Abstract

Proteins Pfs230 and Pfs48/45 are Plasmodium falciparum transmission-blocking (TB) vaccine candidates that form a membrane-bound protein complex on gametes. The biological role of Pfs230 or the Pfs230-Pfs48/45 complex remains poorly understood. Here, we present the crystal structure of recombinant Pfs230 domain 1 (Pfs230D1M), a 6-cysteine domain, in complex with the Fab fragment of a TB monoclonal antibody (mAb) 4F12. We observed the arrangement of Pfs230 on the surface of macrogametes differed from that on microgametes, and that Pfs230, with no known membrane anchor, may exist on the membrane surface in the absence of Pfs48/45. 4F12 appears to sterically interfere with Pfs230 function. Combining mAbs against different epitopes of Pfs230D1 or of Pfs230D1 and Pfs48/45, significantly increased TB activity. These studies elucidate a mechanism of action of the Pfs230D1 vaccine, model the functional activity induced by a polyclonal antibody response and support the development of TB vaccines targeting Pfs230D1 and Pfs230D1-Pfs48/45.

With the aim to advance the development of a P. falciparum transmission blocking vaccine, Singh et al. determine the crystal structure of Pfs230D1 in complex with the Fab fragment of TB mAb 4F12. They further study the cellular localization of Pfs230 on the surface of sexual stages of parasites and the effect of combining TB mAbs against Pfs230 and Pfs48/45.

Details

Title
Structure and function of a malaria transmission blocking vaccine targeting Pfs230 and Pfs230-Pfs48/45 proteins
Author
Singh, Kavita 1 ; Burkhardt, Martin 2 ; Nakuchima Sofia 2 ; Herrera, Raul 2 ; Muratova Olga 2 ; Gittis, Apostolos G 1 ; Kelnhofer Emily 2 ; Reiter Karine 2 ; Smelkinson Margery 3 ; Veltri, Daniel 4   VIAFID ORCID Logo  ; Swihart, Bruce J 5 ; Richard, Shimp, Jr 2 ; Nguyen, Vu 2 ; Zhang, Baoshan 6 ; MacDonald, Nicholas J 2 ; Duffy, Patrick E 2   VIAFID ORCID Logo  ; Garboczi, David N 1 ; Narum, David L 2   VIAFID ORCID Logo 

1  National Institutes of Health, Structural Biology Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
2  National Institutes of Health, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
3  National Institutes of Health, Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
4  National Institutes of Health, Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Rockville, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075) 
5  National Institutes of Health, Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Rockville, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075) 
6  National Institutes of Health, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s42003-020-01123-9
ProQuest document ID
2426704994
Copyright
© This is a U.S. government work and not under copyright protection in the US; foreign copyright protection may apply 2020. 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.