antigen would appear then to differ from that on mammalian cells, either in the cellular components involved or in that specialized areas of the plasma membrane are involved.

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.

High frequency of antigenic variation inTrypanosoma brucei rhodesienseinfections

Parasitology ◽  
1989 ◽  
Vol 99 (1) ◽  
pp. 67-75 ◽  
Author(s):  
C. M. R. Turner ◽  
J. D. Barry
Keyword(s):  
High Frequency ◽  
Antigenic Variation ◽  
Bloodstream Infections ◽  
Tsetse Fly ◽  
Cell Generation ◽  
Switching Rate ◽  
Parental Stock ◽  
Variable Antigen ◽  
Growth Chambers ◽  
Systemic Infections

SUMMARYRates at whichTrypanosoma bruceirhodesiense trypanosomes switch from expression of one variable antigen type (VAT) to that of another have been determined in cloned populations that have been recently tsetse-fly transmitted. Switching rates have been determined between several, specific pairs of VATs in each population. High rates of switching were observed in 2 cloned trypanosome lines, each derived from a separate cyclical transmission of the same parental stock and each expressing a different major VAT. Five estimates of the switching rate between one particular pair of VATs were consistently high (approximately 1 × 103switches/cell/generation). These high switching rates were similar both in bloodstream populations of mice and in populations confined to subcutaneously implanted growth chambers in mice, thus indicating that the interaction of the bloodstream population with other trypanosome populations in the lymphatics or extravascular sites in systemic infections did not influence the estimates of the rate of switching. Fourteen estimates were made of VAT-specific switching rates in bloodstream infections involving 8 combinations from among 6 VATs. Switching rate estimates were VAT-specific and showed considerable variation between different combinations of VATs — from 1.9 × 10−6to 6.9 × 10−3switches/cel/generation. The rates of switching to different metacyclic-VATs were, however, very similar. Summation of between 3 and 5 VAT-specific switching rate values in each of 4 experiments conducted in bloodstream infections has provided minimum estimates of the overall rate of antigenic variation: 2.0−9.3 × 10−3switches/cell/generation. These values are between 20 and 66000-fold higher than previously published estimates. It is likely that at least 1 in every 100 trypanosomes switches its VAT expression every generation.

Onset of expression of the variant surface glycoproteins of Trypanosoma brucei in the tsetse fly studied using immunoelectron microscopy

1987 ◽  
Vol 87 (2) ◽  
pp. 363-372 ◽  
Author(s):  
L. Tetley ◽  
C.M. Turner ◽  
J.D. Barry ◽  
J.S. Crowe ◽  
K. Vickerman
Keyword(s):  
Trypanosoma Brucei ◽  
Tsetse Fly ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Fixed Sequence ◽  
Individual Variant ◽  
Variable Antigen ◽  
Variant Surface Glycoproteins ◽  
Scanning Electron

The acquisition of the variant surface glycoprotein (variable antigen) coat by metacyclic stage Trypanosoma brucei in the salivary glands of the tsetse fly, Glossina morsitans, has been studied in situ by transmission and scanning electron microscopy using monoclonal antibodies raised against metacyclic variable antigen types and complexed with horseradish peroxidase or colloidal gold. The coat is acquired after binary fission has ceased but while the parasite is still attached to the gland epithelium, i.e. before the mature metacyclic is released into the gland lumen. The variable antigen type heterogeneity previously observed in discharged mature metacyclics is here demonstrated in the nascent (attached) metacyclic population. The variant surface glycoprotein genes are thus not expressed in a fixed sequence since different metacyclic variable antigen types are present ab initio. The distribution of immunogold-marked nascent metacyclics of a particular variable antigen type, as shown by quadrat analysis of a scanning electron micrograph montage of the infected salivary gland epithelium, conforms to a Poisson series. This provides evidence that individual variant surface glycoprotein genes are stochastically activated and suggests that selective activation occurs after trypanosome division has ceased.

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