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Published on: June 13, 2021
The essential malaria protein PfCyRPA targets glycans to invade erythrocytes
Christopher J Day1, Paola Favuzza2, Sabrina Bielfeld3
1Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
Abstract:
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.
Insights
Plasmodium falciparum cysteine-rich protective antigen (PfCyRPA) is a lectin that binds to specific human cell surface sugars. Targeting this lectin activity offers a new strategy against malaria.
Area of Science:
- Parasitology
- Molecular Biology
- Immunology
Background:
- Plasmodium falciparum causes severe malaria.
- PfCyRPA is crucial for erythrocyte invasion but its role is unclear.
Purpose of the Study:
- To elucidate the function of PfCyRPA in malaria parasite invasion.
- To investigate PfCyRPA as a potential therapeutic target.
Main Methods:
- Molecular modeling to predict PfCyRPA lectin sites.
- Mutagenesis studies to validate binding sites.
- Development of transgenic parasite lines for functional analysis.
Main Results:
- PfCyRPA functions as a lectin, specifically binding α2-6-linked N-acetylneuraminic acid (Neu5Ac).
- Demonstrated a >50-fold preference for human Neu5Ac over non-human forms.
- Mutant PfCyRPA lacking lectin activity impaired parasite invasion.
- Inhibition of PfCyRPA lectin activity reduced parasite multiplication.
Conclusions:
- PfCyRPA's lectin activity is essential for Plasmodium falciparum invasion.
- Targeting PfCyRPA lectin activity presents a promising strategy for malaria treatment and prevention.
- Potential for drug development, immunotherapy, and vaccines targeting PfCyRPA.
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