CD44 cross-linking promotes Plasmodium falciparum invasion

Area of Science:

• Cell Biology
• Parasitology
• Immunology

Background:

• Plasmodium falciparum invasion of human red blood cells (RBCs) is critical for malaria pathogenesis.
• Host factors mediating RBC invasion are underexplored due to the difficulty of studying mature RBCs.
• CD44 was previously identified as a host factor for P. falciparum invasion.

Purpose of the Study:

• To investigate the role of CD44 in P. falciparum invasion.
• To identify mechanisms by which CD44 influences RBC permissiveness to parasite invasion.

Main Methods:

• Utilized a forward genetic screen with genetically modified human RBCs.
• Employed an anti-CD44 monoclonal antibody (BRIC 222) to induce CD44 cross-linking.
• Analyzed changes in RBC protein phosphorylation, membrane accessibility, and ligand-receptor binding.

Main Results:

• BRIC 222 significantly promoted P. falciparum invasion through CD44 cross-linking.
• CD44 cross-linking altered RBC cytoskeletal protein phosphorylation and increased surface protein accessibility, including Basigin.
• The parasite ligand Erythrocyte Binding Antigen-175 (EBA-175) mimicked BRIC 222 effects and enhanced invasion.
• Both BRIC 222 and EBA-175 increased binding of the PfRH5/PCRCR complex to Basigin.

Conclusions:

• CD44 cross-linking enhances P. falciparum invasion by modulating RBC membrane properties and facilitating key invasion complex interactions.
• EBA-175 may trigger CD44-mediated signaling pathways that increase RBC permissiveness to invasion.
• CD44 acts as a co-receptor, coordinating downstream events crucial for malaria parasite entry.