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[Antigenic variation of African trypanosomes].

Although several hundred of different antigen genes exist in the trypanosome genome, only one is usually expressed at a time. This expression occurs in one of several possible telomeric expression sites. Besides being exclusively telomeric, transcription of the antigen gene exhibits other particular characteristics: the RNA polymerase is highly resistant to alpha-amanitin, and the transcription unit comprises several other genes, one of which may encode an adenylate cyclase. Post-transcriptional controls modulate the activity of this transcription unit during the parasite life-cycle. Antigenic variation is achieved through either alternative activation of different expression sites, or gene recombination within a given expression site. These mechanisms ensure a relative programming of antigen expression.

Animals↗

Antigenic variation of Borrelia turicatae Vsp surface lipoproteins occurs in vitro and generates novel serotypes.

As a means of avoiding the host immune response, the tick-borne relapsing fever spirochete Borrelia turicatae undergoes antigenic variation in its abundant surface lipoproteins. In this study, B. turicatae strain Oz1, serotype B, was subcultured in vitro and cloned by limited dilutions after 50 passages. Four different serotypes (serotypes A, B, E, and F) differing by their expressed Vsp lipoproteins were isolated. Using pulsed-field gel electrophoresis, we showed that the variability in surface-exposed proteins is correlated with rearrangement between different linear plasmids, defining serotype-specific plasmid profiles. Moreover, we determined the nucleotide sequence of genes encoding the VspE and VspF lipoproteins, corresponding to the two novel serotypes E and F, respectively. Our results showed that antigenic variation in B. turicatae occurs spontaneously in vitro, in the absence of immune selection.

Antigenic Variation↗

Antigenic divergence suggested by correlation between antigenic variation and pulsed-field gel electrophoresis profiles of Bordetella pertussis isolates in Japan.

Antigenic divergence has been found between Bordetella pertussis vaccine strains and circulating strains in several countries. In the present study, we analyzed B. pertussis isolates collected in Japan from 1988 to 2001 using pulsed-field gel electrophoresis (PFGE) and sequencing of two virulence-associated proteins. The 107 isolates were classified into three major groups by PFGE analysis; 87 (81%) were type A, 19 (18%) were type B, and 1 (1%) was type C. Sequence analysis of the S1 subunit of pertussis toxin (ptxS1) and adhesion pertactin (prn) genes revealed the presence of two (ptxS1A and ptxS1B) and three (prn1, prn2, and prn3) variants, respectively, in the isolates. Among those isolates, 82 (95%) of the 87 type A strains and the type C strain had the same combination of ptxS1B and prn1 alleles (ptxS1B/prn1) as the Japanese vaccine strain. On the other hand, 17 (90%) of 19 type B strains had an allele (ptxS1A/prn2) distinct from that of the vaccine strain. A correlation was found between the antigenic variation and the PFGE profile in the isolates. In addition, the frequency of the type B strain was 0, 27, 0, 42, and 37% of the isolates in the periods 1988 to 1993, 1994 to 1995, 1996 to 1997, 1998 to 1999, and 2000 to 2001, respectively. In contrast, the number of reported pertussis-like and pertussis cases decreased gradually from 1991 on, suggesting that the antigenic divergence did not affect the efficacy of pertussis vaccination in Japan.

Amino Acid Sequence↗

Variable var transition rates underlie antigenic variation in malaria.

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is expressed on the surface of infected erythrocytes where it plays a central role in both infected erythrocytes cytoadhesion and immune evasion. Switches in clonal expression of PfEMP1 result in antigenic variation that facilitates long-term chronic infection of the host. The var gene family encodes PfEMP1 variants, with transcriptional switching between different var variants providing the molecular basis for antigenic variation. Despite the importance of var transcriptional switching in the evasion of the immune response, little is known about the way in which this process is regulated. Here we report the measurement of transition on and off rates for a series of var gene variants. We find (i) that on and off rates for a given variant are dissimilar, (ii) that these rates vary dramatically among different variants, and (iii) that in isogenic clones expressing the same var gene, both on and off rates are constant and appear to be an intrinsic property of that particular gene. These data would suggest that the information that determines the probability of the activation or silencing of var genes is present in their surrounding DNA. Furthermore, some transitions appear to be disallowed depending on the recent variant antigen expression history of the parasite clone. These findings have important implications for both the underlying molecular mechanisms of antigenic variation and the processes that promote chronicity of infection in vivo.

