Antigenic Variation, Adherence, and Virulence in Malaria

Smith, Joseph D.; Deitsch, Kirk W.

doi:10.1002/9781118308165.ch18

Cited by 5 publications

(3 citation statements)

References 163 publications

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“…Of the five Plasmodium spp. that infect humans, P. falciparum is responsible for nearly all deaths and is the only one that undergoes massive IE sequestration in host microvasculature (Smith and Deitsch, ). As homologues of DBL‐EBP erythrocyte invasion ligands are found in human, rodent and primate malaria species (Duraisingh et al ., ), it is likely that this unique cytoadhesion trait evolved from parasite invasion ligands.…”

Section: Molecular Mechanisms Of Ie Bindingmentioning

confidence: 99%

Malaria's deadly grip: cytoadhesion ofPlasmodium falciparum-infected erythrocytes

et al. 2013

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Summary Cytoadhesion of Plasmodium falciparum infected erythrocytes to host microvasculature is a key virulence determinant. Parasite binding is mediated by a large family of clonally variant adhesion proteins, termed P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by var genes and expressed at the infected-erythrocyte surface. Although PfEMP1 proteins have extensively diverged under opposing selection pressure to maintain ligand binding while avoiding antibody-mediated detection, recent work has revealed they can be classified into different groups based on chromosome location and domain composition. This grouping reflects functional specialization of PfEMP1 proteins for different human host and microvascular binding niches and appears to be maintained by gene recombination hierarchies. In one extreme, a specific PfEMP1 variant is associated with placental binding and malaria during pregnancy, while other PfEMP1 subtypes appear to be specialized for infection of malaria naïve hosts. Here, we discuss recent findings on the origins and evolution of the var gene family, the structure-function of PfEMP1 proteins, and a distinct subset of PfEMP1 variants that have been associated with severe childhood malaria.

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Section: Molecular Mechanisms Of Ie Bindingmentioning

confidence: 99%

Malaria's deadly grip: cytoadhesion ofPlasmodium falciparum-infected erythrocytes

et al. 2013

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“…iRBCs avoid clearance by the spleen by tethering to the linings of small blood vessels in various host tissues, and by binding uninfected cells-a phenomenon called rosetting. Massive iRBC sequestration in host microvasculature strongly contributes to virulence (10). Some severe complications of malaria are associated with parasite sequestration in particular tissues: e.g.…”

Section: Introductionmentioning

confidence: 99%

Conservation of single amino-acid polymorphisms inPlasmodium falciparumerythrocyte membrane protein 1 and association with severe pathophysiology

Zinder

Rorick

Tiedje

et al. 2017

Preprint

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Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a parasite protein encoded by a multigene family known as var. Expressed on the surface of infected red blood cells, PfEMP1 plays a central role in parasite virulence. The DBLα domain of PfEMP1 contains short sequence motifs termed homology blocks. Variation within homology blocks, at the level of single amino-acid modifications, has not been considered before in association with severe disease. Here we identify a total of 2701 amino-acid polymorphisms within DBLα homology blocks, the majority of which are shared between two geographically distant study populations in existing transcription data from Kenya and in a new genomic dataset sampled in Ghana. Parasitemia levels and the transcription levels of specific polymorphisms are as predictive of severe disease (AUC=0.83) and of the degree of rosetting (forecast skill SS=0.45) as the transcription of classic var groups. 11 newly categorized polymorphisms were strongly correlated with grpA var gene expression (SS=0.93) and a different set of 16 polymorphisms was associated with the H3 subset (SS=0.20). These associations provide the basis for a novel method of relating pathophysiology to parasite gene expression levels-one that, being site-specific, has more molecular detail than previous models based on var groups or homology blocks. This newly described variation influences disease outcome, and can help develop anti-malarial intervention strategies such as vaccines that target severe disease. Further replication of this analysis in geographically disparate populations and for larger sample sizes can help improve the identification of the molecular causes of severe disease.

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“…For each pathogen, the pressure to diversify surface proteins exposed to the immune system is counterbalanced by the need to preserve function, which in the case of P. falciparum is the maintenance of binding capacity to receptors on vasculature endothelial cells (2). Each pathogen has developed a systematic method to diversify surface proteins while balancing these strong but opposing selection pressures.…”

Section: Introductionmentioning

confidence: 99%

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

Kirkman

Deitsch

2014

Microbiol Spectr

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The most severe form of human malaria is caused by the protozoan parasite Plasmodium falciparum. 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 P. falciparum 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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Antigenic Variation, Adherence, and Virulence in Malaria

Cited by 5 publications

References 163 publications

Malaria's deadly grip: cytoadhesion ofPlasmodium falciparum-infected erythrocytes

Malaria's deadly grip: cytoadhesion ofPlasmodium falciparum-infected erythrocytes

Conservation of single amino-acid polymorphisms inPlasmodium falciparumerythrocyte membrane protein 1 and association with severe pathophysiology

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

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