TY - JOUR

T1 - 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

AU - Olsen, Rebecca W

AU - Ecklu-Mensah, Gertrude

AU - Bengtsson, Anja

AU - Ofori, Michael F

AU - Lusingu, John P A

AU - Castberg, Filip C

AU - Hviid, Lars

AU - Adams, Yvonne

AU - Jensen, Anja T R

N1 - Copyright © 2018 Olsen et al.

PY - 2018

Y1 - 2018

N2 - Cerebral malaria (CM) is a potentially deadly outcome of Plasmodium falciparummalaria 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 (DBLβ_motif) in the constituent ICAM-1-binding DBLβ domain. The rate of natural acquisition of DBLβ_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 DBLβ-specific IgG in plasma from Ghanaian children with malaria. The ability of human immune plasma and DBLβ-specific rat antisera to inhibit the interaction between ICAM-1 and DBLβ was assessed using ELISA andin vitroassays of IE adhesion under flow. The acquisition of DBLβ_motif-specific IgG coincided with age-specific susceptibility to CM. Broadly cross-reactive antibodies inhibiting the interaction between ICAM-1 and DBLβ_motif domains were detectable in immune plasma and in sera of rats immunized with specific DBLβ_motif antigens. Importantly, antibodies against the DBLβ_motif inhibited ICAM-1-specificin vitroadhesion of erythrocytes infected by four of fiveP. falciparumisolates from cerebral malaria patients. We conclude that natural exposure toP. falciparumas well as immunization with specific DBLβ_motif antigens can induce cross-reactive antibodies that inhibit the interaction between ICAM-1 and a broad range of DBLβ_motif domains. These findings raise hope that a vaccine designed specifically to prevent CM is feasible.

AB - Cerebral malaria (CM) is a potentially deadly outcome of Plasmodium falciparummalaria 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 (DBLβ_motif) in the constituent ICAM-1-binding DBLβ domain. The rate of natural acquisition of DBLβ_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 DBLβ-specific IgG in plasma from Ghanaian children with malaria. The ability of human immune plasma and DBLβ-specific rat antisera to inhibit the interaction between ICAM-1 and DBLβ was assessed using ELISA andin vitroassays of IE adhesion under flow. The acquisition of DBLβ_motif-specific IgG coincided with age-specific susceptibility to CM. Broadly cross-reactive antibodies inhibiting the interaction between ICAM-1 and DBLβ_motif domains were detectable in immune plasma and in sera of rats immunized with specific DBLβ_motif antigens. Importantly, antibodies against the DBLβ_motif inhibited ICAM-1-specificin vitroadhesion of erythrocytes infected by four of fiveP. falciparumisolates from cerebral malaria patients. We conclude that natural exposure toP. falciparumas well as immunization with specific DBLβ_motif antigens can induce cross-reactive antibodies that inhibit the interaction between ICAM-1 and a broad range of DBLβ_motif domains. These findings raise hope that a vaccine designed specifically to prevent CM is feasible.

U2 - 10.1128/IAI.00622-17

DO - 10.1128/IAI.00622-17

M3 - Journal article

C2 - 29426042

VL - 86

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 4

M1 - e00622-17

ER -