CD44 cross-linking promotes Plasmodium falciparum invasion

Area of Science:

• Cell Biology
• Parasitology
• Immunology

Background:

• Plasmodium falciparum (P. falciparum) invasion of human red blood cells (RBCs) is crucial for malaria pathogenesis.
• Host factors mediating P. falciparum invasion are not fully understood due to the difficulty in studying mature RBCs.

Purpose of the Study:

• To investigate the role of the transmembrane protein CD44 as a host factor in P. falciparum invasion.
• To explore how modulating CD44 function affects RBC permissiveness to parasite entry.

Main Methods:

• Utilized a novel forward genetic screen to identify host factors for P. falciparum invasion.
• Employed an anti-CD44 monoclonal antibody (BRIC 222) to induce CD44 cross-linking.
• Analyzed changes in RBC cytoskeletal protein phosphorylation and membrane accessibility of surface proteins.
• Investigated the interaction of parasite ligand Erythrocyte Binding Antigen-175 (EBA-175) with CD44 and its effect on invasion.

Main Results:

• Anti-CD44 antibody BRIC 222 significantly promoted P. falciparum invasion via CD44 cross-linking.
• CD44 cross-linking altered RBC membrane properties and increased accessibility of invasion receptors like Basigin.
• The parasite ligand EBA-175 also enhanced invasion and induced similar RBC membrane changes.
• Both BRIC 222 and EBA-175 increased the binding of the PfRH5/PCRCR invasion complex to Basigin.

Conclusions:

• CD44 functions as a co-receptor that facilitates P. falciparum invasion into RBCs.
• CD44 cross-linking, potentially mediated by EBA-175, enhances invasion by coordinating receptor interactions and signaling to the RBC cytoskeleton.
• These findings reveal a mechanism by which host cell modification promotes parasite entry, offering potential therapeutic targets.