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Natural and Vaccine-Induced Acquisition of Cross-Reactive IgG-Inhibiting ICAM-1-Specific Binding of a Plasmodium falciparum PfEMP1 Subtype Associated Specifically with Cerebral Malaria.

ABSTRACT: Cerebral malaria (CM) is a potentially deadly outcome of Plasmodium falciparum malaria that is precipitated by sequestration of infected erythrocytes (IEs) in the brain. The adhesion of IEs to brain endothelial cells is mediated by a subtype of parasite-encoded erythrocyte membrane protein 1 (PfEMP1) that facilitates dual binding to host intercellular adhesion molecule 1 (ICAM-1) and endothelial protein receptor C (EPCR). The PfEMP1 subtype is characterized by the presence of a particular motif (DBL?_motif) in the constituent ICAM-1-binding DBL? domain. The rate of natural acquisition of DBL?_motif-specific IgG antibodies and the ability to induce such antibodies by vaccination are unknown, and the aim of this study was to provide such data. We used an enzyme-linked immunosorbent assay (ELISA) to measure DBL?-specific IgG in plasma from Ghanaian children with malaria. The ability of human immune plasma and DBL?-specific rat antisera to inhibit the interaction between ICAM-1 and DBL? was assessed using ELISA and in vitro assays of IE adhesion under flow. The acquisition of DBL?_motif-specific IgG coincided with age-specific susceptibility to CM. Broadly cross-reactive antibodies inhibiting the interaction between ICAM-1 and DBL?_motif domains were detectable in immune plasma and in sera of rats immunized with specific DBL?_motif antigens. Importantly, antibodies against the DBL?_motif inhibited ICAM-1-specific in vitro adhesion of erythrocytes infected by four of five P. falciparum isolates from cerebral malaria patients. We conclude that natural exposure to P. falciparum as well as immunization with specific DBL?_motif antigens can induce cross-reactive antibodies that inhibit the interaction between ICAM-1 and a broad range of DBL?_motif domains. These findings raise hope that a vaccine designed specifically to prevent CM is feasible.

SUBMITTER: Olsen RW

PROVIDER: S-EPMC5865037 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Natural and Vaccine-Induced Acquisition of Cross-Reactive IgG-Inhibiting ICAM-1-Specific Binding of a Plasmodium falciparum PfEMP1 Subtype Associated Specifically with Cerebral Malaria.

Olsen Rebecca W RW Ecklu-Mensah Gertrude G Bengtsson Anja A Ofori Michael F MF Lusingu John P A JPA Castberg Filip C FC Hviid Lars L Adams Yvonne Y Jensen Anja T R ATR

Infection and immunity 20180322 4

Cerebral malaria (CM) is a potentially deadly outcome of <i>Plasmodium falciparum</i> malaria that is precipitated by sequestration of infected erythrocytes (IEs) in the brain. The adhesion of IEs to brain endothelial cells is mediated by a subtype of parasite-encoded erythrocyte membrane protein 1 (PfEMP1) that facilitates dual binding to host intercellular adhesion molecule 1 (ICAM-1) and endothelial protein receptor C (EPCR). The PfEMP1 subtype is characterized by the presence of a particular ...[more]

PMID: 29426042

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Project description:BackgroundEndemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma linked to Plasmodium falciparum (Pf) malaria in sub-Saharan Africa. We investigated antibody reactivity to several human receptor-binding domains of the Pf erythrocyte membrane protein 1 (PfEMP1) that play a key role in malaria pathogenesis and are targets of acquired immunity to malaria.MethodsSerum/plasma IgG antibody reactivity was measured to 22 Pf antigens, including 18 to PfEMP1 CIDR domains between cases and controls from two populations (149 eBL cases and 150 controls from Ghana and 194 eBL cases and 600 controls from Uganda). Adjusted odds ratios (aORs) for case-control associations were estimated by logistic regression.FindingsThere was stronger reactivity to the severe malaria associated CIDR?1 domains than other CIDR domains both in cases and controls. eBL cases reacted to fewer antigens than controls (Ghana: p?=?0·001; Uganda: p?=?0·03), with statistically significant lower ORs associated with reactivity to 13+ antigens in Ghana (aOR 0·39, 95% CI 0·24-0·63; pheterogeneity?=?0·00011) and Uganda (aOR 0·60, 95% CI 0.41-0·88; pheterogeneity?=?0·008). eBL was inversely associated with reactivity, coded as quartiles, to group A variant CIDR?1 (ptrend?=?0·035) in Ghana and group B CD36-binding variants CIDR?2·2 (ptrend?=?0·006) and CIDR?2·4 (ptrend?=?0·033) in Uganda, and positively associated with reactivity to SERA5 in Ghana (ptrend?=?0·017) and Uganda (ptrend?=?0·007) and group A CIDR?1·5 variant in Uganda only (ptrend?=?0·034).InterpretationeBL cases reacted to fewer antigens than controls using samples from two populations, Ghana and Uganda. Attenuated humoral immunity to Pf EMP1 may contribute to susceptibility to low-grade malaria and eBL risk.FundingIntramural Research Program, National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services.

Dataset Information

Natural and Vaccine-Induced Acquisition of Cross-Reactive IgG-Inhibiting ICAM-1-Specific Binding of a Plasmodium falciparum PfEMP1 Subtype Associated Specifically with Cerebral Malaria.

Publications

Natural and Vaccine-Induced Acquisition of Cross-Reactive IgG-Inhibiting ICAM-1-Specific Binding of a Plasmodium falciparum PfEMP1 Subtype Associated Specifically with Cerebral Malaria.

Similar Datasets

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