CD44 cross-linking promotes Plasmodium falciparum invasion

Kongsomboonvech, AK; Scally, SW; Le Guen, Y; Valissery, P; Salinas, ND; Cowman, AF; Tolia, NH; Egan, ES

Author(s): Kongsomboonvech, AK; Scally, SW; Le Guen, Y; Valissery, P; Salinas, ND; Cowman, AF; Tolia, NH; Egan, ES;
Details: Publication Year 2025-12-07,Volume 17,Issue #1,Page 319
Journal Title: Nature Communications
Publication Type: Dec 7
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.
Publisher: Springer Nature
Keywords: *Plasmodium falciparum/pathogenicity/metabolism/physiology; *Hyaluronan Receptors/metabolism/immunology; Humans; *Erythrocytes/parasitology/metabolism; Protozoan Proteins/metabolism; Basigin/metabolism; Antigens, Protozoan/metabolism; *Malaria, Falciparum/parasitology/metabolism/immunology; Host-Parasite Interactions; Antibodies, Monoclonal/pharmacology/immunology; Phosphorylation; Erythrocyte Membrane/metabolism/parasitology; Cross-Linking Reagents; Carrier Proteins
Research Division(s): Infection and Global Health
PubMed ID: 41354647
Publisher's Version: https://doi.org/10.1038/s41467-025-67030-x
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-67030-x
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-29 01:41:41

Last Modified: 2026-01-29 01:42:34