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Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s

Antibody responses to variant surface antigens (VSAs) produced by the malaria parasite Plasmodium falciparum may contribute to age-related natural immunity to severe malaria. One VSA family, P. falciparum erythrocyte membrane protein-1 (PfEMP1), includes a subset of proteins that binds endothelial p...

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Autores principales: Tewey, Madison A., Coulibaly, Drissa, Lawton, Jonathan G., Stucke, Emily M., Zhou, Albert E., Berry, Andrea A., Bailey, Jason A., Pike, Andrew, Dara, Antoine, Ouattara, Amed, Lyke, Kirsten E., Ifeonu, Olukemi, Laurens, Matthew B., Adams, Matthew, Takala-Harrison, Shannon, Niangaly, Amadou, Kouriba, Bourema, Koné, Abdoulaye K., Rowe, J. Alexandra, Doumbo, Ogobara K., Patel, Jigar J., Tan, John C., Felgner, Philip L., Plowe, Christopher V., Thera, Mahamadou A., Travassos, Mark A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10597466/
https://www.ncbi.nlm.nih.gov/pubmed/37791774
http://dx.doi.org/10.1128/msphere.00451-23
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author Tewey, Madison A.
Coulibaly, Drissa
Lawton, Jonathan G.
Stucke, Emily M.
Zhou, Albert E.
Berry, Andrea A.
Bailey, Jason A.
Pike, Andrew
Dara, Antoine
Ouattara, Amed
Lyke, Kirsten E.
Ifeonu, Olukemi
Laurens, Matthew B.
Adams, Matthew
Takala-Harrison, Shannon
Niangaly, Amadou
Kouriba, Bourema
Koné, Abdoulaye K.
Rowe, J. Alexandra
Doumbo, Ogobara K.
Patel, Jigar J.
Tan, John C.
Felgner, Philip L.
Plowe, Christopher V.
Thera, Mahamadou A.
Travassos, Mark A.
author_facet Tewey, Madison A.
Coulibaly, Drissa
Lawton, Jonathan G.
Stucke, Emily M.
Zhou, Albert E.
Berry, Andrea A.
Bailey, Jason A.
Pike, Andrew
Dara, Antoine
Ouattara, Amed
Lyke, Kirsten E.
Ifeonu, Olukemi
Laurens, Matthew B.
Adams, Matthew
Takala-Harrison, Shannon
Niangaly, Amadou
Kouriba, Bourema
Koné, Abdoulaye K.
Rowe, J. Alexandra
Doumbo, Ogobara K.
Patel, Jigar J.
Tan, John C.
Felgner, Philip L.
Plowe, Christopher V.
Thera, Mahamadou A.
Travassos, Mark A.
author_sort Tewey, Madison A.
collection PubMed
description Antibody responses to variant surface antigens (VSAs) produced by the malaria parasite Plasmodium falciparum may contribute to age-related natural immunity to severe malaria. One VSA family, P. falciparum erythrocyte membrane protein-1 (PfEMP1), includes a subset of proteins that binds endothelial protein C receptor (EPCR) in human hosts and potentially disrupts the regulation of inflammatory responses, which may lead to the development of severe malaria. We probed peptide microarrays containing segments spanning five PfEMP1 EPCR-binding domain variants with sera from 10 Malian adults and 10 children to determine the differences between adult and pediatric immune responses. We defined serorecognized peptides and amino acid residues as those that elicited a significantly higher antibody response than malaria-naïve controls. We aimed to identify regions consistently serorecognized among adults but not among children across PfEMP1 variants, potentially indicating regions that drive the development of immunity to severe malaria. Adult sera consistently demonstrated broader and more intense serologic responses to constitutive PfEMP1 peptides than pediatric sera, including peptides in EPCR-binding domains. Both adults and children serorecognized a significantly higher proportion of EPCR-binding peptides than peptides that do not directly participate in receptor binding, indicating a preferential development of serologic responses at functional residues. Over the course of a single malaria transmission season, pediatric serological responses increased between the start and the peak of the season, but waned as the transmission season ended. IMPORTANCE: Severe malaria and death related to malaria disproportionately affect sub-Saharan children under 5 years of age, commonly manifesting as cerebral malaria and/or severe malarial anemia. In contrast, adults in malaria-endemic regions tend to experience asymptomatic or mild disease. Our findings indicate that natural immunity to malaria targets specific regions within the EPCR-binding domain, particularly peptides containing EPCR-binding residues. Epitopes containing these residues may be promising targets for vaccines or therapeutics directed against severe malaria. Our approach provides insight into the development of natural immunity to a binding target linked to severe malaria by characterizing an “adult-like” response as recognizing a proportion of epitopes within the PfEMP1 protein, particularly regions that mediate EPCR binding. This “adult-like” response likely requires multiple years of malaria exposure, as increases in pediatric serologic response over a single malaria transmission season do not appear significant.
