4.5 Article

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

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NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 22, 期 7, 页码 532-+

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NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3048

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资金

  1. PATH-Malaria Vaccine Initiative
  2. Bloomberg Family Foundation through the Johns Hopkins Malaria Research Institute
  3. Johns Hopkins Malaria Research Institute predoctoral fellow
  4. Calvin and Helen Lang Postdoctoral Fellow in the Biological Sciences
  5. Institut de Recherche pour le Developpement Fellowship
  6. Ifakara Health Institute
  7. Australian National Health and Medical Research Council Early Career Fellowship [1072267]
  8. Medical Research Council Early Career Fellowship [1072267]
  9. Australian Research Council Future Fellowship [110100223]
  10. National Health and Medical Research Council of Australia [1072267] Funding Source: NHMRC

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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-angstrom 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.

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