Abstract
Background Plasmodium development in the mosquito is crucial for malaria transmission and depends on the parasite's interaction with a variety of cell types and specific mosquito factors that have both positive and negative effects on infection. Whereas the defensive response of the mosquito contributes to a decrease in parasite numbers during these stages, some components of the blood meal are known to favor infection, potentiating the risk of increased transmission. The presence of the antimalarial drug chloroquine in the mosquito's blood meal has been associated with an increase in Plasmodium infectivity for the mosquito, which is possibly caused by chloroquine interfering with the capacity of the mosquito to defend against the infection.Methodology/Principal FindingsIn this study, we report a detailed survey of the Anopheles gambiae genes that are differentially regulated by the presence of chloroquine in the blood meal, using an A. gambiae cDNA microarray. The effect of chloroquine on transcript abundance was evaluated separately for non-infected and Plasmodium berghei-infected mosquitoes. Chloroquine was found to affect the abundance of transcripts that encode proteins involved in a variety of processes, including immunity, apoptosis, cytoskeleton and the response to oxidative stress. This pattern of differential gene expression may explain the weakened mosquito defense response which accounts for the increased infectivity observed in chloroquine-treated mosquitoes.Conclusions/SignificanceThe results of the present study suggest that chloroquine can interfere with several putative mosquito mechanisms of defense against Plasmodium at the level of gene expression and highlight the need for a better understanding of the impacts of antimalarial agents on parasite transmission.
Highlights
Plasmodium development in the mosquito vector involves several critical steps and the sporogonic cycle needs to be completed successfully within the mosquito for the parasite to be transmitted to the vertebrate host
The effect of chloroquine on A. gambiae midgut transcript abundance was assessed by comparing the gene expression levels of i) mosquitoes fed on a blood meal that contained chloroquine and those fed on a normal blood meal (Chl 50), and ii) mosquitoes fed a P. berghei-infected blood meal that contained chloroquine and those fed a normal P. berghei-infected blood meal (Chl 50Pb)
While chloroquine affected mosquito genes that are implicated in very diverse functions, the present study focused on those genes that have been linked to innate immunity and processes that are known to be affected by Plasmodium infection
Summary
Plasmodium development in the mosquito vector involves several critical steps and the sporogonic cycle needs to be completed successfully within the mosquito for the parasite to be transmitted to the vertebrate host. We have recently analyzed the impact of chloroquine on the expression of two previously undescribed Plasmodium yoelli genes that are upregulated during transmission in the presence of chloroquine [7] These results suggests that enhanced infectivity for the mosquito results from chloroquine interference with mosquito defense mechanisms rather than from a direct effect on parasite virulence, given that the chloroquine- mediated downregulation of immune-related genes was observed both with different doses of the drug and in the absence of infection, while the affected genes have previously been shown to respond positively to Plasmodium invasion of midgut cells [8,9,10,11,12]. The presence of the antimalarial drug chloroquine in the mosquito’s blood meal has been associated with an increase in Plasmodium infectivity for the mosquito, which is possibly caused by chloroquine interfering with the capacity of the mosquito to defend against the infection
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