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spelling pubmed-105974662023-10-25 Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s Tewey, Madison A. Coulibaly, Drissa Lawton, Jonathan G. Stucke, Emily M. Zhou, Albert E. Berry, Andrea A. Bailey, Jason A. Pike, Andrew Dara, Antoine Ouattara, Amed Lyke, Kirsten E. Ifeonu, Olukemi Laurens, Matthew B. Adams, Matthew Takala-Harrison, Shannon Niangaly, Amadou Kouriba, Bourema Koné, Abdoulaye K. Rowe, J. Alexandra Doumbo, Ogobara K. Patel, Jigar J. Tan, John C. Felgner, Philip L. Plowe, Christopher V. Thera, Mahamadou A. Travassos, Mark A. mSphere Research Article Antibody responses to variant surface antigens (VSAs) produced by the malaria parasite Plasmodium falciparum may contribute to age-related natural immunity to severe malaria. One VSA family, P. falciparum erythrocyte membrane protein-1 (PfEMP1), includes a subset of proteins that binds endothelial protein C receptor (EPCR) in human hosts and potentially disrupts the regulation of inflammatory responses, which may lead to the development of severe malaria. We probed peptide microarrays containing segments spanning five PfEMP1 EPCR-binding domain variants with sera from 10 Malian adults and 10 children to determine the differences between adult and pediatric immune responses. We defined serorecognized peptides and amino acid residues as those that elicited a significantly higher antibody response than malaria-naïve controls. We aimed to identify regions consistently serorecognized among adults but not among children across PfEMP1 variants, potentially indicating regions that drive the development of immunity to severe malaria. Adult sera consistently demonstrated broader and more intense serologic responses to constitutive PfEMP1 peptides than pediatric sera, including peptides in EPCR-binding domains. Both adults and children serorecognized a significantly higher proportion of EPCR-binding peptides than peptides that do not directly participate in receptor binding, indicating a preferential development of serologic responses at functional residues. Over the course of a single malaria transmission season, pediatric serological responses increased between the start and the peak of the season, but waned as the transmission season ended. IMPORTANCE: Severe malaria and death related to malaria disproportionately affect sub-Saharan children under 5 years of age, commonly manifesting as cerebral malaria and/or severe malarial anemia. In contrast, adults in malaria-endemic regions tend to experience asymptomatic or mild disease. Our findings indicate that natural immunity to malaria targets specific regions within the EPCR-binding domain, particularly peptides containing EPCR-binding residues. Epitopes containing these residues may be promising targets for vaccines or therapeutics directed against severe malaria. Our approach provides insight into the development of natural immunity to a binding target linked to severe malaria by characterizing an “adult-like” response as recognizing a proportion of epitopes within the PfEMP1 protein, particularly regions that mediate EPCR binding. This “adult-like” response likely requires multiple years of malaria exposure, as increases in pediatric serologic response over a single malaria transmission season do not appear significant. American Society for Microbiology 2023-10-04 /pmc/articles/PMC10597466/ /pubmed/37791774 http://dx.doi.org/10.1128/msphere.00451-23 Text en Copyright © 2023 Tewey et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Tewey, Madison A.
Coulibaly, Drissa
Lawton, Jonathan G.
Stucke, Emily M.
Zhou, Albert E.
Berry, Andrea A.
Bailey, Jason A.
Pike, Andrew
Dara, Antoine
Ouattara, Amed
Lyke, Kirsten E.
Ifeonu, Olukemi
Laurens, Matthew B.
Adams, Matthew
Takala-Harrison, Shannon
Niangaly, Amadou
Kouriba, Bourema
Koné, Abdoulaye K.
Rowe, J. Alexandra
Doumbo, Ogobara K.
Patel, Jigar J.
Tan, John C.
Felgner, Philip L.
Plowe, Christopher V.
Thera, Mahamadou A.
Travassos, Mark A.
Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s
title Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s
title_full Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s
title_fullStr Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s
title_full_unstemmed Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s
title_short Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s
title_sort natural immunity to malaria preferentially targets the endothelial protein c receptor-binding regions of pfemp1s
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10597466/
https://www.ncbi.nlm.nih.gov/pubmed/37791774
http://dx.doi.org/10.1128/msphere.00451-23
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