Hypoxia-induced transcription factor signaling is essential for larval growth of the mosquitoAedes aegypti

Abstract

Gut microbes positively affect the physiology of many animals, but the molecular mechanisms underlying these benefits remain poorly understood. We recently reported that bacteria-induced gut hypoxia functions as a signal for growth and molting of the mosquito In this study, we tested the hypothesis that transduction of a gut hypoxia signal requires hypoxia-induced transcription factors (HIFs). Expression studies showed that HIF-α was stabilized in larvae containing bacteria that induce gut hypoxia but was destabilized in larvae that exhibit normoxia. However, we could rescue growth of larvae exhibiting gut normoxia by treating them with a prolyl hydroxylase inhibitor, FG-4592, that stabilized HIF-α, and inhibit growth of larvae exhibiting gut hypoxia by treating them with an inhibitor, PX-478, that destabilized HIF-α. Using these tools, we determined that HIF signaling activated the insulin/insulin growth factor pathway plus select mitogen-activated kinases and inhibited the adenosine monophosphate-activated protein kinase pathway. HIF signaling was also required for growth of the larval midgut and storage of neutral lipids by the fat body. Altogether, our results indicate that gut hypoxia and HIF signaling activate multiple processes in larvae, with conserved functions in growth and metabolism.

Composition and functional roles of the gut microbiota in mosquitoes

“…Functional assays supporting this hypothesis include the finding that gut hypoxia activates hypoxia-induced transcription factors (HIFs) in Ae. aegypti larvae which leads to activation of the insulin/insulin growth factor pathway, select mitogen activated kinases and other processes with essential growth functions [61, 70] (Figure 1). Transcriptome analysis also identifies several genes with functions in digestion and nutrient acquisition as additional targets that are potentially regulated by the gut microbiota or microbiota-induced hypoxia [71].…”

Production of germ-free mosquitoes via transient colonisation allows stage-specific investigation of host-microbiota interactions

“…To determine whether hypoxia-induced signalling was affected in third-instar germ-free larvae, we specifically checked the expression level of hypoxia-induced factors (HIF)-alpha and -beta (AAEL019499 and AAEL010343) and of prolyl hydroxylase (PHD)-1 and -2 genes (AAEL024908 and AAEL028025) in our samples, as HIF were reported to be induced in the presence of a microbiota in first instar larvae (Valzania et al, 2018) and are targets of PHDs. Only phd-2 was slightly down-regulated at 20h (gut: log2 fold = -1.39, padj = 0,0015; whole larvae: log2 fold = -0.6, padj = 0,015).…”

Comparison of gut bacterial communities and their associations with host diets in four fruit borers

“…Additionally, microbiota play an important role in the detoxification of noxious secondary metabolites and xenobiotics, such as terpenes, caffeine, nicotine, and insecticides, thereby enabling their insect hosts to feed on chemically defended plants . The host's physiology and behavior are often affected by microbial symbionts …”

“…6 The host's physiology and behavior are often affected by microbial symbionts. 14,15 Previous studies indicated that the structure of insect bacterial communities can be shaped by multiple endogenous and exogenous factors, such as host phylogeny, environment, and diet. [16][17][18] The gut bacterial diversity of termites and cockroaches revealed that host phylogeny was an important factor that determined gut microbial composition.…”