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PubMed2004

Antigenic variation in African trypanosomes: monitoring progress.

Antigenic variation is central to the success of African trypanosomes and other eukaryotic, bacterial and viral pathogens. Our understanding of the control and execution of this immune evasion strategy in trypanosomes is incomplete, despite the molecular basis of antigenic variation being first described over 20 years ago. Recent research progress in this field is highlighted here and some of the unresolved questions raised.

Animals↗
PubMed1996

Antigenic variation and immune evasion in Plasmodium falciparum malaria.

Plasmodium falciparum malaria is responsible for 2 million deaths each year. Even in endemic regions, immunity to malaria builds slowly and is rarely complete. Strategies such as antigenic variation and antigenic diversity are critical to a parasite's ability to evade the host immune response and infect previously exposed individuals. In this short review, the phenomenon of antigenic variation is discussed in relation to immune evasion and its impact on parasite pathogenesis. Recent advances in the understanding of the underlying molecular mechanisms of antigenic variation are examined and questions posed for future research.

Animals↗
PubMed1994

Modulation of immunodominant sites in influenza hemagglutinin compromise antigenic variation and select receptor-binding variant viruses.

The regions of antigenic variation in influenza hemagglutinin (HA) are located on surface-accessible regions in the three-dimensional structure of the HA1 monomer. The aim of this study was to establish whether a novel variant virus, IMUT4, in which we had mutated specific amino acid residues (HA1 63, 144, 158, and 193) in these regions, previously shown to be immunodominant for CBA/Ca mice, would either (a) establish holes in the antibody (ab) repertoire or (b) preclude further antigenic variation in IMUT4. CBA/Ca mice were able to mount a neutralizing ab response to IMUT4 infection and molecular recognition sites were established by sequencing of the HA genes of monoclonal antibody (mAb)-selected laboratory variants of wild-type X31 virus (HA1 131, 145, 155, and 196). However, each of these mAbs failed to select further antigenic variants of IMUT4, in ovo, but rather a receptor binding mutant (HA1 190 Glu-->Asp; 226 Leu-->Gln) that was still recognized by the selecting mAb, specific for HA1 155 of X31 virus. The facility for antigenic variation in influenza would appear to be compromised, therefore, by targeted mutation of immunodominant sites, as initially proposed by S. Fazekas de St. Groth (Fazekas de St. Groth, S. 1977. Antigenic, adaptive and adsorptive variants of the influenza haemagglutinin. In Topics in Infectious Diseases. Vol. 3. R.G. Laver, H. Bachmayer, and R. Weil, editors. Springer-Verlag, Vienna. 25-48.). It is interesting to note that recent isolates of the H3 subtype, (e.g., A/Beijing/92) obtained between 1991 and 1993, contain the same substitutions at HA1 190 and 226, which may indicate similar constraints to immune evasion and the relevance of our findings to antigenic variation in the human population.

Animals↗
PubMed2001

vsp gene expression by Giardia lamblia clone GS/M-83-H7 during antigenic variation in vivo and in vitro.

Giardia lamblia infections are associated with antigenic variation of the parasite, which is generated by a continuous change of the variant-specific surface proteins (VSPs). Many investigations on the process of antigenic variation were based on the use of G. lamblia clone GS/M-83-H7, which expresses VSP H7 as its major surface antigen. In the present study, mice were infected with the aforementioned clonal line to investigate vsp gene expression during the complex process of antigenic variation of the parasite. Trophozoites collected from the intestines of individual animals at different time points postinfection (p.i.) were analyzed directly for their vsp gene expression patterns, i.e., without cultivating the recovered parasites in vitro. Because few trophozoites were recovered at late time points p.i., a combined 5' rapid amplification of cDNA ends-reverse transcription-PCR approach was utilized. This allowed detection and subsequent sequence analysis of vsp gene transcripts upon generation of amplified cDNA analogues. The same PCR approach was applied for analysis of vsp gene expression in variants obtained after negative selection of axenic GS/M-83-H7 trophozoites by treatment with a cytotoxic, VSP H7-specific monoclonal antibody. In an overall view of the entire panel of in vivo- and in vitro-derived parasite populations, expression of 29 different vsp gene sequences could be demonstrated. In vivo antigenic variation of G. lamblia clone GS/M-83-H7 was shown to be a continuous process involving the consecutive appearance of relatively distinct sets of vsp transcripts. During the 42-day infection period investigated, this process activated at least 22 different vsp genes. Comparative molecular analyses of the amino acid level demonstrated that all cDNA segments identified encode structural elements typical of the terminal segment of Giardia VSP. The similarity of most of the GS/M-83-H7 VSP sequences identified in the present study supports previous suggestions that vsp gene diversification in G. lamblia is the result of ancestral gene duplication, mutation, and/or recombination events.

