Two insulin-like peptides differentially regulate malaria parasite infection in the mosquito through effects on intermediary metabolism

Abstract

Insulin-like peptides (ILPs) play important roles in growth and metabolic homeostasis, but have also emerged as key regulators of stress responses and immunity in a variety of vertebrates and invertebrates. Furthermore, a growing literature suggests that insulin signaling-dependent metabolic provisioning can influence host responses to infection and affect infection outcomes. In line with these studies, we previously showed that knockdown of either of two closely related, infection-induced ILPs, ILP3 and ILP4, in the mosquito Anopheles stephensi decreased infection with the human malaria parasite Plasmodium falciparum through kinetically distinct effects on parasite death. However, the precise mechanisms by which ILP3 and ILP4 control the response to infection remained unknown. To address this knowledge gap, we used a complementary approach of direct ILP supplementation into the blood meal to further define ILP-specific effects on mosquito biology and parasite infection. Notably, we observed that feeding resulted in differential effects of ILP3 and ILP4 on blood-feeding behavior and P. falciparum development. These effects depended on ILP-specific regulation of intermediary metabolism in the mosquito midgut, suggesting a major contribution of ILP-dependent metabolic shifts to the regulation of infection resistance and parasite transmission. Accordingly, our data implicate endogenous ILP signaling in balancing intermediary metabolism for the host response to infection, affirming this emerging tenet in host–pathogen interactions with novel insights from a system of significant public health importance.

Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection

“…falciparum resistance in A . stephensi [22], so this approach was chosen to help us define the nature of parasite resistance associated with JNK inhibition. While our data suggested that MKP4 activity is likely specific to JNK signaling in the A .…”

“…Resistance was independent of effects on NF-κB-dependent innate immunity, adding to the list of similar observations in A . stephensi that highlight the importance of alternative signaling pathways and intermediary metabolism in mediating anti-parasite resistance [14, 20, 22]. The phenotypic effects of JNK inhibition may be due in part to inhibition of IIS in the A .…”

“…Signaling proteins and pathways that finely tune mosquito defense against parasite infection include the mitogen activated protein kinases (MAPKs) [11, 12], insulin/insulin-like growth factor signaling (IIS) [13–16], and the transforming growth factor (TGF)-β signaling pathway [17]. These pathways regulate mosquito NO synthase (NOS) and production of RNOS [16, 18, 19] as well as intermediary metabolism and epithelial barrier function in the mosquito midgut to control parasite infection [12, 16, 20–22].…”

Abscisic acid induces a transient shift in signaling that enhances NF-κB-mediated parasite killing in the midgut of Anopheles stephensi without reducing lifespan or fecundity

“…To determine whether ABA activates these pathways to regulate host immunity, we examined insulin-like peptide ( ilp ) gene expression, which is regulated by IIS [12], as well as activation of the MAPKs ERK, JNK, and p38 MAPK and the MAP3K TAK1 in the A. stephensi midgut. We focused our analyses on ILP3 and ILP4, which regulate P. falciparum development in A. stephensi through effects on midgut intermediary metabolism and mitochondrial function [13]. In contrast to ABA enhancement of insulin secretion in mammalian cells, ABA significantly repressed expression of ilp3 mRNA at 8 h post-infection ( t  = 2.953, df  = 6, P  = 0.026) and ilp4 mRNA at 4 ( t  = 3.472, df  = 5, P  = 0.018), 6 ( t  = 13.42, df  = 5, P  < 0.0001), and 8 ( t  = 3.079, df  = 6, P  = 0.022) hours post-infection in the mosquito midgut relative to controls (Fig.…”

Glucose-mediated expansion of a gut commensal bacterium promotesPlasmodiuminfection through alkalizing mosquito midgut

“…A reduction of trehalose level by knocking down trehalose transporter, AgTret1, impaired Plasmodium falciparum infection in mosquitoes . Insulin/insulin-like growth factor signaling (IIS) is also involved in regulating of Plasmodium falciparum infection in mosquitoes (Corby-Harris et al, 2010;Luckhart et al, 2013;Pietri et al, 2016). Thus, glucose metabolism in mosquito is expected to play a role in the development of Plasmodium parasites.…”