Reactive Oxygen Species-Dependent Cell Signaling Regulates the Mosquito Immune Response to Plasmodium falciparum

Abstract

Reactive oxygen species (ROS) have been implicated in direct killing of pathogens, increased tissue damage, and regulation of immune signaling pathways in mammalian cells. Available research suggests that analogous phenomena affect the establishment of Plasmodium infection in Anopheles mosquitoes. We have previously shown that provision of human insulin in a blood meal leads to increased ROS levels in Anopheles stephensi. Here, we demonstrate that provision of human insulin significantly increased parasite development in the same mosquito host in a manner that was not consistent with ROS-induced parasite killing or parasite escape through damaged tissue. Rather, our studies demonstrate that ROS are important mediators of both the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling branches of the mosquito insulin signaling cascade. Further, ROS alone can directly activate these signaling pathways and this activation is growth factor specific. Our data, therefore, highlight a novel role for ROS as signaling mediators in the mosquito innate immune response to Plasmodium parasites.

Human IGF1 extends lifespan and enhances resistance to Plasmodium falciparum infection in the malaria vector Anopheles stephensi

“…In particular, human insulin consistently induced significant phosphorylation of FOXO in the A. stephensi midgut relative to controls (Surachetpong and Pakpour et al, 2011), whereas in the present study low IGF1 enhanced phosphorylation of FOXO, but to a lesser degree. Further, IGF1 induced phosphorylation of p70S6K in the A. stephensi midgut (Fig.4), whereas insulin had no such effect (not shown).…”

“…FOXO and ERK are key mediators of the IIS downstream of the MIR, and both are phosphorylated above control levels in A. stephensi midguts in response to human insulin (Surachetpong and Pakpour et al, 2011 ). Phosphorylation levels of FOXO and p70S6K were moderately enhanced at low levels of human IGF1 (0.013mmoll -1 ), but signaling protein activation in mosquitoes treated with the higher dose of IGF1 was not different from controls (Fig.4A,B).…”

“…Although human insulin enhances P. falciparum development in A. stephensi (Surachetpong and Pakpour et al, 2011), we hypothesized that IGF1 was not likely to have the same effect on infection based on differences in midgut IIS activation following provision of insulin or IGF1. To test our hypothesis, we fed female A. stephensi with artificial blood meals containing P. falciparum and 0.0013, 0.013 or 0.133mmoll -1 IGF1 or an equivalent volume of buffer (0.1% BSA/PBS) as a control.…”

“…The most vulnerable point of the malaria parasite life cycle is the transition from the human blood stream to the mosquito midgut. During this transition, hormones, growth factors and cytokines in infected blood can regulate aspects of mosquito physiology and lifespan that directly affect parasite development (Kang et al, 2008;Luckhart et al, 2003;Luckhart and Riehle, 2007;Pakpour et al, 2012;Surachetpong et al, 2009;Surachetpong et al, 2011).…”

ERK signaling couples nutrient status to antiviral defense in the insect gut

“…Thus, the set point of ERK signaling in the gut may alter the permissivity to viral infection. In contrast, studies of Plasmodium falciparum in mosquitoes demonstrate that ingested human insulin increases the susceptibility of Anopheles stephensi by promoting replication of Plasmodium via the down-regulation of NF-κB signaling (51,52). Furthermore, ERK pathway activation by another mammalian blood product, TGF-β, in Anopheles mosquitoes has been found to down-regulate ROS production and also promote parasite growth (30).…”