Intestinal Immune Deficiency and Juvenile Hormone Signaling Mediate a Metabolic Trade-off in Adult Drosophila Females
<p>Fecundity does not increase when midgut motility, progenitor and enterocyte septate junctions, or regeneration is compromised. Downregulation of the motility-related genes <span class="html-italic">moto</span> (<span class="html-italic">CG11307</span> gene lines 1082330/KK and 30050/GD, LT50 = 5.5; <span class="html-italic">p</span> < 0.0001) and <span class="html-italic">Myosuppressin</span> (<span class="html-italic">Ms</span>) (LT50 = 4.9; <span class="html-italic">p</span> < 0.0001) resulted in a significant decrease in survival upon infection, relative to control flies (LT50 = 7.3) (<b>A</b>), but also caused a significant reduction in eggs per fly per day (<span class="html-italic">p</span> < 0.05) (<b>B</b>). Downregulation of the genes encoding septate junction proteins <span class="html-italic">bbg</span> (LT50 = 5.5; <span class="html-italic">p</span> < 0.05) and <span class="html-italic">tsp2A</span> (LT50 = 5.4; <span class="html-italic">p</span> = 0.0001) resulted in a significant decrease in survival upon infection, relative to control flies (LT50 = 6.8) (<b>C</b>). <span class="html-italic">bbg<sup>RNAi</sup></span> also caused a significant reduction in eggs per fly per day (<span class="html-italic">p</span> < 0.05) (<b>D</b>). Downregulation and overexpression of <span class="html-italic">cycE</span> in ISCs (LT50 = 4.5; <span class="html-italic">p</span> < 0.05) resulted in a decrease and an increase in survival upon infection, respectively, relative to control (LT50 = 5.3) (<b>E</b>) and had no effect on fecundity (<b>F</b>). <span class="html-italic">n</span> = 45 flies for (<b>A</b>,<b>C</b>,<b>E</b>). Six replicates of 7–8 flies each for (<b>B</b>,<b>D</b>,<b>F</b>); “*” and “**” stand for <span class="html-italic">p</span>-value < 0.05 and <0.01, respectively.</p> "> Figure 2
<p>Fecundity and enterocyte metabolism are compromised by the midgut innate immunity. (<b>A</b>) Wild-type <span class="html-italic">Oregon-R</span> females fed with live (<span class="html-italic">p</span> < 0.01) or heat-killed (<span class="html-italic">p</span> < 0.05) <span class="html-italic">P</span>. <span class="html-italic">aeruginosa</span> PA14 reduced egg production per fly per day, compared to mock-infected flies. (<b>B</b>) Feeding with heat-killed bacteria in control flies reduced egg laying (<span class="html-italic">p</span> < 0.01), but not upon downregulation of <span class="html-italic">rel</span> or <span class="html-italic">Duox</span> in enterocytes via <span class="html-italic">MyoG4<sup>ts</sup></span>. Eggs per fly per day was significantly reduced upon JAK/STAT pathway inactivation through the expression of <span class="html-italic">dome<sup>ΔC</sup></span> (<span class="html-italic">p</span> < 0.05). (<b>C</b>) Feeding with live PA14 caused a significant reduction in egg laying in control flies (<span class="html-italic">p</span> < 0.05). The reduction was rescued upon downregulation of <span class="html-italic">rel</span> and <span class="html-italic">duox</span>, but not upon expression of <span class="html-italic">dome<sup>ΔC</sup></span> (<span class="html-italic">p</span> < 0.01) in the midgut enterocytes. (<b>D</b>) Immune challenge with heat-killed PA14 lowered <span class="html-italic">InR</span> mRNA levels in <span class="html-italic">Myo-G4/+</span> females, as measured by RT-qPCR (<span class="html-italic">p</span> < 0.05), and <span class="html-italic">InR</span> mRNA levels remained low in <span class="html-italic">Myo-G4/U-rel<sup>RNAi</sup></span> females, regardless of immune challenge. (<b>E</b>) Nile Red stained lipid droplets increased in the anterior midgut of <span class="html-italic">Myo-G4/+</span> females upon immune activation with heat-killed PA14. (<b>F</b>) Lipid droplets in <span class="html-italic">Myo-G4/U-rel<sup>RNAi</sup></span> females did not increase upon immune challenge. Representative images for each condition are shown (<b>E</b>,<b>F</b>). “ns”, “*” and “**” stand for <span class="html-italic">p</span>-value > 0.05, <0.05 and <0.01, respectively.</p> "> Figure 3
