Preferential expression of domain cassettes 4, 8 and 13 of Plasmodium falciparum erythrocyte membrane protein 1 in severe malaria imported in France

Plasmodium falciparumerythrocyte membrane protein 1 (PfEMP1), expressed onP. falciparum-infected erythrocytes, is a major family of clonally variant targets of naturally acquired immunity to malaria. Previous studies have demonstrated that in areas where malaria is endemic, antibodies to infected erythrocytes from children with severe malaria tend to be more seroprevalent than antibodies to infected erythrocytes from children with nonsevere malaria. These data have led to a working hypothesis that PfEMP1 variants associated with parasite virulence are relatively conserved in structure. However, the longevity of such serologically conserved variants in the parasite population is unknown. Here, using infected erythrocytes from recently sampled clinicalP. falciparumsamples, we measured serological conservation using pools of antibodies in sera that had been sampled 10 to 12 years earlier. The serological conservation of infected erythrocytes strongly correlated with the expression of specific PfEMP1 subsets previously found to be associated with severe malaria. However, we found no association between serological conservationper seand disease severity within these data. This contrasts with the simple hypothesis thatP. falciparumisolates with a serologically conserved group of PfEMP1 variants cause severe malaria. The data are instead consistent with periodic turnover of the immunodominant epitopes of PfEMP1 associated with severe malaria.

Download Full-text

Identification of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) molecules involved in the interaction with various human endothelial receptors

10.26226/morressier.5991c409d462b80292388c72 ◽

2017 ◽

Author(s):

Lisa K. Roth

Keyword(s):

Plasmodium Falciparum ◽

Membrane Protein ◽

Erythrocyte Membrane ◽

Erythrocyte Membrane Protein ◽

Falciparum Erythrocyte Membrane Protein

Download Full-text

Identifying targets of protective antibodies against severe malaria in Papua, Indonesia using locally expressed domains of Plasmodium falciparum Erythrocyte Membrane Protein 1.

Infection and Immunity ◽

10.1128/iai.00435-21 ◽

2021 ◽

Author(s):

Janavi S Rambhatla ◽

Gerry Q Tonkin-Hill ◽

Eizo Takashima ◽

Takafumi Tsuboi ◽

Rintis Noviyanti ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Membrane Protein ◽

Severe Malaria ◽

Erythrocyte Membrane ◽

Uncomplicated Malaria ◽

Igg Antibodies ◽

Erythrocyte Membrane Protein ◽

African Children ◽

Genes Encoding ◽

Malaria Severity

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a diverse family of multi-domain proteins expressed on the surface of malaria-infected erythrocytes, is an important target of protective immunity against malaria. Our group recently studied transcription of the var genes encoding PfEMP1 in individuals from Papua, Indonesia with severe or uncomplicated malaria. We cloned and expressed domains from 32 PfEMP1s including 22 that were upregulated in severe malaria and 10 that were upregulated in uncomplicated malaria, using a wheat germ cell-free expression system. We used Luminex technology to measure IgG antibodies to these 32 domains and control proteins in 63 individuals (11 children). At presentation to hospital, levels of antibodies to PfEMP1 domains were either higher in uncomplicated malaria or were not significantly different between groups. Using principal components analysis, antibodies to three of 32 domains were highly discriminatory between groups. These included two domains upregulated in severe malaria, a DBLβ13 domain and a CIDRα1.6 domain (which has been previously implicated in severe malaria pathogenesis), and a DBLδ domain that was upregulated in uncomplicated malaria. Antibody to control non-PfEMP1 antigens did not differ with disease severity. Antibodies to PfEMP1 domains differ with malaria severity. Lack of antibodies to locally expressed PfEMP1 types, including both domains previously associated with severe malaria and newly identified targets, may in part explain malaria severity in Papuan adults. Importance Severe Plasmodium falciparum malaria kills many African children, and lack of antibody immunity predisposes to severe disease. A critical antibody target is the P. falciparum erythrocyte membrane 1 (PfEMP1) family of multidomain proteins, which are expressed on the infected erythrocyte surface and mediate parasite sequestration in deep organs. We previously identified var genes encoding PfEMP1 that were differentially expressed between severe and uncomplicated malaria in Papua, Indonesia. Here, we have expressed domains from 32 of these PfEMP1s and measured IgG antibody responses to them in Papuan adults and children. Using Principal Component Analysis, IgG antibodies to three domains distinguished between severe and uncomplicated malaria and were higher in uncomplicated malaria. Domains included CIDRα1.6, implicated in severe malaria; a DBLβ13 domain; and a DBLδ domain of unknown function. Immunity to locally relevant PfEMP1 domains may protect from severe malaria. Targets of immunity show important overlap between Asian adults and African children.

