Disruption of Plasmodium falciparum development by antibodies against a conserved mosquito midgut antigen

doi:10.1073/pnas.0702239104

Disruption of Plasmodium falciparum development by antibodies against a conserved mosquito midgut antigen

*Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205;
^‡Institute of Genetic Medicine, Johns Hopkins School of Medicine, 733 North Broadway, Baltimore, MD 21205; and
^¶Malaria Vaccine Development Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5640 Fishers Lane, Rockville, MD 20852

Edited by Abdu F. Azad, University of Maryland, Baltimore, MD, and accepted by the Editorial Board June 21, 2007 (received for review March 10, 2007)

Abstract

Malaria parasites must undergo development within mosquitoes to be transmitted to a new host. Antivector transmission-blocking vaccines inhibit parasite development by preventing ookinete interaction with mosquito midgut ligands. Therefore, the discovery of novel midgut antigen targets is paramount. Jacalin (a lectin) inhibits ookinete attachment by masking glycan ligands on midgut epithelial surface glycoproteins. However, the identities of these midgut glycoproteins have remained unknown. Here we report on the molecular characterization of an Anopheles gambiae aminopeptidase N (AgAPN1) as the predominant jacalin target on the mosquito midgut luminal surface and provide evidence for its role in ookinete invasion. α-AgAPN1 IgG strongly inhibited both Plasmodium berghei and Plasmodium falciparum development in different mosquito species, implying that AgAPN1 has a conserved role in ookinete invasion of the midgut. Molecules targeting single midgut antigens seldom achieve complete abrogation of parasite development. However, the combined blocking activity of α-AgAPN1 IgG and an unrelated inhibitory peptide, SM1, against P. berghei was incomplete. We also found that SM1 can block only P. berghei, whereas α-AgAPN1 IgG can block both parasite species significantly. Therefore, we hypothesize that ookinetes can evade inhibition by two potent transmission-blocking molecules, presumably through the use of other ligands, and that this process further partitions murine from human parasite midgut invasion models. These results advance our understanding of malaria parasite–mosquito host interactions and guide in the design of transmission-blocking vaccines.

Footnotes

^†To whom correspondence may be addressed. E-mail: rdinglas{at}jhsph.edu or mlorena{at}jhsph.edu
Author contributions: R.R.D. designed research; R.R.D., D.E.K., S.M.K., A.K.G., and O.M. performed research; D.E.K. and A.P. contributed new reagents/analytic tools; R.R.D. and D.E.K. analyzed data; and R.R.D. and M.J.-L. wrote the paper.
↵ ^§Present address: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Epidemiologia Molecular de Doenças Infecciosas, Avenida Brasil, 4365, Manguinhos, RJ 21040-900, Rio de Janeiro, Brazil.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. A.F.A. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/cgi/content/full/0702239104/DC1.
Abbreviations:

AgAPN1,

Anopheles gambiae aminopeptidase N;

TBV,

transmission-blocking vaccines;

MMV,

midgut microvilli;

GAG,

glycosaminoglycan;

APN,

aminopeptidase;

GPI,

glycosylphosphatidyl inositol;

PAb,

polyclonal antibody;

PBF,

post blood-feeding;

Gal,

galactose;

ds,

double-stranded.