<p>Mating compromises host defense to intestinal infection in immunocompetent females of various genetical backgrounds. Mating significantly decreased survival to infection with <span class="html-italic">P</span>. <span class="html-italic">aeruginosa</span> PA14 in Oregon-R (<b>A</b>), <span class="html-italic">w<sup>1118</sup></span> (<b>B</b>), <span class="html-italic">tud<sup>1</sup>/+</span> (<b>C</b>) and Berlin (<b>D</b>) females (<span class="html-italic">n</span> = 45). Mating had no effect on Oregon-R (<b>E</b>) and <span class="html-italic">w<sup>1118</sup></span> (<b>F</b>) males (<span class="html-italic">n</span> = 30).</p> "> Figure 4
<p>Mating increases intestinal permeability, aging-related epithelial dysplasia and suppresses local innate immune signaling. (<b>A</b>) Average and standard deviation of excreta per female per day from 3 replicates of 10 flies. The defecation rate of Oregon-R mated flies was not compromised compared to virgin females. (<b>B</b>) Average number of CFUs in the hemolymph and fly carcass from 6 replicates of three females. (<b>C</b>) Ratio of Smurf to total flies from 6 replicates of ten females. Intestinal permeability was increased upon mating as indicated by the higher number of CFUs in the hemolymph of Oregon-R wild-type mated flies (<span class="html-italic">p</span> < 0.05) (<b>B</b>) and by the higher level of bromophenol blue dye diffusion in their abdominal area (<span class="html-italic">p</span> < 0.001) (<b>C</b>). (<b>D</b>) <span class="html-italic">P</span>. <span class="html-italic">aeruginosa</span> infected midguts of mated Oregon-R females had more nuclei marked by the mitosis marker pH3 (<span class="html-italic">p</span> < 0.01). (<b>E</b>,<b>F</b>) Mated 30-days-old females had more <span class="html-italic">Dl-G4 U-GFP</span> labelled midgut ISC clusters of 3, 4, 5, 6, 7, 8 or >8 cells each, compared to age-matched virgins (<span class="html-italic">n</span> = 12, <span class="html-italic">p</span> < 0.001) (<b>E</b>), and more clusters of <span class="html-italic">prospero</span>-expressing cells (EEs) (<span class="html-italic">n</span> = 12, <span class="html-italic">p</span> < 0.05) (<b>F</b>). (<b>G</b>,<b>H</b>) Systemic and midgut expression of <span class="html-italic">attA, diptB, drsl3</span> and <span class="html-italic">duox</span> in the carcasses (<b>G</b>) and midguts (<b>H</b>), respectively, of mated and virgin Oregon-R females without and upon challenge with heat-killed PA14 (6 replicates of ≥20 female carcasses or midguts). Systemically, <span class="html-italic">attA</span> and <span class="html-italic">diptB</span> expression was induced upon immune challenge in virgin (<span class="html-italic">p</span> < 0.01), rather than mated females (<b>G</b>). Midgut expression of <span class="html-italic">diptB</span> was reduced in mated females at baseline and upon immune challenge, compared to virgins (<span class="html-italic">p</span> < 0.05); <span class="html-italic">attA</span> expression was only tentatively decreased in mated females, compared to virgins (<b>H</b>). “ns”, “*”, “**”, and “***” stand for <span class="html-italic">p</span>-value > 0.05, <0.05, <0.01 and <0.001, respectively.</p> "> Figure 5