Download Full-text

The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.96.9.5198 ◽

1999 ◽

Vol 96 (9) ◽

pp. 5198-5202 ◽

Cited By ~ 153

Author(s):

J. C. Reeder ◽

A. F. Cowman ◽

K. M. Davern ◽

J. G. Beeson ◽

J. K. Thompson ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Membrane Protein ◽

Chondroitin Sulfate ◽

Erythrocyte Membrane ◽

Erythrocyte Membrane Protein ◽

Falciparum Erythrocyte Membrane Protein ◽

Chondroitin Sulfate A

Download Full-text

DNA secondary structures are associated with recombination in major Plasmodium falciparum variable surface antigen gene families

Nucleic Acids Research ◽

10.1093/nar/gkt1174 ◽

2013 ◽

Vol 42 (4) ◽

pp. 2270-2281 ◽

Cited By ~ 31

Author(s):

Adam F. Sander ◽

Thomas Lavstsen ◽

Thomas S. Rask ◽

Michael Lisby ◽

Ali Salanti ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Membrane Protein ◽

Erythrocyte Membrane ◽

Gene Families ◽

Secondary Structures ◽

Erythrocyte Membrane Protein ◽

Sexual Stages ◽

Dna Secondary Structures ◽

Parasitic Pathogens ◽

Falciparum Erythrocyte Membrane Protein

Abstract Many bacterial, viral and parasitic pathogens undergo antigenic variation to counter host immune defense mechanisms. In Plasmodium falciparum, the most lethal of human malaria parasites, switching of var gene expression results in alternating expression of the adhesion proteins of the Plasmodium falciparum-erythrocyte membrane protein 1 class on the infected erythrocyte surface. Recombination clearly generates var diversity, but the nature and control of the genetic exchanges involved remain unclear. By experimental and bioinformatic identification of recombination events and genome-wide recombination hotspots in var genes, we show that during the parasite’s sexual stages, ectopic recombination between isogenous var paralogs occurs near low folding free energy DNA 50-mers and that these sequences are heavily concentrated at the boundaries of regions encoding individual Plasmodium falciparum-erythrocyte membrane protein 1 structural domains. The recombinogenic potential of these 50-mers is not parasite-specific because these sequences also induce recombination when transferred to the yeast Saccharomyces cerevisiae. Genetic cross data suggest that DNA secondary structures (DSS) act as inducers of recombination during DNA replication in P. falciparum sexual stages, and that these DSS-regulated genetic exchanges generate functional and diverse P. falciparum adhesion antigens. DSS-induced recombination may represent a common mechanism for optimizing the evolvability of virulence gene families in pathogens.

Download Full-text

Identification of Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) as the Rosetting Ligand of the Malaria Parasite P. falciparum

Journal of Experimental Medicine ◽

10.1084/jem.187.1.15 ◽

1998 ◽

Vol 187 (1) ◽

pp. 15-23 ◽

Cited By ~ 188

Author(s):

Qijun Chen ◽

Antonio Barragan ◽

Victor Fernandez ◽

Annika Sundström ◽

Martha Schlichtherle ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Membrane Protein ◽

Heparan Sulfate ◽

Erythrocyte Membrane ◽

Plasmodium Falciparum Malaria ◽

Glutathione S Transferase ◽

Binding Motifs ◽

Erythrocyte Membrane Protein ◽

Adhesive Interactions ◽

Falciparum Erythrocyte Membrane Protein

Severe Plasmodium falciparum malaria is characterized by excessive sequestration of infected and uninfected erythrocytes in the microvasculature of the affected organ. Rosetting, the adhesion of P. falciparum–infected erythrocytes to uninfected erythrocytes is a virulent parasite phenotype associated with the occurrence of severe malaria. Here we report on the identification by single-cell reverse transcriptase PCR and cDNA cloning of the adhesive ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1). Rosetting PfEMP1 contains clusters of glycosaminoglycan-binding motifs. A recombinant fusion protein (Duffy binding-like 1–glutathione S transferase; Duffy binding-like-1–GST) was found to adhere directly to normal erythrocytes, disrupt naturally formed rosettes, block rosette reformation, and bind to a heparin-Sepharose matrix. The adhesive interactions could be inhibited with heparan sulfate or enzymes that remove heparan sulfate from the cell surface whereas other enzymes or similar glycosaminoglycans of a like negative charge did not affect the binding. PfEMP1 is suggested to be the rosetting ligand and heparan sulfate, or a heparan sulfate–like molecule, the receptor both for PfEMP1 binding and naturally formed erythrocyte rosettes.

Download Full-text