Insight into Antigenic Diversity of VAR2CSA-DBL5 epsilon Domain from Multiple Plasmodium falciparum Placental Isolates

Sedami Gnidehou, Leon Ivar Jessen, Stephane Gangnard, Caroline Ermont, CHoukri Triqui, Mickael Quiviger, Juliette Guitard, Ole Lund, Philippe Deloron, Nicaise Tuikue Ndam

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    Abstract

    Background: Protection against pregnancy associated malaria (PAM) is associated with high levels of anti-VAR2CSA antibodies. This protection is obtained by the parity dependent acquisition of anti-VAR2CSA antibodies. Distinct parity-associated molecular signatures have been identified in VAR2CSA domains. These two observations combined point to the importance of identifying VAR2CSA sequence variation, which facilitate parasitic evasion or subversion of host immune response. Highly conserved domains of VAR2CSA such as DBL5e are likely to contain conserved epitopes, and therefore do constitute attractive targets for vaccine development. Methodology/Principal Findings: VAR2CSA DBL5e-domain sequences obtained from cDNA of 40 placental isolates were analysed by a combination of experimental and in silico methods. Competition ELISA assays on two DBL5e variants, using plasma samples from women from two different areas and specific mice hyperimmune plasma, indicated that DBL5e possess conserved and cross-reactive B cell epitopes. Peptide ELISA identified conserved areas that are recognised by naturally acquired antibodies. Specific antibodies against these peptides labelled the native proteins on the surface of placental parasites. Despite high DBL5e sequence homology among parasite isolates, sequence analyses identified motifs in DBL5e that discriminate parasites according to donor's parity. Moreover, recombinant proteins of two VAR2CSA DBL5e variants displayed diverse recognition patterns by plasma from malaria-exposed women, and diverse proteoglycan binding abilities. Conclusions/Significance: This study provides insights into conserved and exposed B cell epitopes in DBL5e that might be a focus for cross reactivity. The importance of sequence variation in VAR2CSA as a critical challenge for vaccine development is highlighted. VAR2CSA conformation seems to be essential to its functionality. Therefore, identification of sequence variation sites in distinct locations within VAR2CSA, affecting antigenicity and/or binding properties, is critical to the effort of developing an efficient VAR2CSA-based vaccine. Motifs associated with parasite segregation according to parity constitute one such site.
    Original languageEnglish
    JournalP L o S One
    Volume5
    Issue number10
    Pages (from-to)e13105
    ISSN1932-6203
    DOIs
    Publication statusPublished - 2010

    Bibliographical note

    This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Cite this

    Gnidehou, Sedami ; Jessen, Leon Ivar ; Gangnard, Stephane ; Ermont, Caroline ; Triqui, CHoukri ; Quiviger, Mickael ; Guitard, Juliette ; Lund, Ole ; Deloron, Philippe ; Ndam, Nicaise Tuikue. / Insight into Antigenic Diversity of VAR2CSA-DBL5 epsilon Domain from Multiple Plasmodium falciparum Placental Isolates. In: P L o S One. 2010 ; Vol. 5, No. 10. pp. e13105.
    @article{6c70fa3abbb04f72af21927ca3683c0b,
    title = "Insight into Antigenic Diversity of VAR2CSA-DBL5 epsilon Domain from Multiple Plasmodium falciparum Placental Isolates",
    abstract = "Background: Protection against pregnancy associated malaria (PAM) is associated with high levels of anti-VAR2CSA antibodies. This protection is obtained by the parity dependent acquisition of anti-VAR2CSA antibodies. Distinct parity-associated molecular signatures have been identified in VAR2CSA domains. These two observations combined point to the importance of identifying VAR2CSA sequence variation, which facilitate parasitic evasion or subversion of host immune response. Highly conserved domains of VAR2CSA such as DBL5e are likely to contain conserved epitopes, and therefore do constitute attractive targets for vaccine development. Methodology/Principal Findings: VAR2CSA DBL5e-domain sequences obtained from cDNA of 40 placental isolates were analysed by a combination of experimental and in silico methods. Competition ELISA assays on two DBL5e variants, using plasma samples from women from two different areas and specific mice hyperimmune plasma, indicated that DBL5e possess conserved and cross-reactive B cell epitopes. Peptide ELISA identified conserved areas that are recognised by naturally acquired antibodies. Specific antibodies against these peptides labelled the native proteins on the surface of placental parasites. Despite high DBL5e sequence homology among parasite isolates, sequence analyses identified motifs in DBL5e that discriminate parasites according to donor's parity. Moreover, recombinant proteins of two VAR2CSA DBL5e variants displayed diverse recognition patterns by plasma from malaria-exposed women, and diverse proteoglycan binding abilities. Conclusions/Significance: This study provides insights into conserved and exposed B cell epitopes in DBL5e that might be a focus for cross reactivity. The importance of sequence variation in VAR2CSA as a critical challenge for vaccine development is highlighted. VAR2CSA conformation seems to be essential to its functionality. Therefore, identification of sequence variation sites in distinct locations within VAR2CSA, affecting antigenicity and/or binding properties, is critical to the effort of developing an efficient VAR2CSA-based vaccine. Motifs associated with parasite segregation according to parity constitute one such site.",
    author = "Sedami Gnidehou and Jessen, {Leon Ivar} and Stephane Gangnard and Caroline Ermont and CHoukri Triqui and Mickael Quiviger and Juliette Guitard and Ole Lund and Philippe Deloron and Ndam, {Nicaise Tuikue}",
    note = "This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
    year = "2010",
    doi = "10.1371/journal.pone.0013105",
    language = "English",
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    Gnidehou, S, Jessen, LI, Gangnard, S, Ermont, C, Triqui, CH, Quiviger, M, Guitard, J, Lund, O, Deloron, P & Ndam, NT 2010, 'Insight into Antigenic Diversity of VAR2CSA-DBL5 epsilon Domain from Multiple Plasmodium falciparum Placental Isolates', P L o S One, vol. 5, no. 10, pp. e13105. https://doi.org/10.1371/journal.pone.0013105

