Targeting the Conserved Fusion Loop of HAP2 Inhibits the Transmission of Plasmodium berghei and falciparum

Cell Rep. 2017 Dec 5;21(10):2868-2878. doi: 10.1016/j.celrep.2017.11.024.

Abstract

Inhibiting transmission of Plasmodium is a central strategy in malarial eradication, and the biological process of gamete fusion during fertilization is a proven target for this approach. The lack of a structure or known molecular function of current anti-malarial vaccine targets has previously been a hindrance in the development of transmission-blocking vaccines. Structure/function studies have indicated that the conserved gamete membrane fusion protein HAP2 is a class II viral fusion protein. Here, we demonstrate that targeting a function-critical site of the fusion/cd loop with species-specific antibodies reduces Plasmodium berghei transmission in vivo by 58.9% and in vitro fertilization by up to 89.9%. A corresponding reduction in P. falciparum transmission (75.5%/36.4% reductions in intensity/prevalence) is observed in complimentary field studies. These results emphasize conserved mechanisms of fusion in Apicomplexa, while highlighting an approach to design future anti-malarial transmission-blocking vaccines.

Keywords: HAP2; fusion; malaria; transmission; vaccine.

MeSH terms

  • Animals
  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • Malaria / drug therapy
  • Malaria / genetics
  • Malaria / metabolism
  • Malaria Vaccines / therapeutic use
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / genetics
  • Malaria, Falciparum / metabolism
  • Male
  • Mice
  • Plasmodium berghei / drug effects*
  • Plasmodium berghei / metabolism
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*

Substances

  • Antimalarials
  • Malaria Vaccines
  • Protozoan Proteins