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PubMed1997

Random shuttle mutagenesis: gonococcal mutants deficient in pilin antigenic variation.

Shuttle mutagenesis has been adapted to randomly mutate the genome of Neisseria gonorrhoeae (gonococcus; Gc). A size-restricted plasmid library of Gc strain FA1090 was mutated with the mini-transposon mTnEGNS. Radomness was tested by checking for transposon insertion bias between vector and insert DNA, Gc transformation efficiency of individual mutated clones, and representation of unique clones before and after Gc transformation with a mutated pool of DNA. Mutants created by random shuttle mutagenesis were screened, using a colony-based polymerase chain reaction assay, for the ability to undergo pilin antigenic variation. Out of 8,064 mutants screened, 22 unique transposon insertion mutants were found to be antigenic variation deficient (Avd). The Avd mutants were separated into five types according to recombination defect-associated phenotypes, including colony growth, natural DNA transformation competence, and repair of DNA damage caused by ultraviolet radiation.

Antigenic Variation↗
PubMed1998

Genomic and antigenic variations of porcine reproductive and respiratory syndrome virus major envelope GP5 glycoprotein.

The objective of the present study was to evaluate the importance of genomic and antigenic variations which may have affected the major envelope glycoprotein GP5 of porcine reproductive and respiratory syndrome virus (PRRSV) isolates responsible for outbreaks in Quebec and Ontario, in comparison with the modified-live U.S. vaccine strain (MLV) and the European prototype strain from Lelystad (LV). Nucleotide sequence analyses of the open reading frame (ORF)5 genes showed that all of the isolates studied were heterogenous, amino acid (aa) identities varied from 88 to 99% with the MLV strain, and between 51 and 54% with the LV strain. The aa substitutions were randomly scattered across the protein, although one region between residues 26 and 39 was found to correspond to a hypervariable region which involved 0 to 3 potential N-glycosylation sites. The ORF5 encoded products of 5 of these isolates, including the MLV and LV strains, were expressed in E. coli as recombinant proteins fused to the glutathione S-transferase (GST) protein and used to raise hyperimmune anti-ORF5 sera in rabbits. The reactivity patterns of strain-specific hyperimmune anti-ORF5 sera and a panel of 4 monoclonal antibodies directed against the ORF5 gene product of the Quebec IAF-Klop strain of PRRSV, indicated that GP5 of field isolates also underwent antigenic variations. The data suggest that neutralizing epitopes, independent of conformation and glycosylation, are also associated with antigenic variability of the GP5 of PRRSV.

Amino Acid Sequence↗
PubMed1996

Adaptive surface antigen variation in Mycoplasma bovis to the host immune response.

The variability of predominant Mycoplasma bovis surface antigens in the presence of specific immune pressure was analyzed in an in vitro assay to determine if M. bovis could escape immune destruction. We have shown that serum antibodies from immunized or experimentally infected calves and monoclonal antibodies which specifically react with previously characterized or as yet undefined major M. bovis membrane surface proteins cause repression of expression or shortening of the target protein, or induce switching to expression of an antigenically distinct variant protein. We have further demonstrated that removal of the inducing antibody results in reversion to the original phenotype. These results suggest that the level of expression and the length of M. bovis surface antigens in the host is modulated by cognate antibodies. According to the surface antigenic variation systems, random selection of preexisting variants resistant to antibody-mediated inhibition or direct regulation of gene expression may be means by which this organism evades host immune defences.

Animals↗
PubMed1991

Antigenic variation among strains of Chlamydia pneumoniae.

The antigenic profiles of six strains of Chlamydia pneumoniae were analyzed by the microimmunofluorescence test (MIF) and immunoblotting with human serum and murine monoclonal antibody. MIF-derived antibody titers in serum samples from culture-positive patients were four- to eightfold higher against autologous isolate antigen than they were against the prototype antigen strain TW-183. Sera of patients with respiratory illness that were culture negative and complement fixation positive for Chlamydia spp. produced higher titers by MIF against a strain of C. pneumoniae isolated in the area than they did against TW-183. For two of five cases, the criteria for establishing the diagnosis of acute infection were met only with use of the antigen from the local strain; TW-183 was inadequate for this purpose. Immunoblot profiles revealed antigenic differences between strains that varied with the human serologic response; i.e., unique antigens were recognized by the sera of some individuals and not by the sera of others. Using the reactivity of a genus-specific monoclonal antibody against a major outer membrane protein, we found that strain CWL-011, isolated in Atlanta, Ga., may possess a major outer membrane protein with a molecular mass between those of C. trachomatis L2 and other C. pneumoniae strains. These data provide evidence of several new and unique serotypes of C. pneumoniae and suggest that the serologic diagnosis of C. pneumoniae infection may require the use of antigens from more than one strain of this species.