    Insight into Antigenic Diversity of VAR2CSA-DBL5 epsilon Domain from Multiple Plasmodium falciparum Placental Isolates. / Gnidehou, Sedami; Jessen, Leon Ivar; Gangnard, Stephane; Ermont, Caroline; Triqui, CHoukri; Quiviger, Mickael; Guitard, Juliette; Lund, Ole; Deloron, Philippe; Ndam, Nicaise Tuikue.

    In: P L o S One, Vol. 5, No. 10, 2010, p. e13105.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Insight into Antigenic Diversity of VAR2CSA-DBL5 epsilon Domain from Multiple Plasmodium falciparum Placental Isolates

    AU - Gnidehou, Sedami

    AU - Jessen, Leon Ivar

    AU - Gangnard, Stephane

    AU - Ermont, Caroline

    AU - Triqui, CHoukri

    AU - Quiviger, Mickael

    AU - Guitard, Juliette

    AU - Lund, Ole

    AU - Deloron, Philippe

    AU - Ndam, Nicaise Tuikue

    N1 - This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    PY - 2010

    Y1 - 2010

    N2 - Background: Protection against pregnancy associated malaria (PAM) is associated with high levels of anti-VAR2CSA antibodies. This protection is obtained by the parity dependent acquisition of anti-VAR2CSA antibodies. Distinct parity-associated molecular signatures have been identified in VAR2CSA domains. These two observations combined point to the importance of identifying VAR2CSA sequence variation, which facilitate parasitic evasion or subversion of host immune response. Highly conserved domains of VAR2CSA such as DBL5e are likely to contain conserved epitopes, and therefore do constitute attractive targets for vaccine development. Methodology/Principal Findings: VAR2CSA DBL5e-domain sequences obtained from cDNA of 40 placental isolates were analysed by a combination of experimental and in silico methods. Competition ELISA assays on two DBL5e variants, using plasma samples from women from two different areas and specific mice hyperimmune plasma, indicated that DBL5e possess conserved and cross-reactive B cell epitopes. Peptide ELISA identified conserved areas that are recognised by naturally acquired antibodies. Specific antibodies against these peptides labelled the native proteins on the surface of placental parasites. Despite high DBL5e sequence homology among parasite isolates, sequence analyses identified motifs in DBL5e that discriminate parasites according to donor's parity. Moreover, recombinant proteins of two VAR2CSA DBL5e variants displayed diverse recognition patterns by plasma from malaria-exposed women, and diverse proteoglycan binding abilities. Conclusions/Significance: This study provides insights into conserved and exposed B cell epitopes in DBL5e that might be a focus for cross reactivity. The importance of sequence variation in VAR2CSA as a critical challenge for vaccine development is highlighted. VAR2CSA conformation seems to be essential to its functionality. Therefore, identification of sequence variation sites in distinct locations within VAR2CSA, affecting antigenicity and/or binding properties, is critical to the effort of developing an efficient VAR2CSA-based vaccine. Motifs associated with parasite segregation according to parity constitute one such site.

    AB - Background: Protection against pregnancy associated malaria (PAM) is associated with high levels of anti-VAR2CSA antibodies. This protection is obtained by the parity dependent acquisition of anti-VAR2CSA antibodies. Distinct parity-associated molecular signatures have been identified in VAR2CSA domains. These two observations combined point to the importance of identifying VAR2CSA sequence variation, which facilitate parasitic evasion or subversion of host immune response. Highly conserved domains of VAR2CSA such as DBL5e are likely to contain conserved epitopes, and therefore do constitute attractive targets for vaccine development. Methodology/Principal Findings: VAR2CSA DBL5e-domain sequences obtained from cDNA of 40 placental isolates were analysed by a combination of experimental and in silico methods. Competition ELISA assays on two DBL5e variants, using plasma samples from women from two different areas and specific mice hyperimmune plasma, indicated that DBL5e possess conserved and cross-reactive B cell epitopes. Peptide ELISA identified conserved areas that are recognised by naturally acquired antibodies. Specific antibodies against these peptides labelled the native proteins on the surface of placental parasites. Despite high DBL5e sequence homology among parasite isolates, sequence analyses identified motifs in DBL5e that discriminate parasites according to donor's parity. Moreover, recombinant proteins of two VAR2CSA DBL5e variants displayed diverse recognition patterns by plasma from malaria-exposed women, and diverse proteoglycan binding abilities. Conclusions/Significance: This study provides insights into conserved and exposed B cell epitopes in DBL5e that might be a focus for cross reactivity. The importance of sequence variation in VAR2CSA as a critical challenge for vaccine development is highlighted. VAR2CSA conformation seems to be essential to its functionality. Therefore, identification of sequence variation sites in distinct locations within VAR2CSA, affecting antigenicity and/or binding properties, is critical to the effort of developing an efficient VAR2CSA-based vaccine. Motifs associated with parasite segregation according to parity constitute one such site.

    U2 - 10.1371/journal.pone.0013105

    DO - 10.1371/journal.pone.0013105

    M3 - Journal article

    VL - 5

    SP - e13105

    JO - P L o S One

    JF - P L o S One

    SN - 1932-6203

    IS - 10

    ER -