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PubMed1991

Molecular genetics of antigenic variation.

Antigenic variation is one of the most effective strategies developed by parasites to escape immune destruction. It requires a large wardrobe of surface coats and mechanisms to exchange one coat for an unrelated one. The molecular principles of antigenic variation are now largely known in the bacterial species Borrelia and Neisseria and in the protozoa of the African trypanosome group and these three examples are discussed here by Piet Borst.

Amino Acid Sequence↗
PubMed1992

Gene conversion in Neisseria gonorrhoeae: evidence for its role in pilus antigenic variation.

Antigenic variation of gonococcal pili results from the unidirectional transfer of genetic information from variant-encoding partial pilin genes to an active expression locus. Two potential mechanisms that may result in the observed alterations of gene linkage and organization are conversion and transformation. To determine the relative contributions of these two distinct pathways of recombination to pilus variation, gonococcal strains carrying defined frameshift, missense, and nonsense mutations within the pilin expression locus were constructed. Reversion to a piliated state required correction of the lesions and provided a simple means of scoring productive recombination and antigenic variation. Examination of the mutants revealed a lack of correspondence between the frequencies with which they could be transformed (10(-6) per recipient) and the incidence with which they gave rise to revertants (greater than 10(-4) per colony-forming unit per generation). Further, the rates of reversion demonstrated by these mutants were not altered by growth in the presence of DNase I, conditions that abolished intercellular transfer of chromosomal markers during cultivation. Through the use of a pilin mutant in which a frameshift mutation encompassed the introduction of a restriction endonuclease site, the symmetry of recombination that resulted in reversion could be scored by Southern hybridization. In all cases examined, the DNA alterations responsible for pilin variation were nonreciprocal events. The results favor the model that productive pilin gene rearrangements in gonococci arise by gene conversion.

Amino Acid Sequence↗
PubMedDate not supplied

Antigenic variation in Borrelia.

Antigenic variation was demonstrated for the agent of relapsing fever, Borrelia hermsii. The phenomenon is correlated with changes in major surface proteins called Vmp. The genes encoding these antigens are located on linear plasmids. Expression occurs by transposition of genes encoding Vmp to a telomeric expression site located on another linear plasmid. Activation of a vmp gene occurs by placing it downstream from a promoter. Resemblance to the antigenic variation of trypanosomes is discussed.

Animals↗
PubMed1991

Antigenic variation in Plasmodium falciparum.

Antigenic variation of infectious organisms is a major factor in evasion of the host immune response. However, there has been no definitive demonstration of this phenomenon in the malaria parasite Plasmodium falciparum. In this study, cloned parasites were examined serologically and biochemically for the expression of erythrocyte surface antigens. A cloned line of P. falciparum gave rise to progeny that expressed antigenically distinct forms of an erythrocyte surface antigen but were otherwise identical. This demonstrates that antigenic differences on the surface of P. falciparum-infected erythrocytes can arise by antigenic variation of clonal parasite populations. The antigenic differences were shown to result from antigenic variation of the parasite-encoded protein, the P. falciparum erythrocyte membrane protein 1.

Agglutination↗
PubMed1991

Control of antigenic variation in African trypanosomes.

Antigenic variation of African trypanosomes results from the controlled expression of a single variant cell-surface glycoprotein (VSG) gene from a repertoire of about 1,000 genes. The transcription of the VSG genes occurs uniquely at telomeres, where the expressed VSG gene is part of a large polycistronic transcription unit that appears to be transcribed by a specialized RNA polymerase. Recent developments that enhanced our understanding of the control of VSG gene expression and of the mechanisms of antigenic variation are discussed in this review.

Animals↗
PubMed2026

De Novo Assembly of the Trypanosoma congolense Genome Reveals an Organization Influenced by Antigenic Variation but Distinct from Trypanosoma brucei.

