Receptor and Ligand Domains for Invasion of Erythrocytes by
            <i>Plasmodium falciparum</i>

Sim, B. Kim Lee; Chitnis, Chetan E.; Waśniowska, Kazimiera; Hadley, Terence J.; Miller, Louis H.

doi:10.1126/science.8009226

Cited by 534 publications

(497 citation statements)

References 21 publications

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“…3). As a further control for effective trypsin treatment, we demonstrated that trypsin-treated Kx null erythrocytes failed to bind to EBA-175 (data not shown), a parasite ligand for trypsin-sensitive glycophorin A (12).…”

Section: Resultsmentioning

confidence: 99%

Domain III of Plasmodium falciparum apical membrane antigen 1 binds to the erythrocyte membrane protein Kx

Kato

Mayer

Singh

et al. 2005

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

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Plasmodium falciparum apical membrane antigen 1 (AMA1) is located in the merozoite micronemes, an organelle that contains receptors for invasion, suggesting that AMA1 may play a role in this process. However, direct evidence that P. falciparum AMA1 binds to human erythrocytes is lacking. In this study, we determined that domain III of AMA1 binds to the erythrocyte membrane protein, Kx, and that the rate of invasion of Kx null erythrocytes is reduced, indicating a significant but not unique role of AMA1 and Kx in parasite invasion of erythrocytes. Domains I͞II͞III, domains I͞II and domain III of AMA1 were expressed on the surface of CHO-K1 cells, and their ability to bind erythrocytes was determined. We observed that each of these domains failed to bind untreated human erythrocytes. In contrast, domain III, but not the other domains of AMA1, bound to trypsin-treated human erythrocytes. We tested the binding of AMA1 to trypsin-treated genetically mutant human erythrocytes, missing various erythrocyte membrane proteins. AMA1 failed to bind trypsin-treated Kx null (McLeod) erythrocytes, which lack the Kx protein. Furthermore, treatmentofhumanerythrocyteswithtrypsin,followedby␣-chymotrypsin, cleaved Kx and destroyed the binding of AMA1 to human erythrocytes. Lastly, the rate of invasion of Kx null erythrocytes by P. falciparum was significantly lower than Kx-expressing erythrocytes. Taken together, our data suggest that AMA1 plays an important, but not exclusive, role in invasion of human erythrocytes through a process that involves exposure or modification of the erythrocyte surface protein, Kx, by a trypsin-like enzyme. T he complex multistep process of invasion of erythrocytes byPlasmodium falciparum begins with the binding of any surface of the merozoite, followed by reorientation to put the merozoite's apical end in close apposition to the erythrocyte surface. The apical end of merozoites contains the organelles of invasion, including the micronemes that contain receptors such as members of the Duffy binding protein family of erythrocytebinding ligands (1). A junction forms between P. knowlesi merozoites and the erythrocyte before the merozoite is brought into the erythrocyte. The junction only forms and invasion only occurs between P. knowlesi merozoites and Duffy blood group positive human erythrocytes. Duffy null cells fail to form a junction and are not invaded by P. knowlesi merozoites (2). However, trypsin-or neuraminidase-treated human Duffy null erythrocytes could form a junction and were invaded by P. knowlesi merozoites (3) despite the fact that untreated and trypsin-treated human Duffy null cells fail to bind any of the P. knowlesi Duffy binding proteins expressed on COS-7 cells (2). This result indicates that molecules other than the parasite Duffy binding protein family are exposed by enzyme treatment to form the junction between Duffy negative human erythrocytes and P. knowlesi merozoites. One of the possible junction-forming molecules is apical merozoite antigen 1 (AMA1), which is found in the mic...

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Section: Resultsmentioning

confidence: 99%

Domain III of Plasmodium falciparum apical membrane antigen 1 binds to the erythrocyte membrane protein Kx

Kato

Mayer

Singh

et al. 2005

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

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“…The prototypic member of this family, P. falciparum EBA-175, was first identified as a soluble protein which appeared in in vitro culture supernatants after merozoite release and was shown to bind specifically to erythrocytes (Camus and Hadley, 1985). All the DBL-EBPs initially sequester in micronemes in the form of type I integral membrane proteins, probably mediate their function at invasion in a membrane-bound form at the parasite surface (Sim et al, 1994;Reed et al, 2000;Mayer et al, 2001;Duraisingh et al, 2003a;Maier et al, 2003), and are then shed via proteolytic cleavage to produce the soluble forms which accumulate extracellularly (Adams et al, 1990;Orlandi et al, 1990). Shedding of DBL-EBP and other ZSPs with an adhesive role may be integral to their function, constituting a means of ultimately removing them to allow the completion of invasion once they have performed their adhesive task in the invasion pathway.…”