Antibodies, Bacterial↗
PubMed2001

Variance in fibronectin binding and fnb locus polymorphisms in Staphylococcus aureus: identification of antigenic variation in a fibronectin binding protein adhesin of the epidemic CMRSA-1 strain of methicillin-resistant S. aureus.

The fnbA and fnbB genes of Staphylococcus aureus 8325-4 encode fibronectin (Fn) binding proteins FnBPA and FnBPB, which promote adherence to host tissues. Each adhesin contains three copies of a repeated D motif that binds Fn and is a target for vaccine development. In this study, we assess variability within the Fn-binding domain of the FnBP adhesins and evaluate factors that promote variance in Fn binding among clinical isolates. Based on variation in the number of fnb genes or the number of D motifs, we identified five polymorphism groups. S. aureus 8325-4 and 91% of methicillin-resistant S. aureus (MRSA) isolates belong to polymorphism group I, with two fnb genes and three copies of the D motif. Polymorphism group II contained one fnb gene with only two D motifs and was associated with the epidemic CMRSA-4 strain, which exhibited high protease activity and low Fn binding. Polymorphism group III was unique to the epidemic CMRSA-1 strain, defined by the presence of a fourth D motif that exhibited antigenic variation within a conserved sequence that is essential for Fn binding. However, the sequence of the D motifs was otherwise highly conserved among the other polymorphism groups. Variation in Fn binding among MRSA isolates was inversely related to protease activity but not to the number of fnb genes or the number of D motifs. Therefore, the fnb locus is polymorphic in a small number of strains, but this does not contribute to variation in Fn binding. The antigenic variation that was observed only in the epidemic CMRSA-1 strain may have evolved in response to a host immune response encountered during successive cycles of colonization, transmission, and infection in the nosocomial environment.

Adhesins, Bacterial↗
PubMed2000

A homologue of the recombination-dependent growth gene, rdgC, is involved in gonococcal pilin antigenic variation.

Neisseria gonorrhoeae pilin undergoes high-frequency changes in primary amino acid sequence that aid in the avoidance of the host immune response and alter pilus expression. The pilin amino acid changes reflect nucleotide changes in the expressed gene, pilE, which result from nonreciprocal recombination reactions with numerous silent loci, pilS. A series of mini-transposon insertions affecting pilin antigenic variation were localized to three genes in one region of the Gc chromosome. Mutational analysis with complementation showed that a Gc gene with sequence similarity to the Escherichia coli rdgC gene is involved in pilus-dependent colony phase variation and in pilin antigenic variation. Furthermore, we show that the Gc rdgC homologue is transcriptionally linked in an operon with a gene encoding a predicted GTPase. The inability to disrupt expression of this gene suggests it is an essential gene (engA, essential neisserial GTPase). While some of the transposon mutations in rdgC and insertions in the 5'-untranslated portion of engA showed a growth defect, all transposon insertions investigated conferred an aberrant cellular morphology. Complementation analysis showed that the growth deficiencies are due to the interruption of RdgC expression and not that of EngA. The requirement of RdgC for efficient pilin variation suggests a role for this protein in specialized DNA recombination reactions.

Amino Acid Sequence↗
PubMed2001

Juxtaposition of an active promoter to vsp genes via site-specific DNA inversions generates antigenic variation in Mycoplasma bovis.

