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Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection.

ABSTRACT: BACKGROUNDMalaria pathogenicity is determined, in part, by the adherence of Plasmodium falciparum-infected erythrocytes to the microvasculature mediated via specific interactions between P. falciparum erythrocyte membrane protein (PfEMP1) variant domains and host endothelial receptors. Naturally acquired antibodies against specific PfEMP1 variants can play an important role in clinical protection against malaria.METHODSWe evaluated IgG responses against a repertoire of PfEMP1 CIDR domain variants to determine the rate and order of variant-specific antibody acquisition and their association with protection against febrile malaria in a prospective cohort study conducted in an area of intense, seasonal malaria transmission.RESULTSUsing longitudinal data, we found that IgG antibodies against the pathogenic domain variants CIDR?1.7 and CIDR?1.8 were acquired the earliest. Furthermore, IgG antibodies against CIDR?3 were associated with reduced prospective risk of febrile malaria and recurrent malaria episodes.CONCLUSIONThis study provides evidence that acquisition of IgG antibodies against PfEMP1 variants is ordered and demonstrates that antibodies against CIDR?1 domains are acquired the earliest in children residing in an area of intense, seasonal malaria transmission. Future studies will need to validate these findings in other transmission settings and determine the functional activity of these naturally acquired CIDR variant-specific antibodies.TRIAL REGISTRATIONClinicalTrials.gov NCT01322581.FUNDINGDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.

SUBMITTER: Obeng-Adjei N

PROVIDER: S-EPMC7406271 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection.

Obeng-Adjei Nyamekye N Larremore Daniel B DB Turner Louise L Ongoiba Aissata A Li Shanping S Doumbo Safiatou S Yazew Takele B TB Kayentao Kassoum K Miller Louis H LH Traore Boubacar B Pierce Susan K SK Buckee Caroline O CO Lavstsen Thomas T Crompton Peter D PD Tran Tuan M TM

JCI insight 20200618 12

BACKGROUNDMalaria pathogenicity is determined, in part, by the adherence of Plasmodium falciparum-infected erythrocytes to the microvasculature mediated via specific interactions between P. falciparum erythrocyte membrane protein (PfEMP1) variant domains and host endothelial receptors. Naturally acquired antibodies against specific PfEMP1 variants can play an important role in clinical protection against malaria.METHODSWe evaluated IgG responses against a repertoire of PfEMP1 CIDR domain variant ...[more]

PMID: 32427581

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Project description:Shigella is the second leading cause of diarrheal diseases, accounting for >200,000 infections and >50,000 deaths in children under 5 years of age annually worldwide. The incidence of Shigella-induced diarrhea is relatively low during the first year of life and increases substantially, reaching its peak between 11 to 24 months of age. This epidemiological trend hints at an early protective immunity of maternal origin and an increase in disease incidence when maternally acquired immunity wanes. The magnitude, type, antigenic diversity, and antimicrobial activity of maternal antibodies transferred via placenta that can prevent shigellosis during early infancy are not known. To address this knowledge gap, Shigella-specific antibodies directed against the lipopolysaccharide (LPS) and virulence factors (IpaB, IpaC, IpaD, IpaH, and VirG), and antibody-mediated serum bactericidal (SBA) and opsonophagocytic killing antibody (OPKA) activity were measured in maternal and cord blood sera from a longitudinal cohort of mother-infant pairs living in rural Malawi. Protein-specific (very high levels) and Shigella LPS IgG were detected in maternal and cord blood sera; efficiency of placental transfer was 100% and 60%, respectively, and had preferential IgG subclass distribution (protein-specific IgG1 > LPS-specific IgG2). In contrast, SBA and OPKA activity in cord blood was substantially lower as compared to maternal serum and varied among Shigella serotypes. LPS was identified as the primary target of SBA and OPKA activity. Maternal sera had remarkably elevated Shigella flexneri 2a LPS IgM, indicative of recent exposure. Our study revealed a broad repertoire of maternally acquired antibodies in infants living in a Shigella-endemic region and highlights the abundance of protein-specific antibodies and their likely contribution to disease prevention during the first months of life. These results contribute new knowledge on maternal infant immunity and target antigens that can inform the development of vaccines or therapeutics that can extend protection after maternally transferred immunity wanes.

Dataset Information

Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection.

Publications

Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection.

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