Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA

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

doi:10.1128/mBio.02343-19

Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA

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

VAR2CSA team

6 Citationer (Scopus)

11 Downloads (Pure)

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 vivaxderived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5 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.

Originalsprog	Engelsk
Artikelnummer	e02343-19
Tidsskrift	mBio
Vol/bind	10
Udgave nummer	5
Antal sider	17
ISSN	2161-2129
DOI	https://doi.org/10.1128/mBio.02343-19
Status	Udgivet - 2019

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10.1128/mBio.02343-19Licens: CC BY

Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSAForlagets udgivne version, 2,13 MBLicens: CC BY

Citationsformater

Mitran, C. J., Mena, A., Gnidehou, S., Banman, S., Arango, E., Lima, B. A. S., Lugo, H., Ganesan, A., Salanti, A., Mbonye, A. K., Ntumngia, F., Barakat, K., Adams, J. H., Kano, F. S., Carvalho, L. H., Maestre, A. E., Good, M. F., & Yanow, S. K. (2019). Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA. mBio, 10(5), [e02343-19]. https://doi.org/10.1128/mBio.02343-19

Mitran, CJ, Mena, A, Gnidehou, S, Banman, S, Arango, E, Lima, BAS, Lugo, H, Ganesan, A, Salanti, A, Mbonye, AK, Ntumngia, F, Barakat, K, Adams, JH, Kano, FS, Carvalho, LH, Maestre, AE, Good, MF & Yanow, SK 2019, 'Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA', mBio, bind 10, nr. 5, e02343-19. https://doi.org/10.1128/mBio.02343-19

@article{b7456ae5e77f47418a1cd551c008d7ea,

title = "Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum 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 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 vivaxderived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5 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.",

keywords = "cross-species, cryptic epitopes, epitopes, falciparum, heterologous immunity, malaria, Plasmodium, Plasmodium falciparum, Plasmodium vivax, pregnancy, PvDBP, VAR2CSA, vivax",

author = "Mitran, {Catherine J.} and Angie Mena and Sedami Gnidehou and Shanna Banman and Eliana Arango and Lima, {Barbara A.S.} and Hazel Lugo and Aravindhan Ganesan and Ali Salanti and Mbonye, {Anthony K.} and Francis Ntumngia and Khaled Barakat and Adams, {John H.} and Kano, {Flora S.} and Carvalho, {Luzia H.} and Maestre, {Amanda E.} and Good, {Michael F.} and Yanow, {Stephanie K.}",

year = "2019",

doi = "10.1128/mBio.02343-19",

language = "English",

volume = "10",

journal = "mBio",

issn = "2161-2129",

publisher = "American Society for Microbiology",

number = "5",

}

TY - JOUR

T1 - Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA

AU - Mitran, Catherine J.

AU - Mena, Angie

AU - Gnidehou, Sedami

AU - Banman, Shanna

AU - Arango, Eliana

AU - Lima, Barbara A.S.

AU - Lugo, Hazel

AU - Ganesan, Aravindhan

AU - Salanti, Ali

AU - Mbonye, Anthony K.

AU - Ntumngia, Francis

AU - Barakat, Khaled

AU - Adams, John H.

AU - Kano, Flora S.

AU - Carvalho, Luzia H.

AU - Maestre, Amanda E.

AU - Good, Michael F.

AU - Yanow, Stephanie K.

PY - 2019

Y1 - 2019

N2 - 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 vivaxderived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5 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.

AB - 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 vivaxderived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5 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.

KW - cross-species

KW - cryptic epitopes

KW - epitopes

KW - falciparum

KW - heterologous immunity

KW - malaria

KW - Plasmodium

KW - Plasmodium falciparum

KW - Plasmodium vivax

KW - pregnancy

KW - PvDBP

KW - VAR2CSA

KW - vivax

U2 - 10.1128/mBio.02343-19

DO - 10.1128/mBio.02343-19

M3 - Journal article

C2 - 31594821

AN - SCOPUS:85073074359

SN - 2161-2129

VL - 10

JO - mBio

JF - mBio

IS - 5

M1 - e02343-19

ER -

Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA

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