Antigenic variation allows pathogens to evade mammalian adaptive immunity through the continuous change in exposed antigens. In African trypanosomes, antigenic variation involves changes in expressed Variant Surface Glycoproteins (VSGs). Understanding of VSG expression control and change amongst African trypanosomes is most advanced in Trypanosoma brucei. In the important animal trypanosome, Trypanosoma congolense, incomplete genome assembly has held back understanding of the mechanics of antigenic variation. Here, we have used long-read DNA sequencing and Hi-C DNA interaction analysis to provide a telomere-to-telomere assembly of the T. congolense genome. This assembly reveals a genome comprising 12 diploid chromosomes, one tetraploid chromosome, and more than 100 small chromosomes. With this assembly we reveal several features of VSG organization and expression that differ from T. brucei. The majority of the T. congolense VSG archive, estimated at ∼1,500 genes, localizes to subtelomeres in 12 of the 13 large chromosomes, but these loci are notably smaller than are found in T. brucei. Furthermore, transcriptome analysis suggests expression of VSGs across the T. congolense subtelomeres, which are not separated within the nucleus from non-VSG chromosome regions, suggesting that there is no dedicated VSG expression site. Strikingly, one chromosome contains approximately 40% of the VSG archive and is largely transcriptionally silent, potentially acting as the major reservoir of new VSG variants. Finally, we show that VSG expression can be detected from multiple small chromosomes. In summary, the new genome assembly provides a platform for understanding a potentially unusual operation of VSG expression and switching in T. congolense.

Trypanosoma congolense↗
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↗
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↗
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↗
PubMed1977

Antigenic variation in African trypanosomiasis: a memorandum.

After reviewing the present knowledge on antigenic variation of the trypanosomes of the Trypanosoma (Trypanozoon) brucei species, this Memorandum discusses the relevance of this phenomenon to the possible development of new tools for trypanosomiasis control.As antigenic variation is related to protective immunity and immunopathology, it is of crucial importance for the feasibility of vaccine development and for treatment principles. It is also of interest as a model for understanding antigenic variation occurring during infections with Plasmodium knowlesi, Babesia, and others. Recent methods will permit in depth studies on the antigenic repertoire, the significance of basic antigens, and on the homogeneity of trypanosome populations. For epidemiological purposes, characteristic patterns of variation can be used for strain typing.As regards the basic mechanism of variation, a better insight is required on the molecular structure of the variant antigens. Various methods have so far indicated that they are glycoproteins with a long polypetide chain with 600 amino acids and 15-30 monosaccharide units.The process of variation may be generated by pre-existing genetic information, recombination, or mutation.The stimulus to change variants probably derives, directly or indirectly, from the host immune response, but may also be associated with other environmental factors.The possible relation to acquired resistance, innate immunity, and host specificity, as well as the differences in severity of infection occurring amongst the same host species, are outlined. Histopathological and serological findings are considered in the light of the effect antigenic variation may have on the development of immunopathological lesions.A series of recommendations is included.

Agglutination Tests↗
PubMed1989

Antigenic variation of human RSV strains isolated in Japan.

Antigenic variations of respiratory syncytial virus (RSV) strains were analyzed using a collection of nine, seven, two, and one monoclonal antibodies (MAbs), respectively, raised against the fusion protein (F), large glycoprotein (G), nucleoprotein (NP), and phosphoprotein (P) components of the Long strain of RSV. Competitive binding assay by these MAbs demonstrated eight, four, and two distinct epitopes on F, G, and NP components, respectively. Comparison of prototype Long with ten field strains isolated in Sapporo, Japan, during a 9-year period from 1980 to 1988 by radioimmunoprecipitation (RIP), immunofluorescence (IF), and enzyme-linked immunosorbent assay (ELISA) test revealed four different patterns of reaction to these MAbs. Thus, prototype Long reacted to all 19 MAbs. Six field strains have shown a different reactivity to one of nine anti-F and to one of seven anti-G antibodies (subgroup A). Three of the remaining isolates failed to react with three of nine anti-F and with all of seven anti-G antibodies (subgroup B). One strain (58-104) isolated in 1983 was similar to subgroup A except for a lack of reaction with two anti-G antibodies. All field strains reacted with two anti-NP and one anti-P antibodies. The numbers of altered epitopes in subgroup A were 1/8 and 1/4; in subgroup B, 3/8 and 4/4; and in 58-104, 1/8 and 2/4 on the F and G components, respectively. No other variations have been observed among field isolates tested.

Antibodies, Monoclonal↗
PubMed1979

Antigenic variation in visna virus.

Two antigenic variants of visna virus were isolated sequentially from a single sheep inoculated with a plaque-purified strain of virus designated 1514. The genetically stable variants, LV1-1 and LV1-4, are of two classes: LV1-1 is partially neutralized by antibody to the inoculum strain 1514, while LV1-4 is not neutralized by antibody to 1514. The genetic mechanism responsible for generating the antigenic variants was investigated by comparing the chymotryptic and tryptic maps of the envelope glycoprotein gp135 and core polypeptides (p30, p16, p14), and by comparing the pattern of large oligonucleotides produced by digestion of the RNAs by T1 ribonuclease. We show that only the peptide maps of gp135 differ among strains, that the number of peptide fragments altered is small and that gp135 is the polypeptide that elicits neutralizing antibody. The maps of the RNAs are identical. We conclude that mutation in the glycoprotein gene rather than recombination is more probably responsible for antigenic variation, and speculate on the special aspects of visna virus replication relevant to this phenomenon.

