Complement C1s cleaves PfEMP1 at interdomain conserved sites inhibiting Plasmodium falciparum cytoadherence
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Complement C1s cleaves PfEMP1 at interdomain conserved sites inhibiting Plasmodium falciparum cytoadherence. / Azasi, Yvonne; Low, Leanne M.; Just, Ashley N.; Raghavan, Sai S.R.; Wang, Christian W.; Valenzuela-Leon, Paola; Alexandra Rowe, J.; Smith, Joseph D.; Lavstsen, Thomas; Turner, Louise; Calvo, Eric; Miller, Louis H.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 22, e2104166118, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Complement C1s cleaves PfEMP1 at interdomain conserved sites inhibiting Plasmodium falciparum cytoadherence
AU - Azasi, Yvonne
AU - Low, Leanne M.
AU - Just, Ashley N.
AU - Raghavan, Sai S.R.
AU - Wang, Christian W.
AU - Valenzuela-Leon, Paola
AU - Alexandra Rowe, J.
AU - Smith, Joseph D.
AU - Lavstsen, Thomas
AU - Turner, Louise
AU - Calvo, Eric
AU - Miller, Louis H.
N1 - Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - C1s
KW - Cytoadhesion
KW - EPCR
KW - Malaria
KW - PfEMP1
U2 - 10.1073/pnas.2104166118
DO - 10.1073/pnas.2104166118
M3 - Journal article
C2 - 34035177
AN - SCOPUS:85106928926
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 22
M1 - e2104166118
ER -
ID: 272068191