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Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite

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  • Authors: Laura A. Kirkman1, Kirk W. Deitsch3
  • Editors: Martin Gellert4, Nancy Craig5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Internal Medicine, Division of Infectious Diseases, Weill Medical College of Cornell University, New York, NY, 10065; 2: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, 10065; Kirk W. Deitsch 1300 York Avenue, Box 62, New York, NY 10065; 3: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, 10065; Kirk W. Deitsch 1300 York Avenue, Box 62, New York, NY 10065; 4: National Institutes of Health, Bethesda, MD; 5: Johns Hopkins University, Baltimore, MD
  • Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0022-2014
  • Received 31 March 2014 Accepted 14 April 2014 Published 05 December 2014
  • Kirk Deitsch, kwd2001@med.cornell.edu
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  • Abstract:

    The most severe form of human malaria is caused by the protozoan parasite . These parasites invade and replicate within the circulating red blood cells of infected individuals leading to numerous disease manifestations, including severe anemia, altered circulation, and tissue inflammation. Malaria parasites are also known for their ability to maintain a chronic infection through antigenic variation, the ability to systematically alter the antigens displayed on the surface of infected cells and thereby avoid clearance by the host’s antibody response. The genome of includes several large, multicopy gene families that encode highly variable forms of the surface proteins that are the targets of host immunity. Alterations in expression of genes within these families are responsible for antigenic variation. This process requires the continuous generation of new antigenic variants within these gene families, and studies have shown that new variants arise through extensive recombination and gene conversion events between family members. Malaria parasites possess an unusual complement of DNA repair pathways, thus the study of recombination between variant antigen encoding genes provides a unique view into the evolution of mobile DNA in an organism distantly related to the more closely studied model eukaryotes.

  • Citation: Kirkman L, Deitsch K. 2014. Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite . Microbiol Spectrum 2(6):MDNA3-0022-2014. doi:10.1128/microbiolspec.MDNA3-0022-2014.

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References

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2014-12-05
2017-06-29

Abstract:

The most severe form of human malaria is caused by the protozoan parasite . These parasites invade and replicate within the circulating red blood cells of infected individuals leading to numerous disease manifestations, including severe anemia, altered circulation, and tissue inflammation. Malaria parasites are also known for their ability to maintain a chronic infection through antigenic variation, the ability to systematically alter the antigens displayed on the surface of infected cells and thereby avoid clearance by the host’s antibody response. The genome of includes several large, multicopy gene families that encode highly variable forms of the surface proteins that are the targets of host immunity. Alterations in expression of genes within these families are responsible for antigenic variation. This process requires the continuous generation of new antigenic variants within these gene families, and studies have shown that new variants arise through extensive recombination and gene conversion events between family members. Malaria parasites possess an unusual complement of DNA repair pathways, thus the study of recombination between variant antigen encoding genes provides a unique view into the evolution of mobile DNA in an organism distantly related to the more closely studied model eukaryotes.

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FIGURE 1

Schematic representation of the life cycle highlighting major points of morphological transition and replication. Asexual replication within the erythrocytes of the mammalian host. Male and female gametocytes circulating within the blood stream of the mammalian host prior to being acquired by the mosquito vector during a blood meal. Male and female parasites as they leave the red blood cells prior to fusion and sexual division. The “rounded up” female is shown on the left and the male undergoing exflagellation is shown on the right. The motile ookinete that crosses the gut wall of the blood fed mosquito. An oocyst that forms after the ookinete crosses the gut wall. The parasite undergoes numerous asexual divisions at this point, giving rise to thousands of sporozoites. Sporozoites that infect the salivary glands of the mosquito and are injected into a mammalian host during a subsequent blood meal. They then travel to and invade cells within the liver. A liver cell infected with asexually replicating parasites. These parasites leave the liver and infect circulating red blood cells, thus completing the cycle. Figure adapted with permission from reference 83 . doi:10.1128/microbiolspec.MDNA3-0022-2014.f1

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0022-2014
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FIGURE 2

Structure and genomic arrangement of the gene family in . Schematic showing the two exon structure of all genes. Note that the 5′ UTR, intron, exon 2 and 3′ UTR are all highly conserved (gray). The sequence of the 5′ UTR and upstream regulatory domains can be classified into three basic types called A, B and C. Exon 1 encodes the polymorphic portion of PfEMP1 and is arranged as an alternating series of highly diverse sequences separating regions of higher similarity. Overall the greatest degree of sequence diversity is found at the 3′ end of exon 1 as represented by the color gradient. Exon 2 encodes a highly conserved region of PfEMP1 that is not exposed to the immune system. General chromosomal arrangement of genes, with type C genes typically found in tandem arrangement in the internal regions of the chromosomes while types A and B genes are located next to the telomere repeats. The telomeres are known to cluster into “bouquets” which align the genes in a way that is proposed to facilitate recombination and gene conversion events. Illustration (left) showing the subnuclear localization of the telomere bouquets (yellow spots) that are found near the nuclear envelope within regions of dense heterochromatin (dark blue). Regions of less dense euchromatin are typically found near the center of the nucleus (light blue). Fluorescent hybridization showing the location of the gene clusters within the parasite’s nucleus. A probe that hybridizes to the conserved exon 2 of genes is shown in yellow while the nuclear DNA is stained with DAPI (4′,6-diamidino-2-phenylindole) and is shown in blue. Image in Fig. 2(B) modified with permission from reference 84 . Image in Fig. 2(C) modified with permission from reference 85 . doi:10.1128/microbiolspec.MDNA3-0022-2014.f2

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0022-2014
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FIGURE 3

Phylogenetic tree of the Apicomplexan lineage. The different colors highlight several groups of obligate, Apicomplexan parasites. The (orange) include parasites that cause malaria in humans ( and ), nonhuman primates () and rodents ( and ). The (green) are parasites transmitted by ticks that infect either red blood cells () or white blood cells ( and ). The (blue) are cyst forming parasites that do not undergo antigenic variation. The (purple) also form cysts and have a highly reduced genome. The ciliates, as exemplified by and , are nonparasitic, free living organisms. The ability of the organisms to utilize the C-NHEJ pathway for DSB repair is inferred by the presence or absence of proteins of the Ku family. Note that, of the Apicomplexans, only the have retained these genes within their genomes. The annotations numbers for Ku70/80 are given for both the and the Ciliates. The phylogenetic relationships are shown as described in reference 86 . doi:10.1128/microbiolspec.MDNA3-0022-2014.f3

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0022-2014
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