Cryo-EM reveals the conformational epitope of human monoclonal antibody PAM1.4 broadly reacting with polymorphic malarial protein VAR2CSA
-
Published:2022-11-16
Issue:11
Volume:18
Page:e1010924
-
ISSN:1553-7374
-
Container-title:PLOS Pathogens
-
language:en
-
Short-container-title:PLoS Pathog
Author:
Raghavan Sai Sundar Rajan,
Dagil Robert,
Lopez-Perez Mary,
Conrad Julian,
Bassi Maria Rosaria,
Quintana Maria del Pilar,
Choudhary Swati,
Gustavsson Tobias,
Wang Yong,
Gourdon Pontus,
Ofori Michael Fokuo,
Christensen Sebastian Boje,
Minja Daniel Thomas Remias,
Schmiegelow Christentze,
Nielsen Morten Agertoug,
Barfod Lea,
Hviid Lars,
Salanti Ali,
Lavstsen Thomas,
Wang KaituoORCID
Abstract
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.
Funder
The Lundbeck Foundation
Independent Research Fund Denmark
Danida
National Institutes of Health
EU
Novo Nordisk Foundation
Novo Nordisk Fonden
Carlsberg Foundation
Global Health Innovative Technology Fund
European Union Advance-vac4PM
The Danish Council for Strategic Research
Publisher
Public Library of Science (PLoS)
Subject
Virology,Genetics,Molecular Biology,Immunology,Microbiology,Parasitology
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献