Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between <italic toggle="yes">Plasmodium vivax</italic> PvDBP and <italic toggle="yes">Plasmodium falciparum</italic> VAR2CSA

ABSTRACT Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to eli...

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Autores principales:	Catherine J. Mitran, Angie Mena, Sedami Gnidehou, Shanna Banman, Eliana Arango, Barbara A. S. Lima, Hazel Lugo, Aravindhan Ganesan, Ali Salanti, Anthony K. Mbonye, Francis Ntumngia, Khaled Barakat, John H. Adams, Flora S. Kano, Luzia H. Carvalho, Amanda E. Maestre, Michael F. Good, Stephanie K. Yanow
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Plasmodium vivax falciparum VAR2CSA PvDBP heterologous immunity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/dc9b125d83b4466294dd90ec1b790353
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spelling	oai:doaj.org-article:dc9b125d83b4466294dd90ec1b7903532021-11-15T15:59:41ZAntibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between <italic toggle="yes">Plasmodium vivax</italic> PvDBP and <italic toggle="yes">Plasmodium falciparum</italic> VAR2CSA10.1128/mBio.02343-192150-7511https://doaj.org/article/dc9b125d83b4466294dd90ec1b7903532019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02343-19https://doaj.org/toc/2150-7511ABSTRACT Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure. We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro. The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA. The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5ε domain of VAR2CSA that are recognized by SD1 antibodies. Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes. IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium. Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.Catherine J. MitranAngie MenaSedami GnidehouShanna BanmanEliana ArangoBarbara A. S. LimaHazel LugoAravindhan GanesanAli SalantiAnthony K. MbonyeFrancis NtumngiaKhaled BarakatJohn H. AdamsFlora S. KanoLuzia H. CarvalhoAmanda E. MaestreMichael F. GoodStephanie K. YanowAmerican Society for MicrobiologyarticlePlasmodiumvivaxfalciparumVAR2CSAPvDBPheterologous immunityMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Plasmodium vivax falciparum VAR2CSA PvDBP heterologous immunity Microbiology QR1-502
spellingShingle	Plasmodium vivax falciparum VAR2CSA PvDBP heterologous immunity Microbiology QR1-502 Catherine J. Mitran Angie Mena Sedami Gnidehou Shanna Banman Eliana Arango Barbara A. S. Lima Hazel Lugo Aravindhan Ganesan Ali Salanti Anthony K. Mbonye Francis Ntumngia Khaled Barakat John H. Adams Flora S. Kano Luzia H. Carvalho Amanda E. Maestre Michael F. Good Stephanie K. Yanow Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between <italic toggle="yes">Plasmodium vivax</italic> PvDBP and <italic toggle="yes">Plasmodium falciparum</italic> VAR2CSA
description	ABSTRACT Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure. We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro. The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA. The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5ε domain of VAR2CSA that are recognized by SD1 antibodies. Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes. IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium. Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.
format	article
author	Catherine J. Mitran Angie Mena Sedami Gnidehou Shanna Banman Eliana Arango Barbara A. S. Lima Hazel Lugo Aravindhan Ganesan Ali Salanti Anthony K. Mbonye Francis Ntumngia Khaled Barakat John H. Adams Flora S. Kano Luzia H. Carvalho Amanda E. Maestre Michael F. Good Stephanie K. Yanow
author_facet	Catherine J. Mitran Angie Mena Sedami Gnidehou Shanna Banman Eliana Arango Barbara A. S. Lima Hazel Lugo Aravindhan Ganesan Ali Salanti Anthony K. Mbonye Francis Ntumngia Khaled Barakat John H. Adams Flora S. Kano Luzia H. Carvalho Amanda E. Maestre Michael F. Good Stephanie K. Yanow
author_sort	Catherine J. Mitran
title	Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between <italic toggle="yes">Plasmodium vivax</italic> PvDBP and <italic toggle="yes">Plasmodium falciparum</italic> VAR2CSA
title_short	Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between <italic toggle="yes">Plasmodium vivax</italic> PvDBP and <italic toggle="yes">Plasmodium falciparum</italic> VAR2CSA
title_full	Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between <italic toggle="yes">Plasmodium vivax</italic> PvDBP and <italic toggle="yes">Plasmodium falciparum</italic> VAR2CSA
title_fullStr	Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between <italic toggle="yes">Plasmodium vivax</italic> PvDBP and <italic toggle="yes">Plasmodium falciparum</italic> VAR2CSA
title_full_unstemmed	Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between <italic toggle="yes">Plasmodium vivax</italic> PvDBP and <italic toggle="yes">Plasmodium falciparum</italic> VAR2CSA
title_sort	antibodies to cryptic epitopes in distant homologues underpin a mechanism of heterologous immunity between <italic toggle="yes">plasmodium vivax</italic> pvdbp and <italic toggle="yes">plasmodium falciparum</italic> var2csa
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/dc9b125d83b4466294dd90ec1b790353
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Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between <italic toggle="yes">Plasmodium vivax</italic> PvDBP and <italic toggle="yes">Plasmodium falciparum</italic> VAR2CSA

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