Abstract
Mosquito-transmitted viral pathogens, such as dengue and Zika, afflict tens of thousands of people every year. These viruses are transmitted during the blood-feeding process that is required for mosquito reproduction, the most important vector being Aedes aegypti. While vertebrate blood is rich in protein, its high iron content is potentially toxic to mosquitoes. Although iron transport and sequestration are essential in the reproduction of vector mosquitoes, we discovered that culicine mosquitoes lack homologs of the common iron transporter NRAMP. Using a novel cell-based screen, we identified two ZIP and one ZnT genes as candidate iron transporters in the mosquito A. aegypti, the vector of dengue, Zika, and chikungunya. We determined the organ-specific expression pattern of these genes at critical time points in early reproduction. The result indicates modulation of these genes upon blood feeding, especially a ZIP13 homolog that is highly up-regulated after blood feeding, suggesting its importance in iron mobilization during blood digestion and reproduction. Gene silencing resulted in differential iron accumulation in the midgut and ovaries. This study sets a foundation for further investigation of iron transport and control strategies of this viral vector.
Highlights
In recent years, diseases caused by mosquito-transmitted flaviviruses such as Zika and dengue fever have raised concern internationally (Bhatt et al, 2013; Gatherer and Kohl, 2015; Hennessey et al, 2016)
We conclude that NRAMP is not likely a receptor for Sindbis virus (SINV) in A. aegypti, or for any culicine mosquitoes that serve as a natural vector of this virus
As NRAMP is a highly conserved importer of dietary iron, and its absence in culicine mosquitoes suggests that alternative methods for the import of molecular iron must have evolved to compensate for the loss of this gene
Summary
Diseases caused by mosquito-transmitted flaviviruses such as Zika and dengue fever have raised concern internationally (Bhatt et al, 2013; Gatherer and Kohl, 2015; Hennessey et al, 2016). The incidence of these diseases, especially dengue, show a steady increase over the past 50 years and additional effective measures to reduce the burden of infection are urgently needed (WHO, 2009; Bhatt et al, 2013). Mosquitoes have evolved to use vertebrate blood for their reproduction by overcoming this dilemma. Mosquitoes could use high oxidative stress due to iron in blood meal to control pathogen infection. Activation of the Toll immune pathway in A. aegypti reduced dengue virus titer which is
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