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African trypanosomes switch at rates that are as low as 10 -7 to 10 -6 for syringe-passaged lines 38 or as high as 10 -3 to 10 -2 for field or fly-transmitted lines VSG proteins, which are to amino acids in length, are anchored to the parasite's membrane at their carboxy terminus by a glycosyl-phospatidyl-inositol linkage.
Besides immune evasion, other possible functions of VSGs include shielding other proteins e. A parasite can express several VSGs during infection in the mammalian host. Active genes for VSGs are located in one of 20 possible telomeric expression sites on the chromosomes and are transcribed with at least eight other genes 40 , 41 , one of which encodes one of several variable transferrin receptors that confer different binding affinities for the transferrins of different mammals.
Therefore, African trypanosomes combine antigenic variation of their surface coats with the ability to take up transferrin from their mammalian hosts A given VSG coat protein is encoded by a single vsg gene. Antigenic variation of VSG coats can occur by all the mechanisms described above, namely, transcriptional control, gene conversions, single cross-over events between telomeric genes, and point mutations A complete VSG gene conversion is usual in the early stages of infection, while partial replacement and point mutations that may generate further diversity are observed in the more chronic stages 43 , Short blocks of sequence homology in the upstream and downstream regions of the donor and acceptor genes may be required for the recombination events, but the precise basis for these switching events remains unknown.
A possible mechanism may involve the unusual DNA base J, which is enriched in silent telomeric sites but is absent in expressed regions Site-specific nucleases have not been described, but RAD51, an enzyme involved in DNA break repair and genetic exchange in other eukaryotes, may be involved For transcriptional activation and silencing of vsg expression in the bloodstream forms of African trypanosomes, the presence of a certain sequence within the promoter may not be critical.
When an expression site vsg promoter is replaced by ribosomal DNA promoter, vsg expression sites may still be silenced or activated During malaria infection, the apicomplexan parasites of the genus Plasmodium undergo repeated cycles of growth in erythrocytes. The species P. The best-documented example of true antigenic variation is in the P.
By changing which PfEMP1 is expressed, the parasite evades the immune response directed against these immunodominant antigens. The PfEMP1 proteins also inhibit antigen presentation by dendritic cells and provide the means for the infected red cells to adhere to endothelium and extracellular matrix, thus avoiding clearance of the infected erythrocytes by the spleen 48 - Their extracellular region has variable adhesive domains that confer the parasite-infected erythrocytes with a particular binding specificity that can include the extracellular matrix protein thrombospondin and a variety of endothelial receptors such as CD36, vascular cell adhesion molecule-1 VCAM-1 , E-selectin ELAM-1 , and intercellular cell adhesion molecule type 1 ICAM-1 49 , These adhesive phenotypes lead to the sequestration of infected erythrocytes in the brain, lungs, kidneys, liver, or other organs, thereby determining the clinical manifestations of malaria.
The PfEMP1 proteins are encoded by members of the var family of genes 49 , 51 , Transcription of the var genes can occur from expression sites internal on the chromosomes or near a chromosome telomere Changes in var expression appear to occur in situ by recombination-independent mechanisms 51 , Evidence indicates that a single P.
Two additional variant multigene families that, like PfEMP1, are expressed on the surface of infected red blood cells, induce specific antibodies, and undergo clonal variation have been described recently 56 , These proteins are encoded by the rif and STEVOR genes, which are located near the telomeres that contain the var genes. Members of the genus Babesia cause one of the most common parasitic infections worldwide in wild and domestic animals.
Some of the species, such as B. Like Plasmodium, Babesia are intraerythrocytic parasites, but they are transmitted by ticks, not mosquitoes. While several multigene families have been described for various species of Babesia, clonal antigenic variation of B. The rapid variation of these polymorphic proteins likely contributes to chronic infection in cattle by prolonging the parasite's survival through immune evasion and sequestration of the infected red blood cells in peripheral organs The VESA1 proteins, which have an approximate molecular weight of kDa 59 , are expressed on the external tips of the membrane knobs of infected erythrocytes.
Their cytoadhesive phenotype depends on the antigenic and structural changes of the VESA1 proteins The gene encoding the VESA1a subunit has been recently shown to belong to the ves multigene family The molecular events that determine the switching mechanism in B. The requirement for vector transmission of these infectious pathogens provides a powerful selection for mechanisms that prolong parasitemia.
Through convergent evolution, several vector-borne pathogens have arrived at the same strategy of antigenic variation to achieve this goal. The similarity in the genetic mechanisms that such unrelated pathogens as African trypanosomes and relapsing fever Borrelia spp. Antigenic variation has important implications for the development of vaccines against these pathogens. If the variable antigen is to be the target of immunoprophylaxis, the vaccine would likely need to be multivalent, perhaps to the point of impracticality.
If the infected host animal has not solved the problem of identifying an antigen that is conserved among the variants, thereby neutralizing the infection earlier, how can vaccine developers hope to do this? A possible way to meet this challenge is to focus on the function domains of the variable proteins.
