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Published on: January 3, 2012
CD44 cross-linking promotes Plasmodium falciparum invasion
Angel K Kongsomboonvech1, Stephen W Scally2, Yann Le Guen3
1Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Abstract:
The ability of Plasmodium falciparum to invade and replicate asexually within human red blood cells (RBCs) is central to its pathogenicity. Invasion involves several host-parasite interactions, yet the required host factors remain underexplored, largely due to the intractability of mature RBCs. The transmembrane protein CD44 was identified as a host factor for P. falciparum invasion through a novel forward genetic screen. Here, we identify an anti-CD44 monoclonal antibody, BRIC 222, that significantly promotes P. falciparum invasion through CD44 cross-linking. CD44 cross-linking induced changes in the phosphorylation of RBC cytoskeletal proteins, consistent with a proposed role for CD44 as a co-receptor during invasion. CD44 cross-linking also altered the RBC membrane, increasing the accessibility of several surface proteins, including the essential invasion receptor Basigin. The parasite ligand Erythrocyte Binding Antigen-175 (EBA-175), which interacts with CD44, enhanced P. falciparum invasion and induced RBC membrane changes similarly to BRIC 222. Moreover, both BRIC 222 and EBA-175 increased binding of the PfRH5/PCRCR invasion complex to Basigin, an interaction known to be essential for invasion. We propose that CD44 cross-linking, potentially by EBA-175, serves to coordinate and enhance ligand-receptor interactions and promote signaling to the host cell cytoskeleton, making RBCs more permissive to P. falciparum invasion.
Insights
The transmembrane protein CD44 acts as a co-receptor for Plasmodium falciparum invasion into red blood cells (RBCs). Cross-linking CD44 enhances parasite entry by altering RBC membranes and promoting key ligand-receptor interactions.
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.
