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Cryo-EM reveals the...
Cryo-EM reveals the conformational epitope of human monoclonal antibody PAM1.4 broadly reacting with polymorphic malarial protein VAR2CSA
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- Raghavan, Sai Sundar Rajan (author)
- University of Copenhagen,Copenhagen University Hospital
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- Dagil, Robert (author)
- Copenhagen University Hospital,University of Copenhagen
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- Lopez-Perez, Mary (author)
- University of Copenhagen,Copenhagen University Hospital
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- Conrad, Julian (author)
- Science for Life Laboratory (SciLifeLab)
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- Bassi, Maria Rosaria (author)
- University of Copenhagen,Copenhagen University Hospital
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- del Pilar Quintana, Maria (author)
- Copenhagen University Hospital,University of Copenhagen
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- Choudhary, Swati (author)
- University of Copenhagen,Copenhagen University Hospital
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- Gustavsson, Tobias (author)
- Copenhagen University Hospital,University of Copenhagen
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- Wang, Yong (author)
- University of Edinburgh,Zhejiang University
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- Gourdon, Pontus (author)
- Lund University,Lunds universitet,Membranproteinstrukturbiologi,Forskargrupper vid Lunds universitet,Membrane Protein Structural Biology,Lund University Research Groups,University of Copenhagen
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- Ofori, Michael Fokuo (author)
- University of Ghana
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- Christensen, Sebastian Boje (author)
- Copenhagen University Hospital,University of Copenhagen
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- Minja, Daniel Thomas Remias (author)
- National Institute for Medical Research Tanga
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- Schmiegelow, Christentze (author)
- University of Copenhagen,Copenhagen University Hospital
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- Nielsen, Morten Agertoug (author)
- University of Copenhagen,Copenhagen University Hospital
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- Barfod, Lea (author)
- University of Copenhagen,Copenhagen University Hospital
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- Hviid, Lars (author)
- Copenhagen University Hospital,University of Copenhagen
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- Salanti, Ali (author)
- University of Copenhagen,Copenhagen University Hospital
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- Lavstsen, Thomas (author)
- University of Copenhagen,Copenhagen University Hospital
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- Wang, Kaituo (author)
- University of Copenhagen
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(creator_code:org_t)
- 2022-11-16
- 2022
- English.
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 18:11
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http://dx.doi.org/10... (free)
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
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Raghavan, Sai Su ...
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Dagil, Robert
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Lopez-Perez, Mar ...
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Conrad, Julian
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Bassi, Maria Ros ...
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del Pilar Quinta ...
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Choudhary, Swati
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Gustavsson, Tobi ...
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Wang, Yong
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Gourdon, Pontus
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Ofori, Michael F ...
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Christensen, Seb ...
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Minja, Daniel Th ...
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Schmiegelow, Chr ...
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Nielsen, Morten ...
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Barfod, Lea
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Hviid, Lars
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Salanti, Ali
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Lavstsen, Thomas
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Wang, Kaituo
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
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PLoS Pathogens
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Lund University