The essential malaria protein PfCyRPA targets glycans to invade erythrocytes
Christopher J. Day,
Paola Favuzza,
Sabrina Bielfeld,
Thomas Haselhorst,
Leonie Seefeldt,
Julia Hauser,
Lucy K. Shewell,
Christian Flueck,
Jessica Poole,
Freda E.-C. Jen,
Anja Schäfer,
Jean-Pierre Dangy,
Tim-W. Gilberger,
Camila Tenorio França,
Manoj T. Duraisingh,
Marco Tamborrini,
Nicolas M.B. Brancucci,
Christof Grüring,
Michael Filarsky,
Michael P. Jennings,
Gerd Pluschke
Affiliations
Christopher J. Day
Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
Paola Favuzza
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
Sabrina Bielfeld
Centre for Structural Systems Biology (CSSB), Hamburg, Germany; Department of Biology, University of Hamburg, Hamburg, Germany
Thomas Haselhorst
Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
Leonie Seefeldt
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
Julia Hauser
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
Lucy K. Shewell
Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
Christian Flueck
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
Jessica Poole
Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
Freda E.-C. Jen
Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
Anja Schäfer
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
Jean-Pierre Dangy
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
Tim-W. Gilberger
Centre for Structural Systems Biology (CSSB), Hamburg, Germany; Department of Biology, University of Hamburg, Hamburg, Germany; Department of Cellular Parasitology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
Camila Tenorio França
Department of Immunology & Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA
Manoj T. Duraisingh
Department of Immunology & Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA
Marco Tamborrini
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
Nicolas M.B. Brancucci
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
Christof Grüring
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
Michael Filarsky
Centre for Structural Systems Biology (CSSB), Hamburg, Germany; Department of Biology, University of Hamburg, Hamburg, Germany
Michael P. Jennings
Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia; Corresponding author
Gerd Pluschke
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland; Corresponding author
Summary: 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.