Amino Acid Sequence↗
PubMed2006

Antigenic variation with a twist--the Borrelia story.

A common mechanism of immune evasion in pathogenic bacteria and protozoa is antigenic variation, in which genetic or epigenetic changes result in rapid, sequential shifts in a surface-exposed antigen. In this issue of Molecular Microbiology, Dai et al. provide the most complete description to date of the vlp/vsp antigenic variation system of the relapsing fever spirochaete, Borrelia hermsii. This elaborate, plasmid-encoded system involves an expression site that can acquire either variable large protein (vlp) or variable small protein (vsp) surface lipoprotein genes from 59 different archival copies. The archival vlp and vsp genes are arranged in clusters on at least five different plasmids. Gene conversion occurs through recombination events at upstream homology sequences (UHS) found in each gene copy, and at downstream homology sequences (DHS) found periodically among the vlp/vsp archival genes. Previous studies have shown that antigenic variation in relapsing fever Borrelia not only permits the evasion of host antibody responses, but can also result in changes in neurotropism and other pathogenic properties. The vlsE antigenic variation locus of Lyme disease spirochaetes, although similar in sequence to the relapsing fever vlp genes, has evolved a completely different antigenic variation mechanism involving segmental recombination from a contiguous array of vls silent cassettes. These two systems thus appear to represent divergence from a common precursor followed by functional convergence to create two distinct antigenic variation processes.

Antigenic Variation↗
PubMed2006

Antigenic variation by protozoan parasites: insights from Babesia bovis.

Antigenic variation of surface membrane proteins by protozoan parasites enables these pathogenic organisms to avoid host immune responses and thus perpetuate long-term infections. Babesia bovis, the causative agent of severe babesiosis in cattle, was previously shown to undergo antigenic variation through modifications to its primary surface antigen, a protein called VESA1. In this issue, Al-Khedery and Allred provide a detailed description of the genes that encode VESA1 and present convincing evidence for progressive, segmental gene conversion in the generation of variant forms of this surface antigen.

Animals↗
PubMed1984

Monoclonal antibodies for study of antigenic variation in coxsackievirus type B4: association of antigenic determinants with myocarditic properties of the virus.

Monoclonal antibodies were produced to a field strain ( Mil ) of group B coxsackievirus type 4 (CBV-4), and to the prototype JVB strain. Nine were neutralizing antibodies and four were non-neutralizing antibodies with virus-specific activity in indirect immunofluorescence (IF) staining. On the basis of reactivity with the panel of monoclonal antibodies, nine different strains of CBV-4 were found to fall into five distinct antigenic groups. Antigenic variants were produced by using the neutralizing monoclonal antibodies to select variants from the Mil virus stock which were no longer susceptible to the selecting antibody. A high frequency of antigenic variation was seen. By using the variants in cross-neutralization and IF tests with the monoclonal antibodies, it was possible to identify five tentative antigenic sites functional in neutralization; one site appeared to be complex and possibly to consist of overlapping epitopes. Reactivity of the monoclonal antibodies was similar, but not necessarily identical, by neutralization and by IF staining. The antigenic variants were found to differ from the parent Mil strain, and from one another, in their myocarditic and cardiotropic properties in a murine model. Two of the variants produced more extensive cardiac pathology, and two produced higher virus titres in the heart than was produced by the parent strain. One variant was notable for extensive production of necrotic lesions in the myocardium. Four of the variants showed less histopathology and three produced less virus in the heart than was produced by the parent strain.

Animals↗
PubMed2001

Antigenic variation in babesiosis: is there more than one 'why'?

Many intraerythrocytic hemoparasites survive the host immune system through rapid antigenic variation. Among babesial parasites antigenic variation has been demonstrated convincingly only for Babesia bovis and Babesia rodhaini. The molecular basis for antigenic variation in babesial parasites and its possible connection with cytoadherence and sequestration are discussed.

Amino Acid Sequence↗
PubMed1989

Antigenic variation in Giardia lamblia.

