Abstract
The midgut environment of anopheline mosquitoes plays an important role in the development of the malaria parasite. Using genetic manipulation of anopheline mosquitoes to change the environment in the mosquito midgut may inhibit development of the malaria parasite, thus blocking malaria transmission. Here we generate transgenic Anopheles stephensi mosquitoes that express the C-type lectin CEL-III from the sea cucumber, Cucumaria echinata, in a midgut-specific manner. CEL-III has strong and rapid hemolytic activity toward human and rat erythrocytes in the presence of serum. Importantly, CEL-III binds to ookinetes, leading to strong inhibition of ookinete formation in vitro with an IC50 of 15 nM. Thus, CEL-III exhibits not only hemolytic activity but also cytotoxicity toward ookinetes. In these transgenic mosquitoes, sporogonic development of Plasmodium berghei is severely impaired. Moderate, but significant inhibition was found against Plasmodium falciparum. To our knowledge, this is the first demonstration of stably engineered anophelines that affect the Plasmodium transmission dynamics of human malaria. Although our laboratory-based research does not have immediate applications to block natural malaria transmission, these findings have significant implications for the generation of refractory mosquitoes to all species of human Plasmodium and elucidation of mosquito–parasite interactions.
Highlights
Malaria, transmitted by anopheline mosquitoes, is among the worst health problems in the world, killing 1–2 million people every year, mostly African children
Based on recent advances in the genetic engineering of mosquitoes, the concept of generating genetically modified (GM) mosquitoes that hinder transmission by either killing or interfering with parasite development is a potential means of controlling the disease
To generate these GM mosquitoes, the authors focused on a unique lectin isolated from the sea cucumber, which has both hemolytic and cytotoxic activities, as an anti-parasite effector molecule
Summary
Malaria, transmitted by anopheline mosquitoes, is among the worst health problems in the world, killing 1–2 million people every year, mostly African children. Transgenic mosquitoes expressing either SM-1 or PLA2 in a midgut-specific manner were less able to support transmission of the rodent parasite P. berghei [13,14]. Jacobs-Lorena, unpublished observations), and the PLA2 transgenic mosquito was significantly less fit than the wild-type [15]. In those transgenic mosquitoes generated so far, no single effector molecule has exhibited a ‘‘non-sporozoite’’ phenotype in the salivary glands, i.e., complete Plasmodium transmission blockade. Other effector molecules and/or mechanisms are required to generate a transgenic mosquito that is both fit and refractory to all species and strains of human Plasmodium
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