The variable antigens of both the bacterial and parasite pathogens have other roles in pathogenesis besides immune evasion. These include tissue tropism, shielding of adjacent molecules, inhibition of phagocytosis, modulation of antigen presentation, and selective adherence. Certain regions of the variable protein may be irrelevant for these functions of the pathogen, and consequently the encoding DNA sequences could be highly divergent among alleles.
On the other hand, the regions conferring these functions would likely be more constrained in structure and thus comparatively more susceptible to cross-reacting antibodies. Another possible way to meet the challenge of antigenic variation is to focus on the vector-specific surface antigens of these pathogens. The repertoire expressed in the arthropod vector, which lacks an adaptive immune system, is generally more limited than that expressed in the vertebrate host. The Lyme disease vaccine is an example of successful targeting of a vector-specific protein.
Although B. A vaccine based on OspC would likely need to be multivalent. In contrast, B. Perhaps because of OspA's infrequent encounters with the mammalian adaptive immune system in nature, there is little divergence in ospA sequences between strains of B.
The OspA-based vaccine apparently works by eliciting antibodies that kill or inhibit the spirochetes in the tick, before expression of the more polymorphic ospC and vlsE genes in the mammalian host His research focuses on the molecular pathogenesis of relapsing fever and Lyme disease and the prevention of tick-borne diseases. Her current research interests focus on the molecular and immunologic aspects of neurocysticercosis.
Table of Contents — Volume 6, Number 5—October Please use the form below to submit correspondence to the authors or contact them at the following address:. Highlight and copy the desired format. Section Navigation. What is antigenic variation? Common elements Relapsing Fever Borrelia spp.
Figure 1 Figure 2. Alan G. Abstract Several pathogens of humans and domestic animals depend on hematophagous arthropods to transmit them from one vertebrate reservoir host to another and maintain them in an environment. Common elements. Figure 1 Figure 1. Figure 2 Figure 2. Relapsing Fever Borrelia spp. Anaplasma marginale and Related Bacteria. African Trypanosomes. Plasmodium falciparum During malaria infection, the apicomplexan parasites of the genus Plasmodium undergo repeated cycles of growth in erythrocytes.
Babesia bovis Members of the genus Babesia cause one of the most common parasitic infections worldwide in wild and domestic animals. Genetic diversity of ospC in a local population of Borrelia burgdorferi sensu stricto.
Expression and gene sequence of outer surface protein C of Borrelia burgdorferi reisolated from chronically infected mice. Infect Immun. Antigenic variation in unicellular organisms. Annu Rev Microbiol. Biology of Borrelia species. Microbiol Rev. Nucleotide sequence and variability of the inverted terminal repetitions of African swine fever virus DNA. DOI PubMed. Comparative analysis and immunological characterization of the Borrelia Bdr protein family. Antigenic variation in Trypanosoma brucei infections: an holistic view.
J Cell Sci. Immunobiology of relapsing fever. Contrib Microbiol Immunol. Trypanosome sociology and antigenic variation. Shared themes of antigenic variation and virulence in bacterial, protozoal, and fungal infections. Microbiol Mol Biol Rev. Population structure of the relapsing fever spirochete Borrelia hermsii as indicated by polymorphism of two multigene families that encode immunogenic outer surface lipoproteins. Linear DNA of Borrelia species and antigenic variation. Trends Microbiol. Antigenic variation of Borrelia hermsii. J Exp Med. Variable major proteins of Borrellia hermsii.
The variable antigens Vmp7 and Vmp21 of the relapsing fever bacterium Borrelia hermsii are structurally analogous to the VSG proteins of the African trypanosome. Mol Microbiol. Subtelomeric expression regions of Borrelia hermsii linear plasmids are highly polymorphic. Nat Med. Erythrocyte-aggregating relapsing fever spirochete Borrelia crocidurae induces formation of microemboli. J Infect Dis. Extensive interplasmidic duplications change the virulence phenotype of the relapsing fever agent Borrelia turicatae.
Variability of a bacterial surface protein and disease expression in a possible mouse model of systemic Lyme borreliosis. Arthritis severity and spirochete burden are determined by serotype in the Borrelia turicatae-mouse model of Lyme disease. Juxtaposition of expressed variable antigen genes with a conserved telomere in the bacterium Borrelia hermsii.
 A stochastic microscopic model for the dynamics of antigenic variation
Variable antigen genes of the relapsing fever agent Borrelia hermsii are activated by promoter addition. Intragenic recombination and a chimeric outer membrane protein in the relapsing fever agent Borrelia hermsii. J Bacteriol. Activation of a vmp pseudogene in Borrelia hermsii: an alternate mechanism of antigenic variation during relapsing fever.
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Antigen diversity in the bacterium B. A family of surface-exposed proteins of 20 kilodaltons in the genus Borrelia. Surface protein variation by expression site switching in the relapsing fever agent Borrelia hermsii. In press. Bloodstream- versus tick-associated variants of a relapsing fever bacterium. Antigenic variation in Lyme disease borreliae by promiscuous recombination of VMP-like sequence cassettes. Kinetics and in vivo induction of genetic variation of vlsE in Borrelia burgdorferi.