Rifins: A second family of clonally variant proteins expressed on the surface of red cells infected with
            <i>Plasmodium falciparum</i>

Kyes, Sue; Rowe, J. Alexandra; Kriek, Neline; Newbold, Chris

doi:10.1073/pnas.96.16.9333

Cited by 297 publications

(261 citation statements)

References 33 publications

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“…Therefore, the genes HB3rifA_081, PFD0025w, and IT4rifA_044 also should be considered as encoding potential parasite ligands for HBEC-5i binding, given the known location of rifins on the surface of IEs (35).…”

Section: Resultsmentioning

confidence: 99%

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Claessens

Adams

Ghumra

et al. 2012

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

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Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterized by the accumulation of infected erythrocytes (IEs) in the microvasculature of the brain caused by parasite adhesins on the surface of IEs binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We selected three P. falciparum strains (HB3, 3D7, and IT/FCR3) for binding to a human brain endothelial cell line (HBEC-5i). The whole transcriptome of isogenic pairs of selected and unselected parasites was analyzed using a variant surface antigen-supplemented microarray chip. After selection, the most highly and consistently up-regulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7, and ITvar19) that showed 11-to >100-fold increased transcription levels. These var genes encode P. falciparum erythrocyte membrane protein (PfEMP)1 variants with distinct N-terminal domain types (domain cassette 8 or domain cassette 13). Antibodies to HB3var3 and PFD0020c recognized the surface of live IEs and blocked binding to HBEC-5i, thereby confirming the adhesive function of these variants. The clinical in vivo relevance of the HBEC-selected parasites was supported by significantly higher surface recognition of HBEC-selected parasites compared with unselected parasites by antibodies from young African children suffering cerebral malaria (Mann-Whitney test, P = 0.029) but not by antibodies from controls with uncomplicated malaria (Mann-Whitney test, P = 0.58). This work describes a binding phenotype for virulence-associated group A P. falciparum erythrocyte membrane protein 1 variants and identifies targets for interventions to treat or prevent cerebral malaria.adherence | pathogenesis | sequestration

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Section: Resultsmentioning

confidence: 99%

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Claessens

Adams

Ghumra

et al. 2012

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

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201

230

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“…In this respect, it is interesting to note that evidence for the presence of different domains in the PVM has recently been provided (Spielmann et al, 2006). Although several transmembrane proteins, such as members of the RIFIN (Kyes et al, 1999), STEVOR (Kaviratne et al, 2002), and PfMC-2TM (Sam-Yellowe et al, 2004) families, are exported in a PEXEL-dependent manner (Marti et al, 2004;Przyborski et al, 2005), these proteins are expressed at the trophozoite stage when the Maurer's clefts have already formed. This would not allow them to be exported during cleft biogenesis.…”

Section: Discussionmentioning

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

117

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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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“…[9][10][11][12][13][14][15][16][17] A second family of variable parasite antigens, the rifins, has recently been described, and they also may contribute to the constellation of antibody-inducing VSA expressed on IE. 18,19 Naturally acquired antibodies agglutinate parasite-infected erythrocytes in a variant-specific manner, and switches in agglutinating phenotype correlate with switches in cytoadherent phenotype and var gene expression. 4,[20][21][22] Sera that agglutinate P. falciparum-infected erythrocytes also inhibit binding to CD36 and immunoprecipate a protein equivalent in size to PfEMP-1.…”

Section: Introductionmentioning

confidence: 99%

Low antibody responses to variant surface antigens of Plasmodium falciparum are associated with severe malaria and increased susceptibility to malaria attacks in Gabonese children.

Tebo

Kremsner²,

Piper³

et al. 2002

Am J Trop Med Hyg

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Abstract:We measured the levels of IgG antibodies with specificity for the variant surface antigens (VSA) of Plasmodium falciparum in plasma samples from a cohort of Gabonese children participating in a longitudinal casecontrol malaria study. Children with mild malaria had significantly higher anti-VSA IgG responses than their matched counterparts with severe malaria, most markedly during convalescence and when they were healthy. Over the course of the study, almost twice as many children who presented initially with mild rather than severe malaria developed antibodies recognizing the VSA expressed by each of a panel of three isolates, and those with the highest anti-VSA IgG responses had the lowest malaria attack rates. The results suggest that the clinical outcome of P. falciparum infection in young African children depends on their ability to both develop and maintain a broad profile of anti-VSA IgG antibodies, and that this ability is diminished in children who have experienced a severe malaria attack.

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Rifins: A second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum

Cited by 297 publications

References 33 publications

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

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

Low antibody responses to variant surface antigens of Plasmodium falciparum are associated with severe malaria and increased susceptibility to malaria attacks in Gabonese children.

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