Mycoplasma bovis, the most important etiological agent of bovine mycoplasmosis, undergoes extensive antigenic variation of major and highly immunogenic surface lipoprotein antigens (Vsps). A family of 13 related but divergent vsp genes, which occur as single chromosomal copies, was recently found in the chromosome of M. bovis. In the present study, the molecular mechanism mediating the high-frequency phase variation of two Vsps (VspA and VspC) as representatives of the Vsp family was investigated. Analysis of clonal isolates exhibiting phase transitions of VspA or of VspC (i.e., ON-->OFF-->ON) has shown that DNA inversions occur during Vsp phase variation. The upstream region of each vsp gene contains two sequence cassettes. The first (cassette no. 1), a 71-bp region upstream of the ATG initiation codon, exhibits 98% homology among all vsp genes, while the second (cassette no. 2), upstream of cassette no. 1, ranges in size from 50 to 180 bp and is more divergent. Examination of the ends of the inverted fragments during VspA or VspC phase variation revealed that in both cases, a change in the organization of vsp upstream cassettes involving three vsp genes had occurred. Primer extension and Northern blot analysis have shown that a specific cassette no. 2, designated A(2), is an active promoter and that juxtaposition of this regulatory element to a silent vsp gene by DNA inversions allows transcription initiation of the recipient gene. Further genetic analysis revealed that phase variation of VspA or of VspC involves two site-specific DNA inversions occurring between inverted copies of a specific 35-bp sequence present within the conserved cassette no. 1. A model for the control of Vsp phase variation is proposed.

Antigenic Variation↗
PubMed1999

Predominance of duplicative VSG gene conversion in antigenic variation in African trypanosomes.

A number of mechanisms have been described by which African trypanosomes undergo the genetic switches that differentially activate their variant surface glycoprotein genes (VSGs) and bring about antigenic variation. These mechanisms have been observed mainly in trypanosome lines adapted, by rapid syringe passaging, to laboratory conditions. Such "monomorphic" lines, which routinely yield only the proliferative bloodstream form and do not develop through their life cycle, have VSG switch rates up to 4 or 5 orders of magnitude lower than those of nonadapted lines. We have proposed that nonadapted, or pleomorphic, trypanosomes normally have an active VSG switch mechanism, involving gene duplication, that is depressed, or from which a component is absent, in monomorphic lines. We have characterized 88 trypanosome clones from the first two relapse peaks of a single rabbit infection with pleomorphic trypanosomes and shown that they represent 11 different variable antigen types (VATs). The pattern of appearance in the first relapse peak was generally reproducible in three more rabbit infections. Nine of these VATs had activated VSGs by gene duplication, the tenth possibly also had done so, and only one had activated a VSG by the transcriptional switch mechanism that predominates in monomorphic lines. At least 10 of the donor genes have telomeric silent copies, and many reside on minichromosomes. It appears that trypanosome antigenic variation is dominated by one, relatively highly active, mechanism rather than by the plethora of pathways described before.

Animals↗
PubMed1985

Antigenic variation is associated with DNA rearrangements in a relapsing fever Borrelia.

Borrelia hermsii, an agent of relapsing fever, undergoes antigenic variation in its host. Surface-exposed proteins with differing primary structures determine the serotype of each organism. Using amino acid sequence data from two of these variable proteins, we synthesized two mixed-sequence oligonucleotides and then used the oligonucleotides to probe mRNA and DNA of three isogenic serotypes of B. hermsii. In Northern blots the probes were specific for the mRNA of the homologous serotype. Southern blots revealed two classes of hybridizing fragments: those common to the three serotypes and those specific for a particular serotype. A serotype-specific DNA fragment, which had hybridized to both oligonucleotide probes, was cloned. Subsequent use of the cloned fragment as a probe provided further evidence that antigenic variation in B. hermsii is associated with DNA rearrangements and with occurrence of expression-linked copies of all, or part, of an antigen-specifying gene.

Antigens, Bacterial↗
PubMed1994

Mechanism of antigenic variation in Shigella flexneri. II. Sensitivity to complement as a selection factor for antigenic mutant 3b in 1b serotype.

In the first report we stated that the antigenic mutant of Shigella flexneri 6713 3b serovar with antigenic formula III: 3, 4, 6 was less sensitive to bactericidal action of normal calf serum in comparison to its parent strain S. flexneri 6713 1b with antigenic formula III: 3, 4, 6. In this paper we show that the phenomenon is rather a general one; the difference in sensitivity was observed in three other strains S. flexneri 1b of independent clinical origin and its antigenic mutants 3b respectively. As the result of serial treatment of these strain with the serum among the survivors the antigenic mutants have been found. In the artificial mixtures of the mutants and isogenic original strains treated with the serum the later show clear cut higher survival.

