Afucosylated Plasmodium falciparum-specific IgG is induced by infection but not by subunit vaccination

Mads Delbo Larsen,Agnes L Hipgrave Ederveen,Ali Salanti,Emmanuel Kakra Dickson,Michael F Ofori,Morten Agertoug Nielsen,Gestur Vidarsson,Benjamin Mordmüller,Manfred Wuhrer,Nicaise Tuikue Ndam,Paulina Ampomah,Achille Massougbodji,C Ellen Van Der Schoot,Mary Lopez-Perez,Carolien A M Koeleman,Lars Hviid,Jan Nouta

doi:10.1038/s41467-021-26118-w

Abstract

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate receptor- and tissue-specific sequestration of infected erythrocytes (IEs) in malaria. Antibody responses are a central component of naturally acquired malaria immunity. PfEMP1-specific IgG likely protects by inhibiting IE sequestration and through IgG-Fc Receptor (FcγR) mediated phagocytosis and killing of antibody-opsonized IEs. The affinity of afucosylated IgG to FcγRIIIa is up to 40-fold higher than fucosylated IgG, resulting in enhanced antibody-dependent cellular cytotoxicity. Most IgG in plasma is fully fucosylated, but afucosylated IgG is elicited in response to enveloped viruses and to paternal alloantigens during pregnancy. Here we show that naturally acquired PfEMP1-specific IgG is strongly afucosylated in a stable and exposure-dependent manner, and efficiently induces FcγRIIIa-dependent natural killer (NK) cell degranulation. In contrast, immunization with a subunit PfEMP1 (VAR2CSA) vaccine results in fully fucosylated specific IgG. These results have implications for understanding protective natural- and vaccine-induced immunity to malaria.

Highlights

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate receptor- and tissue-specific sequestration of infected erythrocytes (IEs) in malaria
The particular virulence of P. falciparum is related to the efficient adhesion of the infected erythrocytes (IEs) to host receptors in the vasculature, such as endothelial protein C receptor, intercellular adhesion molecule 1, and oncofetal chondroitin sulfate A2–4, mediated by members of the protein family P. falciparum erythrocyte membrane protein 1 (PfEMP1), embedded in the membrane of IEs5
Severe malaria in children has repeatedly been shown to be associated with parasites expressing particular subsets of PfEMP1, such as Group A and B/A4,8, whereas placental malaria (PM) is strongly associated with parasites expressing VAR2CSA-type PfEMP1 antigen IT4VAR04 (VAR2CSA)-type PfEMP1

Summary

Introduction

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate receptor- and tissue-specific sequestration of infected erythrocytes (IEs) in malaria. Acquired protective immunity to P. falciparum malaria is mainly mediated by IgG with specificity for antigens expressed by the asexual blood-stage parasites[11]. P. falciparum antigens showed higher Fc galactosylation and sialylation levels than total IgG1, similar to what is known for recent immunizations[34,44] (Supplementary Fig. 1A, B).

Results

Conclusion