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 journalArticle

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-Å 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 (US)
Pages (from-to)532-539
Number of pages8
JournalNature Structural and Molecular Biology
Volume22
Issue number7
DOIs
StatePublished - Jul 9 2015

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Fingerprint Dive into the research topics of 'The Anopheles-midgut APN1 structure reveals a new malaria transmission-blocking vaccine epitope'. Together they form a unique fingerprint.

  • Cite this

    Atkinson, S. C., Armistead, J. S., Mathias, D. K., Sandeu, M. M., Tao, D., Borhani-Dizaji, N., Tarimo, B. B., Morlais, I., Dinglasan, R. R., & Borg, N. A. (2015). The Anopheles-midgut APN1 structure reveals a new malaria transmission-blocking vaccine epitope. Nature Structural and Molecular Biology, 22(7), 532-539. https://doi.org/10.1038/nsmb.3048