Antigenic Variation↗
PubMed1988

Antigenic variation of Giardia lamblia in vivo.

A single Giardia lamblia trophozoite can give rise in vitro to G. lamblia with varying surface antigens. To determine whether antigenic variation also occurs in vivo, gerbils were inoculated with defined G. lamblia clones and the surface antigens of the intestinal trophozoites were studied at different times during the infection. The proportion of monoclonal antibody 6E7-reacting trophozoites from WB C1-6E7S-inoculated gerbils had decreased significantly by day 3 postinoculation, indicating the presence of a heterogeneous population. On day 7, the 170-kilodalton antigen was no longer present and was replaced by a variety of antigens, including a major protein of 92 kilodaltons. With the exception of isolates from gerbils inoculated with WB A6-6E7S, the banding patterns of G. lamblia isolated from gerbils on day 7 or later were the same regardless of the clones used for inoculation. These studies show that G. lamblia changes its surface antigen(s) in vivo within 7 days following inoculation and appears to maintain the same set of surface antigens during the course of infection.

Animals↗
PubMed1990

Relationships between sequestration, antigenic variation and chronic parasitism in Plasmodium chabaudi chabaudi--a rodent malaria model.

We describe here a rodent malaria model using cloned lines of Plasmodium chabaudi chabaudi in inbred CBA/Ca mice that exhibits both clonal antigenic variation in late stage-specific surface antigens, and deep vascular schizogony in the liver. We show that both these features are modulated by the spleen, and that surface antigen expression is crucially involved in the sequestering phenotype. Surface antigens are variant in chronic infection, and host protective immune responses can distinguish between these variants. Splenectomy abolishes this difference. The acute infection with non-sequestering cloned lines is kinetically indistinguishable from sequestering clones, but parasites unable to express variant sequestration-associated antigen do not form a chronic recrudescing infection. Another clone, able to re-express this antigen in the presence of the spleen, undergoes typical chronic recrudescence. In this model, the biological significance of sequestration-associated variant antigen seems to enable the establishment of chronic infection in the presence of a primed spleen.

Animals↗
PubMed1988

Antigenic variation of a cysteine-rich protein in Giardia lamblia.

The WB isolate of Giardia lamblia expresses a cysteine-rich 170-kD surface antigen (CRP170) that undergoes antigenic variation. An (6E7), cytotoxic for isolates expressing CRP170, was used in another study to select antigenic variants from clones of the WB isolate of Giardia. CRP170 was replaced by surface-labeled bands ranging in size from approximately 50 to 170 kD. In this study, mAb 6E7 was used to isolate a 1-kb portion of the CRP170 gene (M2-1) from a lambda gt 11 expression library. The M2-1 clone hybridized to a 5.4-kb transcript from isolates expressing CRP170 but did not hybridize to RNA from antigenic variants. Evidence was found for frequent rearrangements at the CRP170 gene locus. DNA sequencing of the M2-1 clone revealed the presence of long tandem repeats. The putative amino acid sequence of M2-1 reveals a 12% cysteine content, and CRP170 is readily labeled in vivo with cysteine.

Amino Acid Sequence↗
PubMedDate not supplied

Antigenic variations in West Nile virus strains isolated in Madagascar since 1978.

The antigenic interrelationship between 52 Madagascan West Nile isolates and two prototype viruses (Eg101 and G2266) was assessed by an immunofluorescent technique using monoclonal antibodies. This analysis enabled us to define 5 groups of variants, 4 of which were closer to the Egyptian strain (Eg101) than to the Indian prototype (G2266). Groups II and V were dominant whereas strains of groups I and IV were less numerous. One strain belonging to group III was antigenically similar to the Indian strain. Antigenic variations were observed among viruses isolated from man, birds and different mosquito genera. Geographic variations were also observed. Exchanges exist between Madagascar and the African continent by means of migratory birds which seem to be instrumental in disseminating the virus and introducing the antigenic variants.

Animals↗
PubMed1986

Antigenic variation during Trypanosoma vivax infections of different host species.

