Further definition of PfEMP-1 DBL-1α domains mediating rosetting adhesion of Plasmodium falciparum

Russell, Clare; Mercereau‐Puijalon, Odile; Scanf, Cécile Le; Steward, M. W.; Arnot, David E.

doi:10.1016/j.molbiopara.2005.06.009

Cited by 16 publications

(16 citation statements)

References 18 publications

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“…Parallel experiments with other DBL orthologs have also identified receptor affinity in this region (28,29), indicating the importance of this domain in binding to host receptors. The recently elucidated structure of DBL of erythrocyte-binding antigen 175 (EBA-175) (21) was here used to place the current study into a structural context by using characterized DBL1␣ sequences of FCR3S1.2, R29, and varO (6,7,30). The ultraconserved ARSFA sequence (homology block D) was, as expected, found to be in the center of the DBL1␣ ( Fig.…”

Section: D Model Constructionmentioning

confidence: 59%

PfEMP1-DBL1α amino acid motifs in severe disease states of Plasmodium falciparum malaria

Normark

Nilsson

Ribacke

et al. 2007

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

110

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An infection with Plasmodium falciparum may lead to severe malaria as a result of excessive binding of infected erythrocytes in the microvasculature. Vascular adhesion is mediated by P. falciparum erythrocyte membrane protein-1 (PfEMP1), which is encoded for by highly polymorphic members of the var-gene family. Here, we profile var gene transcription in fresh P. falciparum trophozoites from Ugandan children with malaria through var-specific DBL1␣-PCR amplification and sequencing. A method for subsectioning region alignments into homology areas (MOTIFF) was developed to examine collected sequences. Specific PfEMP1-DBL1␣ amino acid motifs correlated with rosetting and severe malaria, with motif location corresponding to distinct regions of receptor interaction. The method is potentially applicable to other families of variant proteins and may be useful in identifying sequencephenotype relationships. The results suggest that certain PfEMP1 sequences are predisposed to inducing severe malaria.homology areas ͉ antigenic variation ͉ rosetting P lasmodium falciparum malaria infection is one of the primary contributors to childhood mortality in many developing countries. Despite exhaustive research efforts, no vaccine capable of conferring an adequate level of immunity has been developed to date. Vaccine development is encouraged by the fact that children attain conditional immunity to severe malaria after relatively few infections. However, a lack of insight into the molecular interplay between the parasite and the host continues to thwart efforts at vaccine development. One of the key factors in this process is the ability of the parasite to continually express a plethora of antigenic variants of gene families, whose selection appears to correspond with interactions with the host immune system.Severe malaria, a highly lethal form of the disease, is, in part, attributable to the sequestration of P. falciparum-infected erythrocytes (IE) and uninfected erythrocytes in postcapillary venules of the brain, the lungs, or other organs (1). P. falciparum expresses a number of proteins at the erythrocyte surface that are closely involved in the excessive sequestration characteristic of severe malaria. The polypeptide most closely scrutinized to date, PfEMP1, is a large 200-to 400-kDa clonally variant antigen encoded by a repertoire of Ϸ60 var genes (2). The var genes present a two-exon structure encoding a conserved C terminus that contains a predicted transmembrane region and a polymorphic submodular N terminus. This N terminus region possesses a number of cysteine-rich domains that are intimately involved in the sequestration of the parasite in the microvasculature (3-5). The Duffy binding-like domain-␣ (DBL1␣) located in the Nterminal head structure of PfEMP1 mediates rosetting and endothelial binding of IE. These binding processes occur by means of a range of different receptors, including heparan sulfate, complement receptor 1, and/or the blood group A antigen (6-9). Rosetting and endothelial binding are intimately associa...

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Section: D Model Constructionmentioning

confidence: 59%

PfEMP1-DBL1α amino acid motifs in severe disease states of Plasmodium falciparum malaria

Normark

Nilsson

Ribacke

et al. 2007

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

110

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“…Surface expression of DBL1␣ 1 was associated with binding to uninfected RBC from Saimiri monkeys (data not shown), but the expression levels and the numbers of transfected cells were very low (1 to 3%). However, transfection of Cos7-L cells with a recodoned version of the DBL1␣ 1 domain (rhDBL1␣) improved the surface expression and subsequent binding to human RBC (72).…”

Section: Resultsmentioning

confidence: 99%

“…To overcome expression problems caused by the codon usage bias of P. falciparum genes, codon-optimized versions of domain-encoding sequences were synthesized. Recodoned DBL1␣ 1 optimized for Homo sapiens codon usage (positions 96 to 398 of the deduced varO protein sequence), designated rhDBL1␣, has been described elsewhere (72). Insect cell-optimized coding sequences of the varO CIDR␥, DBL2␤C2, and DBL5␤ domains (positions 399 to 835, 821 to 1241, and 2031 to 2264 of the deduced varO protein sequence, respectively) were custommade (Biomethodes, Evry, France).…”