<p>CA and midgut juvenile hormone biosynthesis compromises intestinal host defense. (<b>A</b>,<b>B</b>) Downregulation of <span class="html-italic">jhamt</span> (via VDRC# 103958/KK and 19172/GD) in the CA reduced eggs per fly per day (<span class="html-italic">p</span> < 0.01) (<b>A</b>), and increased in survival upon infection with <span class="html-italic">P</span>. <span class="html-italic">aeruginosa</span> (<span class="html-italic">p</span> < 0.001) (<b>B</b>). (<b>C</b>,<b>D</b>) Downregulation of <span class="html-italic">jhamt</span> in the midgut EEs reduced eggs per fly per day (<span class="html-italic">p</span> < 0.05) (<b>C</b>), and increased in survival upon infection (<span class="html-italic">p</span> < 0.001) (<b>D</b>). (<b>E</b>,<b>F</b>) Downregulation of <span class="html-italic">jhamt</span> in the midgut progenitors reduced eggs per fly per day (<span class="html-italic">p</span> < 0.05 for 19172/GD) (<b>E</b>), and increased in survival upon infection (<span class="html-italic">p</span> < 0.001) (<b>F</b>). (<b>G</b>,<b>H</b>) Downregulation of <span class="html-italic">jhamt</span> in the midgut enterocytes did not reduce eggs per fly per day (<b>G</b>), nor did it increase survival upon infection (<b>H</b>). Six replicates of 7–8 flies each were used in (<b>A</b>,<b>C</b>,<b>E</b>,<b>G</b>). <span class="html-italic">n</span> = 45 flies of each genotype were used in (<b>B</b>,<b>D</b>,<b>F</b>,<b>H</b>). “ns”, “*” and “**” stand for <span class="html-italic">p</span>-value > 0.05, <0.05, <0.01 and <0.001, respectively.</p> "> Figure 6
<p>Systemic and midgut progenitor Juvenile Hormone signaling compromises intestinal host defense. (<b>A</b>,<b>B</b>) Downregulation of <span class="html-italic">Yp1, Yp2</span> and <span class="html-italic">Met</span> (via VDRC# 10801/GD) in the fat body and hemocytes reduced eggs per fly per day (<span class="html-italic">p</span> < 0.05) (<b>A</b>) and increased survival upon infection with <span class="html-italic">P</span>. <span class="html-italic">aeruginosa</span> upon downregulation of <span class="html-italic">Yp2</span> (LT50 = 8.85, <span class="html-italic">p</span> < 0.05), <span class="html-italic">Yp3</span> (LT50 = 9.72, <span class="html-italic">p</span> < 0.001), <span class="html-italic">Met</span> (100638/KK LT50 = 11.17, <span class="html-italic">p</span> < 0.0001; 10801/GD, LT50 = 9.42, <span class="html-italic">p</span> < 0.01), <span class="html-italic">gce</span> (LT50 = 12.95, <span class="html-italic">p</span> < 0.0001) and <span class="html-italic">tai</span> (LT50 = 13.65, <span class="html-italic">p</span> < 0.0001)), compared to control (LT50 = 7.82) (<b>B</b>). (<b>C</b>,<b>D</b>) Downregulation of <span class="html-italic">Met, gce</span> and <span class="html-italic">tai</span> in the midgut progenitors reduced eggs per fly per day (<span class="html-italic">p</span> < 0.01) (<b>C</b>), and increased survival upon infection upon downregulation of <span class="html-italic">gce</span> (LT50 = 12.9, <span class="html-italic">p</span> < 0.0001), <span class="html-italic">Met</span> (100638/KK LT50 = 6.85, <span class="html-italic">p</span> < 0.01; 10801/GD lines, LT50 = 7.05, <span class="html-italic">p</span> < 0.05) and <span class="html-italic">tai</span> (LT50 = 8.75, <span class="html-italic">p</span> < 0.0001), relative to control (LT50 = 6.4) (<b>D</b>). Six replicates of 7–8 flies each were used in (<b>A</b>,<b>C</b>); “*” and “**” stand for <span class="html-italic">p</span>-value < 0.05 and <0.01, respectively. <span class="html-italic">n</span> = 45 flies of each genotype were used in (<b>B</b>,<b>D</b>).</p> "> Figure 7
<p>Female midgut progenitor juvenile hormone signaling compromises epithelial integrity and innate immunity and increases InR expression. Downregulation of <span class="html-italic">gce</span> in the midgut progenitors reduced mitosis at baseline and upon immune challenge ((<b>A</b>), <span class="html-italic">n</span> ≥ 10, <span class="html-italic">p</span> < 0.01), <span class="html-italic">ISC<sup>ts</sup></span> labelled ISC clusters of 6, 7, 8 and >8 cells ((<b>B</b>), <span class="html-italic">n</span> ≥ 10, <span class="html-italic">p</span> < 0.001), the fraction of Smurf flies ((<b>C</b>), <span class="html-italic">n</span> = 6, <span class="html-italic">p</span> < 0.01), and <span class="html-italic">InR</span> expression at baseline ((<b>E</b>), 3 replicates of ≥20 midguts, <span class="html-italic">p</span> < 0.01), and increased <span class="html-italic">diptB</span> at baseline (<span class="html-italic">p</span> < 0.01) and upon immune challenge (<span class="html-italic">p</span> < 0.05) ((<b>D</b>), 6 replicates of ≥20 midguts). “*”, “**”, and “***” stand for <span class="html-italic">p</span>-value < 0.05, <0.01 and <0.001, respectively.</p> "> Figure 8
