{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:26:37Z","timestamp":1785432397015,"version":"3.56.0"},"posted":{"date-parts":[[2025,7,30]]},"group-title":"Microbiology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL166249"],"award-info":[{"award-number":["R01HL166249"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00knt4f32","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/02nw48b86","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The ability of the malaria parasite\n                  <jats:italic>Plasmodium falciparum<\/jats:italic>\n                  to invade and replicate asexually within human red blood cells (RBCs) is central to its pathogenicity, accounting for hundreds of thousands of deaths each year. RBC invasion is a multi-step process involving several host-parasite interactions, yet the host factors acting during invasion remain underexplored, largely due to the intractability of mature enucleated RBCs. The transmembrane protein CD44 was identified as a host factor for\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  invasion through a forward genetic screen using genetically modified RBCs derived from primary human hematopoietic stem cells. Here, we identify an anti-CD44 monoclonal antibody, BRIC 222, that significantly promotes\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  invasion, and demonstrate that its effect is mediated 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\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  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 downstream ligand-receptor interactions and to promote signaling to the host cell cytoskeleton, making RBCs more permissive to\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  invasion.\n                <\/jats:p>","DOI":"10.1101\/2025.07.30.667750","type":"posted-content","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T05:20:12Z","timestamp":1753939212000},"source":"Crossref","is-referenced-by-count":0,"title":["CD44 cross-linking promotes\n                  <i>Plasmodium falciparum<\/i>\n                  invasion"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2599-131X","authenticated-orcid":false,"given":"Angel K.","family":"Kongsomboonvech","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4264-7772","authenticated-orcid":false,"given":"Stephen W.","family":"Scally","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6649-8364","authenticated-orcid":false,"given":"Yann","family":"Le Guen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveesh","family":"Valissery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4105-3718","authenticated-orcid":false,"given":"Nichole D.","family":"Salinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5145-9004","authenticated-orcid":false,"given":"Alan F.","family":"Cowman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2689-1337","authenticated-orcid":false,"given":"Niraj H.","family":"Tolia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2112-7700","authenticated-orcid":false,"given":"Elizabeth S.","family":"Egan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025080113150962000_2025.07.30.667750v1.1","unstructured":"World Malaria Report 2023. 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