scholarly journals Stringent Selection of Knobby Plasmodium falciparum-Infected Erythrocytes during Cytoadhesion at Febrile Temperature

2020 ◽  
Vol 8 (2) ◽  
pp. 174 ◽  
Author(s):  
Michael Dörpinghaus ◽  
Finn Fürstenwerth ◽  
Lisa K. Roth ◽  
Philip Bouws ◽  
Maximilian Rakotonirinalalao ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Erythrocyte Membrane ◽  
Malaria Infection ◽  
Binding Capacity ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Var Genes ◽  
Stringent Selection ◽  
Falciparum Erythrocyte Membrane Protein ◽  
Selection Of

Changes in the erythrocyte membrane induced by Plasmodium falciparum invasion allow cytoadhesion of infected erythrocytes (IEs) to the host endothelium, which can lead to severe complications. Binding to endothelial cell receptors (ECRs) is mainly mediated by members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, encoded by var genes. Malaria infection causes several common symptoms, with fever being the most apparent. In this study, the effects of febrile conditions on cytoadhesion of predominately knobless erythrocytes infected with the laboratory isolate IT4 to chondroitin-4-sulfate A (CSA), intercellular adhesion molecule 1 (ICAM-1), and CD36 were investigated. IEs enriched for binding to CSA at 40 °C exhibited significantly increased binding capacity relative to parasites enriched at 37 °C. This interaction was due to increased var2csa expression and trafficking of the corresponding PfEMP1 to the IE surface as well as to a selection of knobby IEs. Furthermore, the enrichment of IEs to ICAM-1 at 40 °C also led to selection of knobby IEs over knobless IEs, whereas enrichment on CD36 did not lead to a selection. In summary, these findings demonstrate that knobs are crucial for parasitic survival in the host, especially during fever episodes, and thus, that selection pressure on the formation of knobs could be controlled by the host.

Receptor-binding residues lie in central regions of Duffy-binding–like domains involved in red cell invasion and cytoadherence by malaria parasites

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2557-2563 ◽  
Author(s):  
Alfredo Mayor ◽  
Nivedita Bir ◽  
Ritica Sawhney ◽  
Shailja Singh ◽  
Priyabrata Pattnaik ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Receptor Binding ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Malaria Parasites ◽  
Var Genes ◽  
Binding Domains ◽  
Functional Regions ◽  
Central Regions ◽  
Binding Residues

AbstractErythrocyte invasion by malaria parasites and cytoadherence of Plasmodium falciparum-infected erythrocytes to host capillaries are 2 key pathogenic mechanisms in malaria. The receptor-binding domains of erythrocyte-binding proteins (EBPs) such as Plasmodium falciparum EBA-175, which mediate invasion, and P falciparum erythrocyte membrane protein 1 (PfEMP-1) family members, which are encoded by var genes and mediate cytoadherence, have been mapped to conserved cysteine-rich domains referred to as Duffy-binding–like (DBL) domains. Here, we have mapped regions within DBL domains from EBPs and PfEMP-1 that contain receptor-binding residues. Using biochemical and molecular methods we demonstrate that the receptor-binding residues of parasite ligands that bind sialic acid on glycophorin A for invasion as well as complement receptor-1 and chondroitin sulfate A for cytoadherence map to central regions of DBL domains. In contrast, binding to intercellular adhesion molecule 1 (ICAM-1) requires both the central and terminal regions of DBLβC2 domains. Determination of functional regions within DBL domains is the first step toward understanding the structure-function bases for their interaction with diverse host receptors.

Plasmodium falciparum erythrocyte membrane protein 1 functions as a ligand for P-selectin

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 3132-3135 ◽  
Author(s):  
Anna M. Senczuk ◽  
John C. Reeder ◽  
Magda M. Kosmala ◽  
May Ho
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Protein ◽  
Erythrocyte Membrane ◽  
Adhesion Molecule ◽  
Affinity Purification ◽  
Intercellular Adhesion Molecule ◽  
Microvascular Endothelium ◽  
Parasite Protein ◽  
Erythrocyte Membrane Protein ◽  
Falciparum Erythrocyte Membrane Protein

Abstract The malarial protein Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a parasite protein that is exported to the surface of the infected erythrocyte, where it is inserted into the red cell cytoskeleton in the second half of the parasite life cycle. The surface expression of PfEMP1 coincides with the occurrence of the adhesion of infected erythrocytes to vascular endothelium. This protein has been shown to interact with CD36, intercellular adhesion molecule-1 (ICAM-1) and chondroitin sulfate A (CSA). In this study, it is demonstrated by affinity purification and western blot analysis that PfEMP1 also functions as a cell surface ligand for P-selectin, an adhesion molecule that has been shown to mediate the rolling of infected erythrocytes under physiologic flow conditions, leading to a significant increase in adhesion to CD36 on activated platelets and microvascular endothelium.

scholarly journals Knob-independent cytoadherence of Plasmodium falciparum to the leukocyte differentiation antigen CD36.