Section: Why Shed?mentioning

confidence: 99%

A new release on life: emerging concepts in proteolysis and parasite invasion

Carruthers

Blackman²

2005

Molecular Microbiology

104

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SummaryCell invasion by apicomplexan pathogens such as the malaria parasite and Toxoplasma is accompanied by extensive proteolysis of zoite surface proteins (ZSPs) required for attachment and penetration. Although there is still little known about the proteases involved, a conceptual framework is emerging for the roles of proteolysis in cell invasion. Primary processing of ZSPs, which includes the trimming of terminal peptides or segmentation into multiple fragments, is proposed to activate these adhesive ligands for tight binding to host receptors. Secondary processing, which occurs during penetration, results in the shedding of ZSPs by one of two mechanistically distinct ways, shaving or capping. Resident surface proteins are typically shaved from the surface whereas adhesive ligands mobilized from intracellular secretory vesicles are capped to the posterior end of the parasite before being shed during the final steps of penetration. Intriguingly, recent studies have revealed that ZSPs can be released either by being cleaved adjacent to the membrane anchor or actually within the membrane itself. Mounting evidence suggests that intramembrane cleavage is catalysed by one or more integral membrane serine proteases of the Rhomboid family and we propose that several malaria adhesive ligands may be potential substrates for these enzymes. We also discuss the evidence that the key reason for ZSP shedding during invasion is to break the connection between parasite surface ligands and host receptors. The sequential proteolytic events associated with invasion by pathogenic protozoa may represent vulnerable pathways for the future development of synergistic anti-protozoal therapies.

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“…Invasion phenotypes can be broadly classified into 2 main groups: (a) sialic acid-dependent (SA-dependent) invasion, demonstrated by poor invasion of neuraminidase-treated erythrocytes (neuraminidase cleaves SA on the erythrocyte surface); and (b) SA-independent invasion, demonstrated by efficient invasion of neuraminidasetreated erythrocytes. SA-dependent (neuraminidase-sensitive) invasion involves the 3 EBAs and PfRh1, with EBA175 probably being the most important (11,13,15,17,19,24,28,29). These ligands bind to SA on the erythrocyte surface.…”

Section: Introductionmentioning

confidence: 99%

“…These ligands bind to SA on the erythrocyte surface. EBA175 and EBA140 bind to glycophorin A (28)(29)(30) and C (13), respectively. EBA181 binds to SA on the erythrocyte surface and to band 4.1 protein (15,31).…”

Section: Introductionmentioning

confidence: 99%

Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies

Persson¹,

McCallum²,

Reiling³

et al. 2008

J. Clin. Invest.

169

228

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Antibodies that inhibit Plasmodium falciparum invasion of erythrocytes are believed to be an important component of immunity against malaria. During blood-stage infection, P. falciparum can use different pathways for erythrocyte invasion by varying the expression and/or utilization of members of 2 invasion ligand families: the erythrocyte-binding antigens (EBAs) and reticulocyte-binding homologs (PfRhs). Invasion pathways can be broadly classified into 2 groups based on the use of sialic acid (SA) on the erythrocyte surface by parasite ligands. We found that inhibitory antibodies are acquired by malaria-exposed Kenyan children and adults against ligands of SA-dependent and SA-independent invasion pathways, and the ability of antibodies to inhibit erythrocyte invasion depended on the pathway used by P. falciparum isolates. Differential inhibition of P. falciparum lines that varied in their use of specific EBA and PfRh proteins pointed to these ligand families as major targets of inhibitory antibodies. Antibodies against recombinant EBA and PfRh proteins were acquired in an age-associated manner, and inhibitory antibodies against EBA175 appeared prominent among some individuals. These findings suggest that variation in invasion phenotype might have evolved as a mechanism that facilitates immune evasion by P. falciparum and that a broad inhibitory response against multiple ligands may be required for effective immunity.

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Receptor and Ligand Domains for Invasion of Erythrocytes by Plasmodium falciparum

Cited by 534 publications

References 21 publications

Domain III of Plasmodium falciparum apical membrane antigen 1 binds to the erythrocyte membrane protein Kx

Domain III of Plasmodium falciparum apical membrane antigen 1 binds to the erythrocyte membrane protein Kx

A new release on life: emerging concepts in proteolysis and parasite invasion

Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies

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