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<p>The ability of <i>Plasmodium falciparum</i> 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 <i>P. falciparum</i> invasion through a novel forward genetic screen. Here, we identify an anti-CD44 monoclonal antibody, BRIC 222, that significantly promotes <i>P. falciparum</i> 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 <i>P. falciparum</i> 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 <i>P. falciparum</i> invasion.</p>

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CD44 cross-linking promotes Plasmodium falciparum invasion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月7日

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  • Angel K. Kongsomboonvech,
  • Stephen W. Scally,
  • Yann Le Guen,
  • Praveesh Valissery,
  • Nichole D. Salinas,
  • Alan F. Cowman,
  • Niraj H. Tolia,
  • Elizabeth S. Egan

摘要

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.