Amino Acid Sequence↗
PubMedDate not supplied

Telomeric reciprocal recombination as a possible mechanism for antigenic variation in trypanosomes.

In African trypanosomes, antigenic variation is achieved through differential gene activation, with one antigen gene being expressed at a time among a large collection of antigen-specific sequences. Transcription of the antigen gene always takes place in a telomere, but different telomeres can alternatively act as the expression site. Telomeric antigen genes can be expressed without apparent DNA rearrangement, but they can also, like non-telomeric genes, have access to the telomeric expression site through a duplicative transposition mechanism resembling gene conversion. We report here that, as previously suggested, telomeric genes may use another route to be activated. This mechanism of gene activation is by reciprocal crossing-over upstream from the gene, in the so-called 'barren' region. This allows the antigen gene to be placed in the previously activated telomere, while inactivating the formerly expressed gene by recombination into a silent environment. At least for the telomeric antigen gene described here, three possible activation mechanisms coexist.

Animals↗
PubMed1985

Antigenic variation in Trypanosoma evansi: variable antigen type (VAT) composition of first relapse populations in mice.

The variable antigen type (VAT) composition of first relapse populations developing in mice infected with 11 VAT populations of a stock of T. evansi was shown to be independent of the infecting VAT. Trypanosomes representing three of the VATs were found in all relapse populations resulting from infection with each VAT. A further seven VATs were detected in at least one relapse population from each VAT. These 10 VATs had previously been classed as predominant VATs from studies on VAT development in rabbits, sheep and goats. It is probable, therefore, that the VAT composition of first relapse populations can be used as a basis for the classification of T. evansi stocks into serodemes according to their predominant VAT repertoires.

Animals↗
PubMed1985

Antigenic variation in the hemagglutinin-neuraminidase protein of human parainfluenza type 3 virus.

Sixteen monoclonal antibodies directed to the hemagglutinin-neuraminidase (HN) protein of a 1957 isolate of parainfluenza type 3 virus (PIV3) were produced and used to examine antigenic variation in clinical strains. Analysis of hemagglutination-inhibition reactivity patterns of antigenic variants selected in vitro in the presence of monoclonal antibodies indicated that there were a minimum of six distinct epitopes detectable on the HN molecule. Competitive-binding assays indicated that these epitopes were located in two topologically nonoverlapping antigenic sites. An additional four epitopes were detected when 37 PIV3 clinical strains isolated over a period of 26 years in three geographic regions were tested for reactivity with the antibodies. Of the 10 unique epitopes defined by our monoclonal antibodies, 5 did not undergo detectable antigenic variation in any of the 37 strains examined. These results were expected since PIV3 viruses have been characterized as being antigenically monotypic. In contrast, antigenic variation was detected in the remaining five epitopes. This variation was not characterized by the accumulation of antigenic alterations with time (as for influenza A viruses), but appeared to represent genetic heterogeneity within the PIV3 population.

Animals↗
PubMed1990

Antigenic variation of Giardia lamblia in the feces of Mongolian gerbils.

Enzyme-linked immunoelectrotransfer blot was used to study variations in Giardia lamblia antigens in extracts of feces from infected Mongolian gerbils. A 65-kilodalton antigen was found in feces that contained strain WB (ATCC 30957) cysts and in axenic culture of strains WB and CDC:0284:1 that contained trophozoites. The 65-kilodalton antigen from trophozoites of both strains was membrane associated. A 70-kilodalton antigen was found in feces that contained strain CDC:0284:1 cysts. It was persistent in 16 fecal collections and may be strain specific. Similar variations in antigens may occur in human feces. Coproimmunodiagnostic assays that use monoclonal antibodies will have to include all varieties of G. lamblia antigens present in the feces of giardiasis patients.

Animals↗
PubMed1991

Molecular biology of antigenic variation in Lyme borreliosis and relapsing fever: a comparative analysis.

Lyme borreliosis and relapsing fever are human diseases caused by different members of the genus Borrelia. Antigenic variation has been a well-known feature of the pathogenesis of relapsing fever for decades. More recently it has been recognized that Borrelia burgdorferi, the agent of Lyme borreliosis, also can vary its surface antigens. In this review the biology and molecular biology of antigenic variation of the pathogens in these two disorders are compared.

Antigenic Variation↗