The sequence of appearance of specific lytic activity against more than 20 variable antigen types (VATs) of Trypanosoma vivax in the serum of 27 animals belonging to 5 species has been examined. For each host species there was a characteristic course of infection, with differences in height and duration of parasitaemia and in pathogenicity. The sequence of antigenic variation was similar in all host species, with some VATs consistently eliciting response more rapidly than others. The predominant group, comprising VATs which apparently developed within the first 3 weeks, varied in size according to the total number of trypanosomes in the bloodstream within that period, suggesting there is a spectrum, rather than discrete groupings, in the hierarchy of VAT expression. There was very little evidence for differences in appearance of VATs between host species; the only clear example was one VAT which apparently did not develop in one host species. The sequence of antigenic variation in T. vivax seems to be determined by the parasite rather than the host species.

Animals↗
PubMed2003

Ten families of variant genes encoded in subtelomeric regions of multiple chromosomes of Plasmodium chabaudi, a malaria species that undergoes antigenic variation in the laboratory mouse.

The chromosome ends of human malaria parasites harbour many genes encoding proteins that are exported to the surface of infected red cells, often being involved in host-parasite interactions and immune evasion. Unlike other murine malaria parasites Plasmodium chabaudi undergoes antigenic variation during passage in the laboratory mouse and hence is a model suitable for investigation of switching mechanisms. However, little is known about the subtelomeric regions of P. chabaudi chromosomes and its variable antigens. Here we report 80 kb of sequence from an end of one P. chabaudi chromosome. Hybridization of probes spanning this region to two dimensional pulsed field gels of the genome revealed 10 multicopy gene families located exclusively in subtelomeric regions of multiple P. chabaudi chromosomes, interspersed amongst multicopy intergenic regions. Hence all chromosomes share a common subtelomeric structure, presumably playing a similar role in spatial positioning as the P. falciparum Rep20 sequence. Expression in blood stages, domains characteristic of surface antigens and copy numbers between four and several hundred per genome, indicate a functional role in antigenic variation for some of these families. We identify members of the cir family, as well as novel genes, that although clearly homologous to cir have large low complexity regions in the predicted extracellular domains. Although all families have homologues in other rodent Plasmodium species, four were previously not known to be subtelomeric. Six have homologues in human and simian malarias.

Animals↗
PubMed2004

The molecular control of antigenic variation in Trypanosoma brucei.

The African trypanosome, Trypanosoma brucei, is a protozoan that causes sleeping sickness in humans and N'gana in livestock. These flagellated parasites are directly exposed to immune defences as they circulate in the mammalian host bloodstream but they maintain persistent infections by undergoing antigenic variation. Central to this process is mono-allelic transcription and switching of the expressed variant-surface glycoprotein (VSG) gene which encodes the vast majority of their dense surface coat. The active telomeric VSG is transcribed by RNA polymerase I in an 'expression site body' (ESB) while transcription attenuation occurs at 'inactive' telomeres. Here, I review what is known about the molecular mechanisms involved in achieving antigenic variation and outline how we intend to exploit genome sequence and new tools, particularly RNA interference, to identify and characterise factors required for VSG regulation.

Animals↗
PubMed2006

Loss of both Holliday junction processing pathways is synthetically lethal in the presence of gonococcal pilin antigenic variation.

The obligate human pathogen Neisseria gonorrhoeae (Gc) has co-opted conserved recombination pathways to achieve immune evasion by way of antigenic variation (Av). We show that both the RuvABC and RecG Holliday junction (HJ) processing pathways are required for recombinational repair, each can act during genetic transfer, and both are required for pilin Av. Analysis of double mutants shows that either the RecG or RuvAB HJ processing pathway must be functional for normal growth of Gc when RecA is expressed. HJ processing-deficient survivors of RecA expression are enriched for non-piliated bacteria that carry large deletions of the pilE gene. Mutations that prevent pilin variation such as recO, recQ, and a cis-acting pilE transposon insertion all rescue the RecA-dependent growth inhibition of a HJ processing-deficient strain. These results show that pilin Av produces a recombination intermediate that must be processed by either one of the HJ pathways to retain viability, but requires both HJ processing pathways to yield pilin variants. The need for diversity generation through frequent recombination reactions creates a situation where the HJ processing machinery is essential for growth and presents a possible target for novel antimicrobials against gonorrhoea.

Antigenic Variation↗