1990 ◽  
Vol 171 (6) ◽  
pp. 1883-1892 ◽  
Author(s):  
B A Biggs ◽  
L Goozé ◽  
K Wycherley ◽  
D Wilkinson ◽  
A W Boyd ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Peripheral Circulation ◽  
Melanoma Cells ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Differentiation Antigen ◽  
Erythrocyte Surface ◽  
Falciparum Erythrocyte Membrane Protein

The survival of Plasmodium falciparum-infected erythrocytes is enhanced by the sequestration of mature trophozoites and schizonts from the peripheral circulation. Cytoadherence of infected erythrocytes in vivo is associated with the presence of knobs on the erythrocyte surface, but we and others have shown recently that cytoadherence to C32 melanoma cells may occur in vitro in the absence of knobs. We show here that a knobless clone of P. falciparum adheres to the leukocyte differentiation antigen, CD36, suggesting that binding to CD36 is independent of the presence of knobs on the surface of the infected erythrocyte. This clone showed little cytoadherence to immobilized thrombospondin or to endothelial cells expressing the intercellular adhesion molecule 1. Furthermore, an Mr approximately 300-kD trypsin-sensitive protein doublet was immunoprecipitated from knobless trophozoite-infected erythrocytes. Finding a P. falciparum erythrocyte membrane protein 1 (PfEMP1)-like molecule on these infected erythrocytes is consistent with a role for PfEMP1 in cytoadherence to CD36 and C32 melanoma cells.

scholarly journals Biological and Biochemical Characteristics of Cytoadhesion of Plasmodium falciparum-Infected Erythrocytes to Chondroitin-4-Sulfate

1998 ◽  
Vol 66 (10) ◽  
pp. 4950-4956 ◽  
Author(s):  
Bruno Pouvelle ◽  
Thierry Fusaï ◽  
Catherine Lépolard ◽  
Jürg Gysin
Keyword(s):  
Endothelial Cells ◽  
Plasmodium Falciparum ◽  
Minimum Size ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Prevalence Studies ◽  
Acidic Conditions ◽  
Different Strains ◽  
Selection Of

ABSTRACT The cytoadhesion of Plasmodium falciparum laboratory strains and clones to Saimiri brain microvascular endothelial cells (SBEC 17), with chondroitin-4-sulfate (CSA) as the only adhesion receptor, was tested. Only one strain had significant cytoadhesion. However, CSA-specific infected erythrocytes (IRBCs) were detected in all strains after selection of a CSA-specific subpopulation by culturing the few adherent IRBCs. This demonstrates the lack of sensitivity of cytoadhesion microassays for detecting small quantities of CSA-specific IRBCs in cultures or field isolates. Cytoadhesion to CSA is maximal at 24 h of the cycle and decreases with the onset of schizogony, reaching a minimum just before reinvasion. This fluctuation must be taken into account in comparisons of the cytoadhesion of different strains or isolates. The minimum size of CSA for active inhibition was 4 kDa, and a mass of 9 kDa was required for inhibition similar to that obtained with the 50-kDa CSA. In contrast to cytoadhesion to CSA, which is pH independent or maximal at physiological pH (depending on the target endothelial cells), adhesion to CD36 and intercellular adhesion molecule 1 was pH dependent, requiring acidic conditions to be maximal in all cases. Cytoadhesion to CSA may trigger the occlusion of microvessels and cause the acidosis necessary for the other receptors to be fully efficient. If this key role in the mechanisms of sequestration were to be confirmed in vivo, prevalence studies of the CSA cytoadhesion phenotype would have to be reevaluated, because simple cytoadhesion assays do not detect CSA-specific parasites present in very low numbers, and these parasites might then be undetected in the peripheral blood but present in organs in which sequestration occurs, such as the placenta (M. Fried and P. E. Duffy, Science 272:1502–1504, 1996).

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

2013 ◽  
Vol 42 (4) ◽  
pp. 2270-2281 ◽  
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.

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