Mapping the Binding Site of a Cross-Reactive Plasmodium falciparum PfEMP1 Monoclonal Antibody Inhibitory of ICAM-1 Binding

The Journal of Immunology : Official Journal of the American Association of Immunologists
Frank LennartzAnja T R Jensen

Abstract

The virulence of Plasmodium falciparum is linked to the ability of infected erythrocytes (IE) to adhere to the vascular endothelium, mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). In this article, we report the functional characterization of an mAb that recognizes a panel of PfEMP1s and inhibits ICAM-1 binding. The 24E9 mouse mAb was raised against PFD1235w DBLβ3_D4, a domain from the group A PfEMP1s associated with severe malaria. 24E9 recognizes native PfEMP1 expressed on the IE surface and shows cross-reactivity with and cross-inhibition of the ICAM-1 binding capacity of domain cassette 4 PfEMP1s. 24E9 Fab fragments bind DBLβ3_D4 with nanomolar affinity and inhibit ICAM-1 binding of domain cassette 4-expressing IE. The antigenic regions targeted by 24E9 Fab were identified by hydrogen/deuterium exchange mass spectrometry and revealed three discrete peptides that are solvent protected in the complex. When mapped onto a homology model of DBLβ3_D4, these cluster to a defined, surface-exposed region on the convex surface of DBLβ3_D4. Mutagenesis confirmed that the site most strongly protected is necessary for 24E9 binding, which is consistent with a low-resolution structure of the DBLβ3_D4::24E9 Fab complex d...Continue Reading

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Citations

Jan 14, 2016·Expert Review of Vaccines·Kazutoyo Miura
Jun 13, 2017·Nature Reviews. Microbiology·Mats WahlgrenReetesh R Akhouri
Feb 21, 2018·Scientific Reports·Eilidh CarringtonAlister G Craig
Sep 19, 2019·Proceedings of the National Academy of Sciences of the United States of America·Frank LennartzMatthew K Higgins
Jan 17, 2016·Malaria Journal·Micheline GuillotteOdile Mercereau-Puijalon
Jan 7, 2021·Analytical and Bioanalytical Chemistry·Haofeng SunDewei Song

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Datasets Mentioned

BETA
KJ418726
KJ418727

Methods Mentioned

BETA
x-ray scattering
surface plasmon resonance
size exclusion chromatography
PCR
ELISA
flow-cytometry
genotyping
chip
flow cytometry

Software Mentioned

Schrödinger
SCULPTOR
PRIMUS
TASSER
AutoRG
BIAevaluation
DAMAVER
DAMMIN
SITUS
Softmax Pro

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