TY - JOUR

T1 - Cryo-EM reveals the conformational epitope of human monoclonal antibody PAM1.4 broadly reacting with polymorphic malarial protein VAR2CSA

AU - Raghavan, Sai Sundar Rajan

AU - Dagil, Robert

AU - Lopez-Perez, Mary

AU - Conrad, Julian

AU - Bassi, Maria Rosaria

AU - Quintana, Maria Del Pilar

AU - Choudhary, Swati

AU - Gustavsson, Tobias

AU - Wang, Yong

AU - Gourdon, Pontus

AU - Ofori, Michael Fokuo

AU - Christensen, Sebastian Boje

AU - Minja, Daniel Thomas Remias

AU - Schmiegelow, Christentze

AU - Nielsen, Morten Agertoug

AU - Barfod, Lea

AU - Hviid, Lars

AU - Salanti, Ali

AU - Lavstsen, Thomas

AU - Wang, Kaituo

N1 - Copyright: © 2022 Raghavan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2022

Y1 - 2022

N2 - Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. Immunity to placental malaria is acquired through exposure and mediated through antibodies to VAR2CSA. Through evolution, the VAR2CSA proteins have diversified in sequence to escape immune recognition but retained their overall macromolecular structure to maintain CS binding affinity. This structural conservation may also have allowed development of broadly reactive antibodies to VAR2CSA in immune women. Here we show the negative stain and cryo-EM structure of the only known broadly reactive human monoclonal antibody, PAM1.4, in complex with VAR2CSA. The data shows how PAM1.4's broad VAR2CSA reactivity is achieved through interactions with multiple conserved residues of different sub-domains forming conformational epitope distant from the CS binding site on the VAR2CSA core structure. Thus, while PAM1.4 may represent a class of antibodies mediating placental malaria immunity by inducing phagocytosis or NK cell-mediated cytotoxicity, it is likely that broadly CS binding-inhibitory antibodies target other epitopes at the CS binding site. Insights on both types of broadly reactive monoclonal antibodies may aid the development of a vaccine against placental malaria.

AB - Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. Immunity to placental malaria is acquired through exposure and mediated through antibodies to VAR2CSA. Through evolution, the VAR2CSA proteins have diversified in sequence to escape immune recognition but retained their overall macromolecular structure to maintain CS binding affinity. This structural conservation may also have allowed development of broadly reactive antibodies to VAR2CSA in immune women. Here we show the negative stain and cryo-EM structure of the only known broadly reactive human monoclonal antibody, PAM1.4, in complex with VAR2CSA. The data shows how PAM1.4's broad VAR2CSA reactivity is achieved through interactions with multiple conserved residues of different sub-domains forming conformational epitope distant from the CS binding site on the VAR2CSA core structure. Thus, while PAM1.4 may represent a class of antibodies mediating placental malaria immunity by inducing phagocytosis or NK cell-mediated cytotoxicity, it is likely that broadly CS binding-inhibitory antibodies target other epitopes at the CS binding site. Insights on both types of broadly reactive monoclonal antibodies may aid the development of a vaccine against placental malaria.

KW - Humans

KW - Female

KW - Pregnancy

KW - Antigens, Protozoan

KW - Malaria, Falciparum/parasitology

KW - Epitopes

KW - Antibodies, Protozoan

KW - Antibodies, Monoclonal

KW - Cryoelectron Microscopy

KW - Placenta/metabolism

KW - Plasmodium falciparum/metabolism

KW - Erythrocytes/parasitology

KW - Malaria

KW - Chondroitin Sulfates/metabolism

U2 - 10.1371/journal.ppat.1010924

DO - 10.1371/journal.ppat.1010924

M3 - Journal article

C2 - 36383559

VL - 18

JO - P L o S Pathogens (Online)

JF - P L o S Pathogens (Online)

SN - 1553-7374

IS - 11

M1 - e1010924

ER -