<p>Females compromised in midgut immunity and cell homeostasis are susceptible to intestinal infection, regardless of their virgin vs mated status. (<b>A</b>) Virgin and mated sterile <span class="html-italic">tud<sup>1</sup>/+</span> females (rendered maternally germline-less) exhibited compromised host defense to intestinal infection, compared to isogenic fertile <span class="html-italic">tud<sup>1</sup>/+</span> females (<span class="html-italic">n</span> = 30). (<b>B</b>–<b>D</b>) Virgin and mated sterile <span class="html-italic">tud<sup>1</sup>/+</span> females exhibited very low midgut mitosis at baseline and upon infection ((<b>B</b>), <span class="html-italic">n</span> ≥ 10, <span class="html-italic">p</span> < 0.01), and increased intestinal dysplasia ((<b>C</b>), <span class="html-italic">n</span> ≥ 10, <span class="html-italic">p</span> < 0.001) and permeability ((<b>D</b>), <span class="html-italic">n</span> = 6, <span class="html-italic">p</span> < 0.001), compared to isogenic fertile <span class="html-italic">tud<sup>1</sup>/+</span> females. (<b>E</b>) Mated sterile <span class="html-italic">tud<sup>1</sup>/+</span> females exhibited severely reduced midgut expression of <span class="html-italic">attA, diptB, drsl3</span> and <span class="html-italic">Duox</span> at baseline and upon immune challenge, compared to isogenic fertile <span class="html-italic">tud<sup>1</sup>/+</span> females (3 replicates of ≥20 midguts). “**” and “***” stand for <span class="html-italic">p</span>-value < 0.01 and <0.001, respectively.</p> "> Figure 9
<p>Model diagram of intestinal and systemic interactions between fecundity and intestinal host defence. JHs are synthesized in the midgut progenitors and EEs, facilitating regeneration, but also dysplasia, and in turn leakiness of the gut. Midgut JHs may induce InR signaling and lipid droplet utilization in the enterocytes but may also reduce AMPs and tolerance to intestinal <span class="html-italic">P</span>. <span class="html-italic">aeruginosa</span>. Vice versa, Imd signaling may reduce InR signaling and lipid droplet utilization in the enterocytes. Mating induces JHs in the CA, and in turn Yps (egg ingredients) in the fat body. Finally, fat body induction of AMPs via Imd signaling may inhibit Yps induction via JH signaling, and vice versa. Arrows and stop arrows indicate actions and counteractions, respectively. Dashed lines indicate hypothetical actions or counteractions.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Immune Activation Reduces Reproductive Rate
2.2. Imd and Duox Signaling in Midgut Enterocytes Compromises Fecundity and Insulin-Mediated Metabolism
2.3. Mating Compromises Female Drosophila Intestinal Host Defense
2.4. JH Synthesis and Signaling Compromises Intestinal Host Defense
3. Discussion
4. Materials and Methods
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Shianiou, G.; Teloni, S.; Apidianakis, Y. Intestinal Immune Deficiency and Juvenile Hormone Signaling Mediate a Metabolic Trade-off in Adult Drosophila Females. Metabolites 2023, 13, 340. https://doi.org/10.3390/metabo13030340
Shianiou G, Teloni S, Apidianakis Y. Intestinal Immune Deficiency and Juvenile Hormone Signaling Mediate a Metabolic Trade-off in Adult Drosophila Females. Metabolites. 2023; 13(3):340. https://doi.org/10.3390/metabo13030340
Chicago/Turabian StyleShianiou, Gavriella, Savvas Teloni, and Yiorgos Apidianakis. 2023. "Intestinal Immune Deficiency and Juvenile Hormone Signaling Mediate a Metabolic Trade-off in Adult Drosophila Females" Metabolites 13, no. 3: 340. https://doi.org/10.3390/metabo13030340