Giardia lamblia undergo surface antigenic variation in vitro and in vivo. The presence of variant trophozoites can be detected in clones after exposure to cytotoxic monoclonal antibodies. Surviving Giardia (progeny) no longer possess the initial major surface antigen which is replaced by new antigens. Exposure of a clone from one progeny to another cytotoxic mAb specific to one newly appearing surface antigen resulted in the loss of this antigen and replacement by another set of antigens. The frequency of change was rapid (1:100-1:1000) and was dependent upon the isolate. The presence of variant populations in clones was confirmed by direct and indirect immunofluorescence using mAbs to major surface antigens of subsequent progeny. The putative amino acid sequence of a portion of one antigen revealed a cysteine-rich composition which was confirmed in this variant protein as well as others by preferential uptake of [35S]cysteine. The mechanism(s) responsible most likely involves genomic rearrangements since Southern blots revealed a family of related genes which changed frequently compared to other areas of the genome. However, expression-linked copies have not been detected. Loss and gain of surface antigens have also been found in gerbils and humans infected with defined clones, but there does not appear to be cyclical appearance of variant populations. The biological importance of antigenic variation is not known but it may contribute to chronic and/or repeated infections.

Animals↗
PubMed1997

Antigenic variation in Giardia lamblia and the host's immune response.

Giardia lamblia, a protozoan parasite of the small intestine of humans and other animals, undergoes surface antigenic variation. The antigens involved belong to a family of variant-specific surface proteins (VSPs), which are unique, cysteine-rich zinc finger proteins. The patterns of infection in humans and animals fail to show the expected cyclical waves of increasing and decreasing numbers of parasites expressing unique VSPs. Nevertheless, changes in VSP expression occur within the population in vivo owing to selection of VSPs by both immune and non-immune mechanisms. After inoculation of a single G. lamblia clone (able to persist in the absence of immune pressure) expressing one VSP (> or = 90%) into mice or humans, the original VSP continues to be expressed until 2 weeks post inoculation (p.i.), when many other VSPs gradually replace it. Selection by immune-mediated processes is suggested because switching occurs at the same time that humoral responses are first detected. In most mouse strains, switching also occurs at about two weeks. Almost all trophozoites are eliminated at three weeks (p.i.), but a barely detectable infection persists over months. In neonatal mice, apparent self-cure is delayed until the sixth or seventh week. Antigenic switching does not occur in adult or neonatal severe combined immunodeficiency disease (SCID) mice, but does occur in neonatal nude mice, thus implicating B-cell-mediated mechanisms in immune switching. Not all VSPs are expressed to the same degree in vivo. Some VSPs appear to be preferentially selected whereas others are eliminated on a non-immune basis. In infections in which immunity does not play a role, such as in SCID mice, and during the first week of infection in immunocompetent mice or gerbils, persisting VSPs are preferentially expressed and maintained whereas non-persisting VSPs are replaced within the first week of infection. The purpose of antigenic variation may be presentation of a wide assortment of VSPs to hosts, increasing the chance of a successful initial infection or reinfection. Immune selection of variants comes into play following biological selection.

Animals↗
PubMed1991

The dynamics of antigenic variation and growth of African trypanosomes.

Antigenic variation in African trypanosomes, which is a simple strategy for survival in the immune host, is rendered complex by its magnitude. For protection from nonspecific immunity and escape from specific immunity, each trypanosome is covered by a replaceable surface coat composed of the variant surface glycoprotein (VSG), which specifies the variable antigen type (VAT) of the trypanosome. Antigenic variation is the process by which the trypanosome switches from one coat to another. Here, David Barry and Michael Turner consider this phenomenon within the context of the course of trypanosome infection.

Journal Article↗
PubMedDate not supplied

Antigenic variation and strain heterogeneity in Borrelia spp.