Section: Methodsmentioning

confidence: 99%

An In Vivo and In Vitro Model of Plasmodium falciparum Rosetting and Autoagglutination Mediated by varO , a Group A var Gene Encoding a Frequent Serotype

et al. 2008

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In theSaimiri sciureusmonkey, erythrocytes infected with the varO antigenic variant of thePlasmodium falciparumPalo Alto 89F5 clone bind uninfected red blood cells (rosetting), form autoagglutinates, and have a high multiplication rate, three phenotypic characteristics that are associated with severe malaria in human patients. We report here that varO parasites express avargene having the characteristics of group Avargenes, and we show that the varO Duffy binding-like 1α1(DBL1α1) domain is implicated in the rosetting of bothS. sciureusand human erythrocytes. The soluble varO N-terminal sequence (NTS)-DBL1α1recombinant domain, produced in a baculovirus-insect cell system, induced high titers of antibodies that reacted with varO-infected red blood cells and disrupted varO rosettes. varO parasites were culture adapted in vitro using human erythrocytes. They formed rosettes and autoagglutinates, and they had the same surface serotype and expressed the samevarOgene as the monkey-propagated parasites. To develop an in vitro model with highly homogeneous varO parasites, rosette purification was combined with positive selection by panning with a varO NTS-DBL1α1-specific mouse monoclonal antibody. The single-variant, clonal parasites were used to analyze seroprevalence for varO at the village level in a setting where malaria is holoendemic (Dielmo, Senegal). We found 93.6% (95% confidence interval, 89.7 to 96.4%) seroprevalence for varO surface-reacting antibodies and 86.7% (95% confidence interval, 82.8 to 91.6%) seroprevalence for the recombinant NTS-DBL1α1domain, and virtually all permanent residents had seroconverted by the age of 5 years. These data imply that the varO model is a relevant in vivo and in vitro model for rosetting and autoagglutination that can be used for rational development of vaccine candidates and therapeutic strategies aimed at preventing malaria pathology.

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“…These in vitro studies raise the possibility that NK cells play a role in the immunity against P. falciparum malaria. However, because DBL-1a has been described as a major ligand mediating parasite binding to various receptors [36,37], the interaction between NK cells and P. falciparum merits further attention.…”

Section: Discussionmentioning

confidence: 99%

A Duffy Binding–Like Domain Is Involved in the NKp30‐Mediated Recognition ofPlasmodiumfalciparum–Parasitized Erythrocytes by Natural Killer Cells

Mavoungou

Held²,

Mewono³

et al. 2007

J INFECT DIS

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The recent demonstration that purified natural killer (NK) cells lyse Plasmodium falciparum-parasitized red blood cells (Pf-pRBCs) suggests that innate immunity is important in malaria. NK cell killing--presumably an early host response to infection--requires intimate contact between NK natural cytotoxicity receptors (NCRs) and ligands expressed on the surface of Pf-pRBCs. We investigated whether the Duffy binding-like (DBL)-1 alpha domain of P. falciparum erythrocyte membrane protein-1 (PfEMP-1) expressed on parasitized erythrocytes rendered Pf-pRBCs susceptible to NK cell lysis. We showed that with NKp30-immunoglobulin and NKp46-immunoglobulin fusion proteins and DBL-1alpha peptides NCRs are involved in the NK cell-Pf-pRBC interaction. This interaction was direct, specific, and functional, leading to perforin production and granzyme B release. The prior treatment of NK cells with DBL-1 alpha peptides abolished both this interaction and killing activity, suggesting that DBL-1 alpha -NCRs interaction is the key recognition mechanism leading to parasite killing by NK cells.

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Further definition of PfEMP-1 DBL-1α domains mediating rosetting adhesion of Plasmodium falciparum

Cited by 16 publications

References 18 publications

PfEMP1-DBL1α amino acid motifs in severe disease states of Plasmodium falciparum malaria

PfEMP1-DBL1α amino acid motifs in severe disease states of Plasmodium falciparum malaria

An In Vivo and In Vitro Model of Plasmodium falciparum Rosetting and Autoagglutination Mediated by varO , a Group A var Gene Encoding a Frequent Serotype

A Duffy Binding–Like Domain Is Involved in the NKp30‐Mediated Recognition ofPlasmodiumfalciparum–Parasitized Erythrocytes by Natural Killer Cells

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