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

Abstract

BackgroundAbscisic acid (ABA) is naturally present in mammalian blood and circulating levels can be increased by oral supplementation. We showed previously that oral ABA supplementation in a mouse model of Plasmodium yoelii 17XNL infection reduced parasitemia and gametocytemia, spleen and liver pathology, and parasite transmission to the mosquito Anopheles stephensi fed on these mice. Treatment of cultured Plasmodium falciparum with ABA at levels detected in our model had no effects on asexual growth or gametocyte formation in vitro. However, ABA treatment of cultured P. falciparum immediately prior to mosquito feeding significantly reduced oocyst development in A. stephensi via ABA-dependent synthesis of nitric oxide (NO) in the mosquito midgut.ResultsHere we describe the mechanisms of effects of ABA on mosquito physiology, which are dependent on phosphorylation of TGF-β-activated kinase 1 (TAK1) and associated with changes in homeostatic gene expression and activity of kinases that are central to metabolic regulation in the midgut epithelium. Collectively, the timing of these effects suggests a transient physiological shift that enhances NF-κB-dependent innate immunity without significantly altering mosquito lifespan or fecundity.ConclusionsABA is a highly conserved regulator of immune and metabolic homeostasis within the malaria vector A. stephensi with potential as a transmission-blocking supplemental treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-017-2276-4) contains supplementary material, which is available to authorized users.

Comprehensive and Durable Modulation of Growth, Development, Lifespan and Fecundity in Anopheles stephensi Following Larval Treatment With the Stress Signaling Molecule and Novel Antimalarial Abscisic Acid

“…In contrast to our prediction, median survival in adult females derived from larvae treated with ABA was reduced to 28 ± 10.78 days (1 µM ABA; log rank p = 0.028) and to 30 ± 14.22 days (100 µM ABA; two-stage p = 0.025) relative to the untreated control median lifespan of 34 ± 14.2 days (Figure 7). Consistent with previous observations of no effect of ABA in blood on adult female lifespan (Glennon et al, 2017), the addition of 100 nM ABA in the blood meal had no effect on adult lifespan nor did it alter the effects of larval treatment with ABA on adult lifespan ( Supplementary Table S4).…”

“…In our previous studies, we observed that ingestion of an ABA-supplemented blood meal by female A. stephensi induced signaling kinases associated with a transient metabolic shift in the midgut, fueling immune-mediated killing of P. falciparum prior to completion of oocyst development (Glennon et al, 2016(Glennon et al, , 2017. Interestingly, ingested ABA did not decrease A. stephensi fecundity in the first gonotrophic cycle in contrast to our predictions based on the effects of ABA in A. elliotti and in S. bullata (Glennon et al, 2017).…”

“…While dietary restriction and the resulting impacts on nutrient stores have been associated with lifespan extension in Anopheles mosquitoes (Faiman et al, 2017), we observed reduced survivorship with reduced body protein levels in A. stephensi derived from larvae treated with ABA. Reduced survival of ABA-treated mosquitoes was unexpected as weekly supplementation of adults with ABA in blood meals did not change adult female survival (Glennon et al, 2017). Our data indicate that the substantial effect of ABA on adult lifespan carries over from the larval stage and across not one, but two developmental transitions.…”

“…We previously demonstrated that ABA supplementation in a blood meal reduced the expression of ilp3 and ilp4 in adult female A. stephensi (Glennon et al, 2017), suggesting that ABA might also alter ilp expression in the larval stage. In D. melanogaster larvae, decreased drosulfakinin (DSK) has been associated with increased feeding and reduced food selectivity, with decreased dsk mRNA levels detected in Dilp2,3,5 triple mutants but not Dilp5 mutants (Söderberg et al, 2012).…”

“…In our previous studies, we observed that ingestion of an ABA-supplemented blood meal by female A. stephensi induced signaling kinases associated with a transient metabolic shift in the midgut, fueling immune-mediated killing of P. falciparum prior to completion of oocyst development (Glennon et al, 2016(Glennon et al, , 2017. Interestingly, ingested ABA did not decrease A. stephensi fecundity in the first gonotrophic cycle in contrast to our predictions based on the effects of ABA in A. elliotti and in S. bullata (Glennon et al, 2017). However, given the effects of ABA on metabolism and homeostasis of the A. stephensi midgut, on nutrient stores and 20E levels in other insects, and the potential that ABA in water used for oviposition could impact larval growth, we sought to understand whether ABA, at levels consistent with those released by inundated plants, could affect A. stephensi larval development, pupation and fitness of adult females emerging from treated larvae.…”