Variant antigens and endothelial receptor adhesion in Plasmodium falciparum.

Gardner, Jason P.; Pinches, Robert; Roberts, David J.; Newbold, Chris

doi:10.1073/pnas.93.8.3503

Cited by 162 publications

(145 citation statements)

References 33 publications

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“…Within the A4 clonal line there are parasites that bind ICAM-1 in a trypsin-independent fashion (27). To enrich for this parasite variant(s), an A4 parasite culture was treated with trypsin and selected on ICAM-1.…”

Section: Selection Of A4tresmentioning

confidence: 99%

Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: A parasite adhesion trait implicated in cerebral malaria

Smith

Craig

Kriek

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

217

190

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Binding of infected erythrocytes to brain venules is a central pathogenic event in the lethal malaria disease complication, cerebral malaria. The only parasite adhesion trait linked to cerebral sequestration is binding to intercellular adhesion molecule-1 (ICAM-1). In this report, we show that Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) binds ICAM-1. We have cloned and expressed PfEMP1 recombinant proteins from the A4tres parasite. Using heterologous expression in mammalian cells, the minimal ICAM-1 binding domain was a complex domain consisting of the second Duffy binding-like (DBL) domain and the C2 domain. Constructs that contained either domain alone did not bind ICAM-1. Based on phylogenetic criteria, there are five distinct PfEMP1 DBL types designated α, β, γ, δ, and ɛ. The DBL domain from the A4tres that binds ICAM-1 is DBLβ type. A PfEMP1 cloned from a distinct ICAM-1 binding variant, the A4 parasite, contains a DBLβ domain and a C2 domain in tandem arrangement similar to the A4tres PfEMP1. Anti-PfEMP1 antisera implicate the DBLβ domain from A4var PfEMP1 in ICAM-1 adhesion. The identification of a P. falciparum ICAM-1 binding domain may clarify mechanisms responsible for the pathogenesis of cerebral malaria and lead to interventions or vaccines that reduce malarial disease.

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Section: Selection Of A4tresmentioning

confidence: 99%

Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: A parasite adhesion trait implicated in cerebral malaria

Smith

Craig

Kriek

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

217

190

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“…The immune-based (death rate) hypotheses for how cytoadherence might promote fitness are attractive because the same protein that mediates all three cytoadherence phenotypes in P. falciparum (Baruch et al 1995;Gardner et al 1996;Rowe et al 1997;Chen et al 1998)-known as PfEMP-1 (Leech et al 1984)-also expresses antigens on the surface of the infected red cell. These antigens are highly variable both between parasite clones and within clones owing to an antigenic switching mechanism.…”

Section: (B) Antigenic Variationmentioning

confidence: 99%

Virulence in malaria: an evolutionary viewpoint

Mackinnon

Read

2004

Phil. Trans. R. Soc. Lond. B

227

205

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Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs.

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Section: Introductionmentioning

confidence: 99%

“…This occurs concomitant with other extensive host cell modifications and involves export of a large number of parasite proteins into the RBC, causing dramatic changes in the topology, permeability, deformability and adhesiveness of the host cell (for reviews, see Cooke et al, 2001Cooke et al, , 2004Marti et al, 2005). PfEMP-1 occurs on the RBC surface ϳ16-20 h after invasion (Gardner et al, 1996;Kriek et al, 2003), coin- Address correspondence to: Tobias Spielmann (tobias.spielmann@ gmail.com) or Donald L. Gardiner (don.gardiner@qimr.edu.au).Abbreviations used: GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IRBC, infected red blood cell; KAHRP, Knob-associated histidine-rich protein; MAHRP, membrane-associated histidine-rich protein; PEXEL, Plasmodium export element; PfEMP, Plasmodium falciparum erythrocyte membrane protein; PV, parasitophorous vacuole; PVM, parasitophorous vacuole membrane; RBC, red blood cell; REX, ring-exported protein; SBP, skeleton-binding protein; SERP, serine-rich protein; VTS, vacuolar transport signal. ciding with the end of the ring stage.…”

mentioning

confidence: 99%

A Cluster of Ring Stage–specific Genes Linked to a Locus Implicated in Cytoadherence inPlasmodium falciparumCodes for PEXEL-negative and PEXEL-positive Proteins Exported into the Host Cell

Spielmann

Hawthorne

Dixon

et al. 2006

MBoC

116

162

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Blood stages of Plasmodium falciparum export proteins into their erythrocyte host, thereby inducing extensive host cell modifications that become apparent after the first half of the asexual development cycle (ring stage). This is responsible for a major part of parasite virulence. Export of many parasite proteins depends on a sequence motif termed Plasmodium export element (PEXEL) or vacuolar transport signal (VTS). This motif has allowed the prediction of the Plasmodium exportome. Using published genome sequence, we redetermined the boundaries of a previously studied region linked to P. falciparum virulence, reducing the number of candidate genes in this region to 13. Among these, we identified a cluster of four ring stage-specific genes, one of which is known to encode an exported protein. We demonstrate that all four genes code for proteins exported into the host cell, although only two genes contain an obvious PEXEL/VTS motif. We propose that the systematic analysis of ring stage-specific genes will reveal a cohort of exported proteins not present in the currently predicted exportome. Moreover, this provides further evidence that host cell remodeling is a major task of this developmental stage. Biochemical and photobleaching studies using these proteins reveal new properties of the parasiteinduced membrane compartments in the host cell. This has important implications for the biogenesis and connectivity of these structures. INTRODUCTIONPlasmodium falciparum is the causative agent of the most severe form of human malaria, killing 1-2 million people each year (Snow et al., 2005). The symptoms of this disease are associated with the continuous asexual multiplication of P. falciparum parasites within red blood cells (RBCs) (for review, see Miller et al., 2002). In this part of the life cycle, the parasite develops, within 48 h from the ring stage, to the trophozoite stage and finally to the schizont stage after which the infected RBCs (IRBCs) rupture, releasing up to 32 merozoite stage parasites that infect new RBCs.The ring stage lasts for almost half of this cycle (ϳ0-20 h after invasion) and shows low metabolic activity with little change in size and morphology (Zolg et al., 1984;de Rojas and Wasserman, 1985). P. falciparum ring forms are the only stages apparent in the blood circulation of infected humans, because more mature parasites adhere to the endothelium of various organs to avoid clearance by the spleen (Langreth and Peterson, 1985). The subsequent accumulation of infected RBCs in the microvasculature is largely responsible for malaria-associated morbidity and mortality. This sequestration of IRBCs is mediated by the parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP-1), which is exported to the surface of the IRBCs and is encoded by a family of variant antigens (Baruch et al., 1995;Smith et al., 1995;Su et al., 1995). Because human RBCs are devoid of a functional protein trafficking system, the parasite has to establish a protein export system in the host cell before PfEMP-1 can b...

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Variant antigens and endothelial receptor adhesion in Plasmodium falciparum.

Cited by 162 publications

References 33 publications

Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: A parasite adhesion trait implicated in cerebral malaria

Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: A parasite adhesion trait implicated in cerebral malaria

Virulence in malaria: an evolutionary viewpoint

A Cluster of Ring Stage–specific Genes Linked to a Locus Implicated in Cytoadherence inPlasmodium falciparumCodes for PEXEL-negative and PEXEL-positive Proteins Exported into the Host Cell

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