ABO Blood-Group System↗

Antigenic variation in African trypanosomes.

African trypanosomes evade the humoral immune response by periodically changing the antigenic identity of their variant cell-surface glycoprotein (VSG) coat. Antigenic variation relies on DNA rearrangement events that can translocate a silent VSG gene to a telomerically located VSG gene expression site. Antigenic switches can also be brought about by the differential transcriptional control of the expression sites, only one of which is transcribed at any time.

Animals↗

Antigenic variation in foot-and-mouth disease: studies based on the virus neutralization reaction.

The neutralization reaction is the most appropriate in vitro reference test system for assessing intratypic antigenic variation as it involves the antigenic determinants responsible for virus strain specificity and evoking protective antibody. Antigenic relationships determined in different neutralization test systems were independent of the system used and were assumed to truly reflect antigenic variation. The two-dimensional microneutralization test was found to be appropriate for foot and mouth disease (FMD) virus strain differentiation. To minimize test to test variation, comparisons are performed as matched pairs. The pooled variance of the test system is used to assess the significance of the relationships obtained. Antisera from convalescent animals were less specific than those from vaccinates. Serum quality seemed less critical for the virus neutralization than the complement fixation reaction. A system for FMD virus strain differentiation based on the use of the virus neutralization reaction taking into account the statistical and biological significance of observed r values is recommended.

Animals↗

Frequency of pilin antigenic variation in Neisseria gonorrhoeae.

Variation of the pilus of Neisseria gonorrhoeae occurs by the recombination of silent pilin DNA sequences into the pilin expression locus. We have developed a quantitative, competitive reverse transcription-PCR assay which measures the frequency of pilin antigenic variation independently of changes in gonococcal colony morphology and have determined this frequency within a gonococcal population. We have also studied the frequency of antigenic variation during growth and have concluded that growth does not dramatically influence the frequency of pilin antigenic variation, although a reproducible, twofold increase is observed upon the transition into late log/stationary phase.

Bacterial Outer Membrane Proteins↗

Antigenic variation of equine infectious anemia virus as detected by virus neutralization. Brief report.

The antigenic structure of 16 viruses isolated from four horses which were inoculated with a clone of equine infectious anemia (EIA) virus was compared by the neutralization test. The antigenic structure of viruses isolated after development of neutralizing antibody differed from virus to virus. Back mutation of the antigenic structure was also demonstrated by serial passage of the virus in horses. These results suggest that EIA virus is subject to multidirectional antigenic variation. The possibility that the variants originated in the heterologous virus population in the inoculum seems to be unlikely since the virus used for the primary inoculation was cloned by three repeated high-limiting dilutions.

Animals↗

What the genome sequence is revealing about trypanosome antigenic variation.

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

Animals↗

Spontaneous mutations leading to antigenic variations in the glycoproteins of vesicular stomatitis virus field isolates.

