CD44 cross-linking promotes Plasmodium falciparum invasion.

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.