Abstract

Interventions that can block the transmission of malaria-causing Plasmodium falciparum (Pf) between the human host and Anopheles vector have the potential to reduce the incidence of malaria. Pfs48/45 is a gametocyte surface protein critical for parasite development and transmission, and its targeting by monoclonal antibody (mAb) 85RF45.1 leads to the potent reduction of parasite transmission. Here, we reveal how the Pfs48/45 6C domain adopts a (SAG1)-related-sequence (SRS) fold. We structurally delineate potent epitope I and show how mAb 85RF45.1 recognizes an electronegative surface with nanomolar affinity. Analysis of Pfs48/45 sequences reveals that polymorphisms are rare for residues involved at the binding interface. Humanization of rat-derived mAb 85RF45.1 conserved the mode of recognition and activity of the parental antibody, while also improving its thermostability. Our work has implications for the development of transmission-blocking interventions, both through improving vaccine designs and the testing of passive delivery of mAbs in humans.

Details

Title
Structural delineation of potent transmission-blocking epitope I on malaria antigen Pfs48/45
Author
Kundu, Prasun 1 ; Semesi, Anthony 1 ; Jore, Matthijs M 2 ; Morin, Merribeth J 3 ; Price, Virginia L 3 ; Liang, Alice 4 ; Li, Jingxing 4 ; Miura, Kazutoyo 5 ; Sauerwein, Robert W 2 ; C Richter King 3 ; Jean-Philippe, Julien 6   VIAFID ORCID Logo 

1  Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada 
2  Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands 
3  PATH’s Malaria Vaccine Initiative, Washington, DC, USA 
4  LakePharma Inc., Belmont, CA, USA 
5  Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA 
6  Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada; Departments of Biochemistry and Immunology, University of Toronto, Toronto, ON, Canada 
Pages
1-9
Publication year
2018
Publication date
Oct 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-06742-9
ProQuest document ID
2125648015
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.