title: The Anopheles-midgut APN1 structure reveals a new malaria transmission-blocking vaccine epitope.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Atkinson
authors.affiliation: 1] W. Harry Feinstone Department of Molecular Microbiology &Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. [2] Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Armistead
authors.affiliation: 1] W. Harry Feinstone Department of Molecular Microbiology &Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. [2] Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Derrick K
authors.initials: DK
authors.lastname: Mathias
authors.affiliation: Laboratoire de Recherche sur le Paludisme, Institut de Recherche pour le Développement-Organisation de Coordination et de Coopération pour la Lutte Contre les Grandes Endémies en Afrique Centrale, Yaoundé, Cameroon.
authors.forename: Maurice M
authors.initials: MM
authors.lastname: Sandeu
authors.affiliation: 1] W. Harry Feinstone Department of Molecular Microbiology &Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. [2] Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Dingyin
authors.initials: D
authors.lastname: Tao
authors.affiliation: 1] W. Harry Feinstone Department of Molecular Microbiology &Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. [2] Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Nahid
authors.initials: N
authors.lastname: Borhani-Dizaji
authors.affiliation: 1] W. Harry Feinstone Department of Molecular Microbiology &Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. [2] Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. [3] Nelson Mandela African Institute for Science and Technology, Arusha, Tanzania. [4] Ifakara Health Institute, Dar es Salaam, Tanzania.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Tarimo
authors.affiliation: Laboratoire de Recherche sur le Paludisme, Institut de Recherche pour le Développement-Organisation de Coordination et de Coopération pour la Lutte Contre les Grandes Endémies en Afrique Centrale, Yaoundé, Cameroon.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Morlais
authors.affiliation: 1] W. Harry Feinstone Department of Molecular Microbiology &Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. [2] Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Rhoel R
authors.initials: RR
authors.lastname: Dinglasan
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Borg
mesh_terms: D000818:Animals; D000852:Anopheles / Q000737:chemistry / Q000201:enzymology* / Q000276:immunology / Q000469:parasitology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D018826:CD13 Antigens / Q000737:chemistry* / Q000276:immunology*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D018604:Epitope Mapping; D006801:Humans; D008288:Malaria / Q000276:immunology / Q000635:transmission*; D017780:Malaria Vaccines / Q000276:immunology; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000502:physiology*; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D000911:Antibodies, Monoclonal; D017780:Malaria Vaccines; D018826:CD13 Antigens