The Anopheles-midgut APN1 structure reveals a new malaria transmission-blocking vaccine epitope

Sarah C Atkinson, Jennifer S Armistead, Derrick K Mathias, Maurice M Sandeu, Dingyin Tao, Nahid Borhani-Dizaji, Brian B Tarimo, Isabelle Morlais, Rhoel R Dinglasan, Natalie A Borg

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

Mosquito-based malaria transmission-blocking vaccines (mTBVs) target midgut-surface antigens of the Plasmodium parasite s obligate vector, the Anopheles mosquito. The alanyl aminopeptidase N (AnAPN1) is the leading mTBV immunogen; however, AnAPN1 s role in Plasmodium infection of the mosquito and how anti-AnAPN1 antibodies functionally block parasite transmission have remained elusive. Here we present the 2.65-A crystal structure of AnAPN1 and the immunoreactivity and transmission-blocking profiles of three monoclonal antibodies (mAbs) to AnAPN1, including mAb 4H5B7, which effectively blocks transmission of natural strains of Plasmodium falciparum. Using the AnAPN1 structure, we map the conformation-dependent 4H5B7 neoepitope to a previously uncharacterized region on domain 1 and further demonstrate that nonhuman-primate neoepitope-specific IgG also blocks parasite transmission. We discuss the prospect of a new biological function of AnAPN1 as a receptor for Plasmodium in the mosquito midgut and the implications for redesigning the AnAPN1 mTBV.
Original languageEnglish
Pages (from-to)532 - 539
Number of pages8
JournalNature Structural & Molecular Biology
Volume22
Issue number7
DOIs
Publication statusPublished - 2015

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