Strains of vesicular stomatitis virus, New Jersey serotype (VSV-NJ), isolated from diseased cattle or swine were examined by genomic RNA sequencing for genetic diversity potentially leading to antigenic variations in their type-specific glycoproteins as determined by reactivity with epitope-specific monoclonal antibodies (MAbs). Seven field isolates recovered in Colorado, New Mexico, Georgia, and Mexico during the widespread 1982-1985 epizootic in the western United States resembled the prototypic 1952 Hazelhurst subtype by partial sequence homology, but amino acid reversions to the 1949 Ogden subtype occurred frequently. When studies were performed with MAbs directed to the Ogden subtype glycoprotein, relatively limited antigenic variation, and only in neutralization epitope VIII, was noted among two of five epizootic isolates from Colorado and New Mexico. However, amino acid differences in the glycoprotein of a 1983 isolate from an enzootic region of Georgia resulted in major antigenic deficiencies in epitopes V, VI, and VII as determined by Western blotting and neutralization of infectivity with epitope-specific MAbs. Quite a few genetic but no antigenic differences were noted in an enzootic 1984 isolate from Mexico, a potential origin of the United States epizootic. Marked or complete loss of epitopes VII, VI, VIII, and V can be traced to spontaneous mutations leading to amino acid substitutions at glycoprotein positions 199, 263, 275, and 317, respectively, in the enzootic Georgia isolate 07/83-GA-P and the epizootic New Mexico isolate 06/85-NM-B. By comparison, closely adjacent amino acid substitutions at glycoprotein positions 210, 268, 277, and 364 occurred in epitope-deficient mutants selected for resistance to neutralization by MAbs specific for epitopes VII, VI, VIII, and V, respectively. Two neutralization epitopes designated X and XI were found to be unique for the G protein of the 1952 Hazelhurst isolate..../52-GA-P. The epitope X-specific MAb H21, in particular, failed to neutralize the infectivity not only of the Ogden subtype..../49-UT-B but also was ineffective against all the 1982-1985 field isolates. The classical 1952 Hazelhurst strain of VSV-NJ is genetically and antigenically quite different from those viruses isolated during the 1982-1985 epizootic.

Amino Acid Sequence↗

Antigenic variation in current influenza A viruses: evidence for a high frequency of antigenic 'drift' for the Hong Kong virus.

A new antigenic variant of the Hong Kong (H3N2) subtype of influenzavirus type A is described. The variant, A/Port Chalmers/1/73 (H3N2), was first isolated in Australasia in the autumn of 1973 and subsequently became the predominant influenza A variant in most areas of the world, replacing the previously prevalent strain A/England/42/72 (H3N2). The 1973 variant shows antigenic differences from former Hong Kong variants in both haemagglutinin and neuraminidase antigens. The application of immuno-double-diffusion tests and single-radial-diffusion tests in the antigenic analysis of new variants of the influenzavirus is also described. It is emphasized that since new variants of the Hong Kong virus have appeared in the successive years 1971, 1972, and 1973, the annual frequency of antigenic "drift" for the Hong Kong virus is higher than was recorded for the "Asian" influenzavirus (H2N2) in the first 5 years of the latter's prevalence from 1957 to 1962, during which period little antigenic variation occurred.

Antibodies, Viral↗

Nucleotide substitutions and small-scale insertion produce size and antigenic variation in group A streptococcal M1 protein.

The presence of M protein on the surface of group A streptococci (GAS) confers the ability of the cell to resist phagocytosis in the absence of type-specific antibodies. It undergoes antigenic variation with more than 80 different serotypes having been defined. We have sequenced the M protein gene (emm1.1) from strain CS190 and present evidence that individual nucleotide substitutions are responsible for sequence variation in the N-terminal non-repeat region of emm1.1 and these substitutions have altered antibody recognition of opsonic epitopes. The N-terminal non-repeat domains of two other closely related strains, 71-155 and 76-088, were found to have sequence identical to emm1.1 with the addition of a 21 bp insert. This study provides the first evidence that nucleotide substitutions and small insertions are responsible for size and antigenic variation in the N-terminal non-repeat domain of the M protein of GAS.

Amino Acid Sequence↗

Antigenic variation of Streptococcus mutans colonizing gnotobiotic rats.

Strains of Streptococcus mutans representative of serotypes b and d exhibited antigenic variation in both the oral cavity and in the intestinal canal of gnotobiotic rats. Laboratory-maintained cultures did not vary. The antigenic alterations observed were: (i) loss of detectable levels of both weakly reacting "strain" antigens and the type antigen; (ii) decreased production of the type antigen; (ii) production of altered type antigen; and (iv) production of an antigen not possessed by the parent strain. Immunization of animals before monoinfection with S. mutans strain Bob-1 (serotype d) appeared to increase the rate of emergence of antigenically altered mutants in the intestinal canal, and more diversely altered isolates were obtained. Antigenic variation may account in part for the variation noted by several investigators in attempting to immunize animals against S. mutans-induced dental caries.

Animals↗

Antigenic variation of surface proteins of Borrelia species.

