Polymorphic Molecular Signatures in Variable Regions of the <i>Plasmodium falciparum var2csa</i> DBL3x Domain Are Associated with Virulence in Placental Malaria
The <i>Plasmodium falciparum</i> protein VAR2CSA allows infected erythrocytes to accumulate within the placenta, inducing pathology and poor birth outcomes. Multiple exposures to placental malaria (PM) induce partial immunity against VAR2CSA, making it a promising vaccine candidate. Howe...
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MDPI AG
2022-04-01
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| Online Access: | https://www.mdpi.com/2076-0817/11/5/520 |
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| author | Eldin Talundzic Stephen Scott Simon O. Owino David S. Campo Naomi W. Lucchi Venkatachalam Udhayakumar Julie M. Moore David S. Peterson |
| author_facet | Eldin Talundzic Stephen Scott Simon O. Owino David S. Campo Naomi W. Lucchi Venkatachalam Udhayakumar Julie M. Moore David S. Peterson |
| author_sort | Eldin Talundzic |
| collection | DOAJ |
| description | The <i>Plasmodium falciparum</i> protein VAR2CSA allows infected erythrocytes to accumulate within the placenta, inducing pathology and poor birth outcomes. Multiple exposures to placental malaria (PM) induce partial immunity against VAR2CSA, making it a promising vaccine candidate. However, the extent to which VAR2CSA genetic diversity contributes to immune evasion and virulence remains poorly understood. The deep sequencing of the <i>var2csa</i> DBL3X domain in placental blood from forty-nine primigravid and multigravid women living in malaria-endemic western Kenya revealed numerous unique sequences within individuals in association with chronic PM but not gravidity. Additional analysis unveiled four distinct sequence types that were variably present in mixed proportions amongst the study population. An analysis of the abundance of each of these sequence types revealed that one was inversely related to infant gestational age, another was inversely related to placental parasitemia, and a third was associated with chronic PM. The categorization of women according to the type to which their dominant sequence belonged resulted in the segregation of types as a function of gravidity: two types predominated in multigravidae whereas the other two predominated in primigravidae. The univariate logistic regression analysis of sequence type dominance further revealed that gravidity, maternal age, placental parasitemia, and hemozoin burden (within maternal leukocytes), reported a lack of antimalarial drug use, and infant gestational age and birth weight influenced the odds of membership in one or more of these sequence predominance groups. Cumulatively, these results show that unique <i>var2csa</i> sequences differentially appear in women with different PM exposure histories and segregate to types independently associated with maternal factors, infection parameters, and birth outcomes. The association of some <i>var2csa</i> sequence types with indicators of pathogenesis should motivate vaccine efforts to further identify and target VAR2CSA epitopes associated with maternal morbidity and poor birth outcomes. |
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| issn | 2076-0817 |
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| last_indexed | 2024-03-10T03:12:38Z |
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| series | Pathogens |
| spelling | doaj.art-addee32543154a4d81c2582f0f0390aa2023-11-23T12:31:56ZengMDPI AGPathogens2076-08172022-04-0111552010.3390/pathogens11050520Polymorphic Molecular Signatures in Variable Regions of the <i>Plasmodium falciparum var2csa</i> DBL3x Domain Are Associated with Virulence in Placental MalariaEldin Talundzic0Stephen Scott1Simon O. Owino2David S. Campo3Naomi W. Lucchi4Venkatachalam Udhayakumar5Julie M. Moore6David S. Peterson7Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30329, USADepartment of Infectious Diseases, University of Georgia, Athens, GA 30602, USABoehringer Ingelheim Animal Health, Athens, GA 30601, USAMolecular Epidemiology and Bioinformatics Laboratory, Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA 30329, USAMalaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30329, USAMalaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30329, USADepartment of Infectious Diseases and Immunology, University of Florida, Gainesville, FL 32611, USADepartment of Infectious Diseases, University of Georgia, Athens, GA 30602, USAThe <i>Plasmodium falciparum</i> protein VAR2CSA allows infected erythrocytes to accumulate within the placenta, inducing pathology and poor birth outcomes. Multiple exposures to placental malaria (PM) induce partial immunity against VAR2CSA, making it a promising vaccine candidate. However, the extent to which VAR2CSA genetic diversity contributes to immune evasion and virulence remains poorly understood. The deep sequencing of the <i>var2csa</i> DBL3X domain in placental blood from forty-nine primigravid and multigravid women living in malaria-endemic western Kenya revealed numerous unique sequences within individuals in association with chronic PM but not gravidity. Additional analysis unveiled four distinct sequence types that were variably present in mixed proportions amongst the study population. An analysis of the abundance of each of these sequence types revealed that one was inversely related to infant gestational age, another was inversely related to placental parasitemia, and a third was associated with chronic PM. The categorization of women according to the type to which their dominant sequence belonged resulted in the segregation of types as a function of gravidity: two types predominated in multigravidae whereas the other two predominated in primigravidae. The univariate logistic regression analysis of sequence type dominance further revealed that gravidity, maternal age, placental parasitemia, and hemozoin burden (within maternal leukocytes), reported a lack of antimalarial drug use, and infant gestational age and birth weight influenced the odds of membership in one or more of these sequence predominance groups. Cumulatively, these results show that unique <i>var2csa</i> sequences differentially appear in women with different PM exposure histories and segregate to types independently associated with maternal factors, infection parameters, and birth outcomes. The association of some <i>var2csa</i> sequence types with indicators of pathogenesis should motivate vaccine efforts to further identify and target VAR2CSA epitopes associated with maternal morbidity and poor birth outcomes.https://www.mdpi.com/2076-0817/11/5/520placental malariaVAR2CSAchondroitin sulfate Apolymorphismlow birth weightchronic infection |
| spellingShingle | Eldin Talundzic Stephen Scott Simon O. Owino David S. Campo Naomi W. Lucchi Venkatachalam Udhayakumar Julie M. Moore David S. Peterson Polymorphic Molecular Signatures in Variable Regions of the <i>Plasmodium falciparum var2csa</i> DBL3x Domain Are Associated with Virulence in Placental Malaria Pathogens placental malaria VAR2CSA chondroitin sulfate A polymorphism low birth weight chronic infection |
| title | Polymorphic Molecular Signatures in Variable Regions of the <i>Plasmodium falciparum var2csa</i> DBL3x Domain Are Associated with Virulence in Placental Malaria |
| title_full | Polymorphic Molecular Signatures in Variable Regions of the <i>Plasmodium falciparum var2csa</i> DBL3x Domain Are Associated with Virulence in Placental Malaria |
| title_fullStr | Polymorphic Molecular Signatures in Variable Regions of the <i>Plasmodium falciparum var2csa</i> DBL3x Domain Are Associated with Virulence in Placental Malaria |
| title_full_unstemmed | Polymorphic Molecular Signatures in Variable Regions of the <i>Plasmodium falciparum var2csa</i> DBL3x Domain Are Associated with Virulence in Placental Malaria |
| title_short | Polymorphic Molecular Signatures in Variable Regions of the <i>Plasmodium falciparum var2csa</i> DBL3x Domain Are Associated with Virulence in Placental Malaria |
| title_sort | polymorphic molecular signatures in variable regions of the i plasmodium falciparum var2csa i dbl3x domain are associated with virulence in placental malaria |
| topic | placental malaria VAR2CSA chondroitin sulfate A polymorphism low birth weight chronic infection |
| url | https://www.mdpi.com/2076-0817/11/5/520 |
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