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Plasmodium falciparum exploits CD44 as a coreceptor for erythrocyte invasion
Barbara Baro1, Chi Yong Kim1, Carrie Lin1
1Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
Abstract:
The malaria parasite Plasmodium falciparum invades and replicates asexually within human erythrocytes. CD44 expressed on erythrocytes was previously identified as an important host factor for P falciparum infection through a forward genetic screen, but little is known about its regulation or function in these cells, nor how it may be used by the parasite. We found that CD44 can be efficiently deleted from primary human hematopoietic stem cells using CRISPR/Cas9 genome editing, and that the efficiency of ex vivo erythropoiesis to enucleated cultured red blood cells (cRBCs) is not affected by lack of CD44. However, the rate of P falciparum invasion was reduced in CD44-null cRBCs relative to isogenic wild-type control cells, validating CD44 as an important host factor for this parasite. We identified 2 P falciparum invasion ligands as binding partners for CD44, erythrocyte binding antigen 175 (EBA-175) and EBA-140 and demonstrated that their ability to bind to human erythrocytes relies primarily on their canonical receptors, glycophorin A and glycophorin C, respectively. We further show that EBA-175 induces phosphorylation of erythrocyte cytoskeletal proteins in a CD44-dependent manner. Our findings support a model in which P falciparum exploits CD44 as a coreceptor during invasion of human erythrocytes, stimulating CD44-dependent phosphorylation of host cytoskeletal proteins that alter host cell deformability and facilitate parasite entry.
Insights
Malaria parasite Plasmodium falciparum uses CD44 on red blood cells as a co-receptor for invasion. This interaction, involving EBA-175 and EBA-140 ligands, alters red blood cell structure to facilitate parasite entry.
Area of Science:
- Cell biology
- Parasitology
- Immunology
Background:
- Plasmodium falciparum infects human red blood cells, utilizing host factors for invasion.
- CD44 was previously identified as a potential host factor for malaria parasite infection.
- The precise role and regulation of CD44 in erythrocytes during parasite invasion remain unclear.
Purpose of the Study:
- To investigate the function of CD44 in human erythrocytes during Plasmodium falciparum invasion.
- To identify Plasmodium falciparum invasion ligands that interact with CD44.
- To elucidate the mechanism by which CD44 facilitates parasite entry.
Main Methods:
- CRISPR/Cas9 genome editing to delete CD44 in hematopoietic stem cells.
- Ex vivo erythropoiesis to generate CD44-null and wild-type cultured red blood cells (cRBCs).
- Assays to measure Plasmodium falciparum invasion rates and identify ligand-receptor interactions (EBA-175, EBA-140 with CD44, glycophorin A, glycophorin C).
- Analysis of CD44-dependent phosphorylation of erythrocyte cytoskeletal proteins.
Main Results:
- CD44 deletion did not affect erythropoiesis but significantly reduced Plasmodium falciparum invasion rates in cRBCs.
- Erythrocyte binding antigen 175 (EBA-175) and EBA-140 were identified as CD44 binding partners.
- EBA-175 binding to erythrocytes is primarily mediated by glycophorin A, while EBA-140 binds to glycophorin C.
- EBA-175 induced CD44-dependent phosphorylation of erythrocyte cytoskeletal proteins, altering cell deformability.
Conclusions:
- CD44 acts as a crucial co-receptor for Plasmodium falciparum invasion of human erythrocytes.
- The parasite utilizes CD44 to modulate host cell properties, facilitating entry.
- This study reveals a novel mechanism of malaria parasite invasion involving CD44 and erythrocyte cytoskeletal dynamics.
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