During relapsing fever, the etiologic spirochetes employ antigenic variation to avoid early immune clearance. In Borrelia hermsii, an agent of tick-borne relapsing fever, a switch in serotype is associated with a change in the predominant protein on the surface of the cells. The variable major proteins differ from one another in primary structure along their lengths. Genes encoding the different variable major proteins can be found in both "silent" and "active" environments. At the active site the gene is expressed; at the silent site the gene appears to be in storage. In variant cells, which express the new serotype-specific surface protein in a population, a gene from a silent site has replaced the previously sitting gene at the active site through transposition.

Animals↗

Antigenic variation and lentivirus persistence: variations in envelope gene sequences during EIAV infection resemble changes reported for sequential isolates of HIV.

The extent and nature of genomic variation among nine antigenically distinct EIAV isolates recovered during sequential clinical episodes from two experimentally infected ponies were examined by restriction fragment analysis and nucleotide sequencing. Only minor variations in restriction enzyme patterns were observed among the viral genomes. In contrast, env gene sequences of four isolates from one pony revealed numerous clustered base substitutions. Divergence in env gene nucleotide and deduced amino acid sequences between pairs of virus isolates ranged from 0.62 to 3.4% env gene mutation rates for isolates recovered during sequential febrile episodes were calculated to be greater than 10(-2) base substitutions per site per year. The degree and nature of env gene variation in EIAV is remarkably similar to the human immunodeficiency virus, suggesting common mechanisms for env gene variation among lentiviruses.

Amino Acid Sequence↗

Antigenic variation in Plasmodium falciparum is associated with movement of var loci between subnuclear locations.

Much of the success of Plasmodium falciparum in establishing persistent infections is attributed to immune evasion through antigenic variation. This process involves periodically exchanging variants of the major surface antigen PfEMP1, a protein also responsible for parasite cytoadherence. PfEMP1 is encoded by genes of the 60-member var family, located at subtelomeric and internal chromosome loci. The active or silenced state of var genes is heritable, and its control by nonsequence information remains puzzling. Using FISH analysis, we demonstrate that both internal and subtelomeric var genes are positioned at the nuclear periphery in their repressed state. Upon activation, the same var genes are still found in the periphery, indicating that this zone can be transcriptionally competent, rather than uniformly silenced. However, activation of a var gene is linked with altered positioning at the nuclear periphery, with subtelomeric var loci exiting chromosome end clusters and being relocated to distinct nuclear sites. Serial sectioning of parasite nuclei reveals areas of both condensed and noncondensed chromatin at the nuclear periphery. Our results demonstrate that regulation of antigenic variation is associated with subnuclear position effects and point to the existence of transcriptionally permissive perinuclear zones for var genes.

Animals↗

Antigenic variation of Trypanosoma evansi in rabbits.

In order to study the occurrence and sequential appearance of antigenic variation during the course of T. evansi-infection, rabbits were infected with a clone prepared from T. evansi, Java/55/PTV/1 (stock 1, clone 5). During the course of infection, trypanosome-populations were isolated from the cerebrospinal fluid and from each parasitaemia peak. Specific antisera against the clone, 6 parasitaemia-populations and two different liquor-populations (all isolated from 1 rabbit), were produced in rabbits. These antisera were used for the characterization and comparison of trypanosome populations with each other by means of immunolysis as well as neutralisation-infectivity-(NIF)-test. It was found that in all infected rabbits, the first parasitaemia contained trypanosomes, which were almost identical to those present in the clone. However, the clone contained already minor variant antigenic types ("minor-VATs"). All trypanosome-populations isolated from rabbits were heterogeneous. Heterogeneity was more pronounced in the later phases of the infection. After each fluctuating parasitaemia new dominant variants ("major VAT") were expressed. The sequential appearance of antigenic variation was similar among all infected animals. The effectivity of immunolysis was checked by the NIF-test. As it was expected, complete lysis of all trypanosomes of a population was not achieved, because some "minor VATs" could escape the influence of the antiserum. By this way, they formed the basis of new "major VATs" which dominated in the next fluctuating parasitaemia.

Animals↗