Antigenic variation and strain heterogeneity have been demonstrated for the pathogenic Borrelia species, i.e. B. burgdorferi and the relapsing fever borreliae. In relapsing fever, new borrelia serotypes emerge at a high rate spontaneously, a mechanism that is caused by DNA rearrangements on linear plasmid translocating genes coding for variable major proteins from previous silent to expression sites (i.e. from inner sites to telomeric sites of the plasmid). As a result of this variation, the borreliae escape the immune response of the host, thus leading to the relapse phenomenon. In B. burgdorferi, which is the causative agent of the multisystem disorder Lyme borreliosis, there is also a growing body of findings that antigenic variation is involved in pathogenesis of the disease. Phenotypic variation of strains in vitro concerns the size and the amount of surface-associated proteins (OspA, OspB and pC). There are indications that OspA and OspB truncations are due to deletions within the ospAB operon caused by recombination events, and that OspA/OspB-less mutants lack the 49-kb plasmid that bears the ospAB operon. With the increasing number of isolates obtained from various geographic and biological sources, it became apparent that B. burgdorferi is immunologically and genetically more heterogeneous, as previously believed. The major outer surface proteins OspA and OspB (which have been efficient antigens in vaccine studies) are heterogeneous at a genetic level. The same degree of genetic non-identity was observed for the pC protein. Other proteins like flagellin and the highly specific immunodominant p100 range protein show a lower degree of non-identity. Recombinant OspA, pC, p100 range protein and flagellin have been hyperexpressed in E. coli and these proteins are immunologically reactive. This allows further research for development of vaccines and diagnostic tools. B. burgdorferi isolates have been investigated with genotyping (DNA hybridization, PCR and 16S rRNA analysis) as well as serotyping by various authors. Comparison of the different methods has shown good agreement when the same strains have been investigated. No correlation could be found between different phenotypic and genotypic groups with respect to the ability to cause arthritis in SCID mice. A serotyping system based on immunological differences in OspA detected by a panel of monoclonal antibodies has been proposed. Serotyping a large number of B. burgdorferi isolates has shown a striking predominance of the OspA serotype 2 among European isolates from human skin, in contrast to isolates from ticks or CSF.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigenic Variation↗
PubMed2004

Molecular players of homologous recombination in protozoan parasites: implications for generating antigenic variation.

A major impediment to vaccine development against infections caused by protozoan parasites such as Plasmodium falciparum and Trypanosoma is the extraordinary ability of these parasites to rapidly change their surface molecules, a phenomenon known as antigenic variation. A prominent determinant of antigenic variation in these organisms is associated with rearrangements of genes, especially those known as var in P. falciparum and vsg in Trypanosoma. However, mechanisms underlying generation of anitgenic diversities among these protozoan parasites are poorly understood. The hypothesis that links all the different sections in this review is that antigenic variations in the protozoan parasites is coupled with genetic rearrangements, which occur during the course of DNA break repair. Here, we provide comprehensive and up-to-date information on Rad51 in these organisms, an eukaryotic homologue of bacterial RecA, and homologous recombination mechanisms. In trypanosomes both Rad51-dependent and -independent mechanisms have been suggested to play roles in antigenic variation. Finally, we speculate on how might similar DNA repair mechanisms contribute to genetic rearrangement associated with antigenic variation in the apicomplexan Plasmodium parasites, an immune evasion strategy.

Animals↗
PubMed1984

The ecology of antigenic variation.

A detailed molecular analysis using recombinant DNA technologies is extremely important to our understanding of the phenomena of antigenic variation in the African trypanosomes; however, by itself, it may not completely explain antigenic variation as it occurs in vivo. Several laboratories have demonstrated the ability of one variant population to replace another in vivo as well as the presence of heterogeneous populations of trypanosomes within an individual animal. These two phenomena do not permit us to explain antigen variation solely on the basis of the molecular regulation of variant antigen expression. In addition to studies in molecular biology, it will be necessary to define clearly the differences in growth rates of variant populations and the role of competition between these variants in a single anatomical site. It will also be necessary to determine the influence of various physiological environments on growth rates and the competition between the different variants of a single repertoire. It is concluded that the phenomenon of antigenic variation is a complex problem in ecology and population dynamics as well as molecular regulation. This paper is designated to examine a variety of the ecological parameters presumably involved in antigenic variation.

Animals↗
PubMed2000

A novel mechanism for control of antigenic variation in the haemagglutinin gene family of mycoplasma synoviae.

