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Plasmodium falciparum is a human-adapted apicomplexan parasite that causes the most dangerous form of malaria. P. falciparum cysteine-rich protective antigen (PfCyRPA) is an invasion complex protein essential for erythrocyte invasion. The precise role of PfCyRPA in this process has not been resolved. Here, we show that PfCyRPA is a lectin targeting glycans terminating with α2-6-linked N-acetylneuraminic acid (Neu5Ac). PfCyRPA has a >50-fold binding preference for human, α2-6-linked Neu5Ac over non-human, α2-6-linked N-glycolylneuraminic acid. PfCyRPA lectin sites were predicted by molecular modeling and validated by mutagenesis studies. Transgenic parasite lines expressing endogenous PfCyRPA with single amino acid exchange mutants indicated that the lectin activity of PfCyRPA has an important role in parasite invasion. Blocking PfCyRPA lectin activity with small molecules or with lectin-site-specific monoclonal antibodies can inhibit blood-stage parasite multiplication. Therefore, targeting PfCyRPA lectin activity with drugs, immunotherapy, or a vaccine-primed immune response is a promising strategy to prevent and treat malaria.

Competing Interests: Declaration of interests C.J.D., M.P.J., and G.P. are inventors on a patent related to this publication.

Titel:	The essential malaria protein PfCyRPA targets glycans to invade erythrocytes.
Autor/in / Beteiligte Person:	Day, CJ ; Favuzza, P ; Bielfeld, S ; Haselhorst, T ; Seefeldt, L ; Hauser, J ; Shewell, LK ; Flueck, C ; Poole, J ; Jen, FE ; Schäfer, A ; Dangy, JP ; Gilberger, TW ; França, CT ; Duraisingh, MT ; Tamborrini, M ; Brancucci, NMB ; Grüring, C ; Filarsky, M ; Jennings, MP ; Pluschke, G
Zeitschrift:	Cell reports, Jg. 43 (2024-04-23), Heft 4, S. 114012
Veröffentlichung:	[Cambridge, MA] : Cell Press, c 2012-, 2024
Medientyp:	academicJournal
ISSN:	2211-1247 (electronic)
DOI:	10.1016/j.celrep.2024.114012
Schlagwort:	Humans Antigens, Protozoan metabolism Antigens, Protozoan immunology Antigens, Protozoan genetics Lectins metabolism Lectins genetics Malaria, Falciparum parasitology Protein Binding Erythrocytes parasitology Erythrocytes metabolism Plasmodium falciparum metabolism Polysaccharides metabolism Protozoan Proteins metabolism Protozoan Proteins genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural Language: English [Cell Rep] 2024 Apr 23; Vol. 43 (4), pp. 114012. <i>Date of Electronic Publication: </i>2024 Apr 03. MeSH Terms: Erythrocytes* / parasitology ; Erythrocytes* / metabolism ; Plasmodium falciparum* / metabolism ; Polysaccharides* / metabolism ; Protozoan Proteins* / metabolism ; Protozoan Proteins* / genetics ; Humans ; Antigens, Protozoan / metabolism ; Antigens, Protozoan / immunology ; Antigens, Protozoan / genetics ; Lectins / metabolism ; Lectins / genetics ; Malaria, Falciparum / parasitology ; Protein Binding Contributed Indexing: Keywords: CP: Microbiology; N-acetylneuraminic acid; Plasmodium falciparum cysteine-rich protective antigen; erythrocyte invasion; glycan array; lectin; malaria Substance Nomenclature: 0 (Antigens, Protozoan) ; 0 (Lectins) ; 0 (Polysaccharides) ; 0 (Protozoan Proteins) Entry Date(s): Date Created: 20240404 Date Completed: 20240426 Latest Revision: 20240510 Update Code: 20240510

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The essential malaria protein PfCyRPA targets glycans to invade erythrocytes.