Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11.

Iga Kucharska,Elaine Thai,Régis Pomès,John L Rubinstein,Ananya Srivastava,Jean-Philippe Julien

doi:10.7554/elife.59018

Iga Kucharska, Elaine Thai + Show 4 more

Open Access

https://doi.org/10.7554/elife.59018

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Journal: eLife	Publication Date: Nov 30, 2020
Citations: 17	License type: CC BY 4.0

Affiliation: University of Toronto, SickKids Foundation

Abstract

Plasmodium sporozoites express circumsporozoite protein (CSP) on their surface, an essential protein that contains central repeating motifs. Antibodies targeting this region can neutralize infection, and the partial efficacy of RTS,S/AS01 - the leading malaria vaccine against P. falciparum (Pf) - has been associated with the humoral response against the repeats. Although structural details of antibody recognition of PfCSP have recently emerged, the molecular basis of antibody-mediated inhibition of other Plasmodium species via CSP binding remains unclear. Here, we analyze the structure and molecular interactions of potent monoclonal antibody (mAb) 3D11 binding to P. berghei CSP (PbCSP) using molecular dynamics simulations, X-ray crystallography, and cryoEM. We reveal that mAb 3D11 can accommodate all subtle variances of the PbCSP repeating motifs, and, upon binding, induces structural ordering of PbCSP through homotypic interactions. Together, our findings uncover common mechanisms of antibody evolution in mammals against the CSP repeats of Plasmodium sporozoites.

Highlights

Despite extensive biomedical and public health measures, malaria persists as a major global health concern, with an estimated 405,000 deaths and 228 million cases annually (WHO, 2019)
To examine and compare the structural properties of the various Plasmodium falciparum (Pf) and P. berghei (Pb) repeat motifs in solution, we performed molecular dynamics (MD) simulations using eight different peptides ranging in length from 15 to 20 aa, with four peptides derived from Pf [KQPADGNPDPNANPN (‘KQPA’); NPD PNANPNVDPNANP (‘NPDP’); (NVDPNANP)2NVDP (‘NVDP’); and (NPNA)5 (‘NPNA’)], and four peptides from Pb [(PPPPNPND)2 (‘NPND’); (PPPPNAND)2 (‘NAND’); (PAPPNAND)2 (‘PAPP’); and PPPPNPNDPAPPNANAD (‘Mixed’); Figure 1B–G]
The circumsporozoite protein (CSP) repeat is of broad interest for malaria vaccine design because it is targeted by inhibitory antibodies capable of preventing sporozoite infection as the parasite transits from Anopheles mosquitoes to mammalian hosts

Summary

Introduction

Despite extensive biomedical and public health measures, malaria persists as a major global health concern, with an estimated 405,000 deaths and 228 million cases annually (WHO, 2019). ~94% of deaths are caused by Plasmodium falciparum (Pf) (WHO, 2019), other Plasmodium species that infect humans (P. vivax, P. malariae, P. knowlesi and P. ovale) cause debilitating disease and have been associated with fatal outcomes (Lover et al, 2018). All Plasmodium species have a complex life cycle divided between a vertebrate host and an Anopheles mosquito vector (Hall and Fauci, 2009). Due to the small number of parasites transmitted and the expression of protein antigens that possess conserved functional regions (Rosenberg et al, 1990; Smith et al, 2014), the pre-erythrocytic sporozoite stage of the Plasmodium life cycle has long been considered a promising target for the development of an anti-malarial vaccine (Nussenzweig and Nussenzweig, 1984)

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