High-frequency phase and antigenic variation of homologous lipoprotein haemagglutinins has been seen in both the major avian mycoplasma pathogens, Mycoplasma synoviae and Mycoplasma gallisepticum. The expression and, hence, antigenic variation of the pMGA gene family (encoding these lipoproteins in M. gallisepticum) is controlled by variation in the length of a trinucleotide repeat motif 5' to the promoter of each gene. However, such a mechanism was not detected in preliminary observations on M. synoviae. Thus, the basis for control of variation in the vlhA gene family (which encodes the homologous haemagglutinin in M. synoviae) was investigated to enable comparison with its homologue in M. gallisepticum and with other lipoprotein gene families in mycoplasmas. The start point of transcription was identified 119 bp upstream of the initiation codon, but features associated with control of transcription in other mycoplasma lipoprotein genes were not seen. Comparison of three copies of vlhA revealed considerable sequence divergence at the 3' end of the gene, but conservation of the 5' end. Southern blot analysis of M. synoviae genomic DNA revealed that the promoter region and part of the conserved 5' coding sequence occurred as a single copy, whereas the remainder of the coding sequence occurred as multiple copies. A 9.7 kb fragment of the genome was found to contain eight tandemly repeated regions partially homologous to vlhA, all lacking the putative promoter region and the single-copy 5' end of vlhA, but extending over one of four distinct overlapping regions of the 3' coding sequence. Examination of sequential clones of M. synoviae established that unidirectional recombination occurs between the pseudogenes and the expressed vlhA, with duplication of pseudogene sequence and loss of the corresponding region previously seen in the expressed gene. Expression of the 5' end of two variants of the vlhA gene showed that they differed in their reaction with monoclonal antibodies specific for this region. These data suggest that the control of vlhA antigenic variation in M. synoviae is achieved by multiple gene conversion events using a repertoire of coding sequences to generate a chimeric expressed gene, with the greatest potential for variation generated in the region encoding the haemagglutinin. Thus, completely distinct mechanisms have been adopted to control antigenic variation in homologous gene families.

Amino Acid Sequence↗
PubMed1979

Antigenic variation in Klebsiella.

The serological reactions of klebsiella strains repeatedly isolated from four patients were examined. Variations in capsular antigens of strains from the same patient were mainly restricted to slight changes in the titre of quellung reactions and occasionally differences in cross-reactions were noted. In one case a strain reacted more strongly with a heterologous antiserum than with homologous antiserum after it had been resident in the bowel of a patient for five weeks. No significant antigenic variation was observed when multiple colonies from the same klebsiella culture were tested.

Antigens, Bacterial↗
PubMed2001

Antigenic variation in trypanosomes: enhanced phenotypic variation in a eukaryotic parasite.

African trypanosomes are unicellular, eukaryotic parasites that live extracellularly in a wide range of mammals, including humans. They have a surface coat, composed of variant surface glycoprotein (VSG), which probably is essential and acts as a defence against general innate immunity and against acquired immunity directed at invariant surface antigens. In effect, the VSG is the only antigen that the host can target, and each trypanosome expresses only one VSG. To counter specific antibodies against the VSG, trypanosomes periodically undergo antigenic variation, the change to expression of another VSG. Antigenic variation belongs to the general survival strategy of enhanced phenotypic variation, where a subset of 'contingency' genes of viruses, bacteria and parasites hypermutate, allowing rapid adaptation to hostile or changing environments. A fundamental feature of antigenic variation is its link with the population dynamics of trypanosomes within the single host. Antigenic variants appear hierarchically within the mammalian host, with a mixture of order and randomness. The underlying mechanisms of this are not understood, although differential VSG gene activation may play a prominent part. Trypanosome antigenic variation has evolved a second arm in which the infective metacyclic population in the tsetse fly expresses a defined mixture of VSGs, although again each trypanosome expresses a single VSG. Differential VSG expression enhances transmission to new hosts, in the case of bloodstream trypanosomes by prolonging infection, and in the metacyclic population by generating diversity that may counter existing partial immunity in reservoir hosts. Antigenic variation employs a huge repertoire of VSG genes. Only one is expressed at a time in bloodstream trypanosomes, as a result of transcription being restricted to a set of about 20 bloodstream expression sites (BESs), which are at chromosome telomeres. Only one BES is active at a time, probably through transcriptional elongation being inhibited in the silent BESs. Although transcriptional switching between BESs can effect a VSG switch, the most prolific switch route involves homologous recombination of deoxyribonucleic acid, usually by the copying of a silent gene into a BES. Hierarchical expression of VSGs may be dictated in part by the different types of locus occupied by VSG genes. The VSG genes expressed in the metacyclic population also occupy telomeric sites, which appear to be derived from BESs but have a simpler structure. Their differential expression is achieved by random transcriptional activation; the detailed story requires direct study of the metacyclic stage itself. Available evidence suggests that the VSG originated as a surface receptor, and it can be proposed that a number of selective events have contributed to the evolution of the complex, multisystem phenomenon that antigenic variation has become.

Animals↗