Complement C1s cleaves PfEMP1 at interdomain conserved sites inhibiting Plasmodium falciparum cytoadherence

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Cytoadhesion of Plasmodium falciparum-infected erythrocytes (IEs) to the endothelial lining of blood vessels protects parasites from splenic destruction, but also leads to detrimental inflammation and vessel occlusion. Surface display of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion ligands exposes them to host antibodies and serum proteins. PfEMP1 are important targets of acquired immunity to malaria, and through evolution, the protein family has expanded and diversified to bind a select set of host receptors through antigenically diversified receptor-binding domains. Here, we show that complement component 1s (C1s) in serum cleaves PfEMP1 at semiconserved arginine motifs located at interdomain regions between the receptor-binding domains, rendering the IE incapable of binding the two main PfEMP1 receptors, CD36 and endothelial protein C receptor (EPCR). Bioinformatic analyses of PfEMP1 protein sequences from 15 P. falciparum genomes found the C1s motif was present in most PfEMP1 variants. Prediction of C1s cleavage and loss of binding to endothelial receptors was further corroborated by testing of several different parasite lines. These observations suggest that the parasites have maintained susceptibility for cleavage by the serine protease, C1s, and provides evidence for a complex relationship between the complement system and the P. falciparum cytoadhesion virulence determinant.

OriginalsprogEngelsk
Artikelnummere2104166118
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind118
Udgave nummer22
ISSN0027-8424
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
We thank Drs. Michal Fried, Patrick Duffy, and Yai Doritchamou (NIAID, NIH) for the FCR3 parasites, FCR3VAR2CSA rat antibody, and CSA. We are also grateful to Drs. Lisa Renee Olano and Glenn Nardone of the Protein Chemistry Section, Research Technologies Branch, NIAID, NIH, for their assistance in proteomics analysis and to Dr. Anja TR Jensen (Department of Immunology and Microbiology, University of Copenhagen) for recombinant ICAM-1. We thank Dr. Michael P. Fay (NIAID, NIH) for his advice on statistical analysis. The study was supported by the Intramural Research Program of NIAID/NIH, Kirsten og Freddy Johansens Fond, L?ge Sofus Carl Emil Friis og hustru Olga Doris Friis Fond, The Lundbeck Foundation, The Independent Research Fund Denmark, and by funds from NIH Grant R01AI141602 (J.D.S.).

Funding Information:
ACKNOWLEDGMENTS. We thank Drs. Michal Fried, Patrick Duffy, and Yai Doritchamou (NIAID, NIH) for the FCR3 parasites, FCR3VAR2CSA rat antibody, and CSA. We are also grateful to Drs. Lisa Renee Olano and Glenn Nardone of the Protein Chemistry Section, Research Technologies Branch, NIAID, NIH, for their assistance in proteomics analysis and to Dr. Anja TR Jensen (Department of Immunology and Microbiology, University of Copenhagen) for recombinant ICAM-1. We thank Dr. Michael P. Fay (NIAID, NIH) for his advice on statistical analysis. The study was supported by the Intramural Research Program of NIAID/NIH, Kirsten og Freddy Johansens Fond, Læge Sofus Carl Emil Friis og hustru Olga Doris Friis Fond, The Lundbeck Foundation, The Independent Research Fund Denmark, and by funds from NIH Grant R01AI141602 (J.D.S.).

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© 2021 National Academy of Sciences. All rights reserved.

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