Forkhead, a new cross regulator of metabolism and innate immunity downstream of TOR in Drosophila

Varma, Disha; Bülow, Margret H.; Pesch, Yanina-Yasmin; Loch, Gerrit; Hoch, Michael

doi:10.1016/j.jinsphys.2014.04.006

Cited by 46 publications

(45 citation statements)

References 27 publications

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“…These transcription factors are activated upon infection by two major signaling cascades, the Toll and immune deficiency (IMD) pathways [5]. Additionally, subsets of AMPs can be directly activated by the transcription factors Drosophila Forkhead box O (dFOXO) or Forkhead (FKH), depending on the metabolic status of the fly, demonstrating a cross regulation between metabolism and innate immunity [6,7]. In the midgut AMP expression is not regulated by Toll signaling but by the IMD and the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways [8] and controlled by the negative transcriptional regulator caudal [9].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial peptides extend lifespan in Drosophila

et al. 2017

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Antimicrobial peptides (AMPs) are important defense molecules of the innate immune system. High levels of AMPs are induced in response to infections to fight pathogens, whereas moderate levels induced by metabolic stress are thought to shape commensal microbial communities at barrier tissues. We expressed single AMPs in adult flies either ubiquitously or in the gut by using the inducible GeneSwitch system to tightly regulate AMP expression. We found that activation of single AMPs, including Drosocin, resulted in a significant extension of Drosophila lifespan. These animals showed reduced activity of immune pathways over lifetime, less intestinal regenerative processes, reduced stress response and a delayed loss of gut barrier integrity. Furthermore, intestinal Drosocin induction protected the animals against infections with the natural Drosophila pathogen Pseudomonas entomophila, whereas a germ-reduced environment prevented the lifespan extending effect of Drosocin. Our study provides new insights into the crosstalk of innate immunity, intestinal homeostasis and ageing.

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Section: Introductionmentioning

confidence: 99%

Antimicrobial peptides extend lifespan in Drosophila

et al. 2017

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“…Indeed, the Drosophila transcription factor Forkhead box O (dFOXO) in the insulin/insulin-like growth factor signaling pathway could regulate the expressions of the antimicrobial peptides (AMPs) under normal physiological conditions (3). The target of rapamycin cascade, another nutrient-dependent pathway in Drosophila, also has the potential impact on the innate immunity and the transcriptions of AMPs (4)(5)(6).…”

mentioning

confidence: 99%

Ecdysone Titer Determined by 3DE-3β-Reductase Enhances the Immune Response in the Silkworm

Sun

Shen

Zhou

et al. 2016

The Journal of Immunology

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Although recent studies have demonstrated that 20-hydroxyecdysone (20E), one of the two most important hormones for development, could promote the insect innate immune response, how insects regulate 20E titer to affect the immunity after suffering pathogen attack remains unknown. In this study, to our knowledge, we first found that 20E titer was significantly elevated after bacterial infection in the domesticated silkworm, Bombyx mori. Furthermore, the elevated 20E enhanced the silkworm innate immune system against invading bacteria via ecdysone receptor. During immune response, the expression of the silkworm 3-dehydroecdysone-3β-reductase (3DE-3β-reductase) that converts 3DE released from prothoracic glands into ecdysone was induced. RNA interference experiments suggested that 3DE-3β-reductase is essential to upregulate the 20E titer after bacterial infection. The rescue experiments showed that injection with the recombinant 3DE-3β-reductase protein can significantly elevate the 20E concentration and modulate the expressions of the silkworm immune-related genes. Taken together, 20E titer determined by 3DE-3β-reductase enhances the silkworm defense against the bacterial infection. Thus, our findings reveal an important role of the 20E synthesis pathway from 3DE in enhancing the silkworm immune response and have profound implications for the understanding of interaction mechanisms between insect hormone and immunity.

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“…For example, depletion of the insulin receptor from the fat body alters the expression of immune response genes, and alters sensitivity to infection (Musselman et al, 2017). Furthermore, mutations of the IRS homolog chico increase survival after infection with Pseudomonas aeruginosa and Enterococcus faecalis (Libert et al, 2008); challenges with Mycobacterium marinum lower AKT phosphorylation, and diminish systemic insulin activity (Dionne et al, 2006); activation of TOR blocks AMP expression (Varma et al, 2014); infection increases expression of the FOXO-responsive transcript 4E-BP ortholog thor (Bernal and Kimbrell, 2000); and FOXO regulates the expression of intestinal antimicrobial peptides (Becker et al, 2010). Combined, these findings suggest a direct relationship between bacterial challenges and insulin-sensitive pathways in the fly.…”

Section: Discussionmentioning

confidence: 99%

The Immune Deficiency Pathway Regulates Metabolic Homeostasis inDrosophila

Davoodi

Galenza

Panteluk

et al. 2018

Preprint

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Immune and metabolic pathways collectively contribute to the containment of microbial invaders, and persistent activation of immune responses contribute to the development of severe metabolic disorders.To determine how a prolonged immune response impacts metabolism, we induced a constitutive inflammatory response in the Drosophila fat body, a key regulator of humoral immunity and metabolic homeostasis. We found that persistent immune activity replicated key features of a suppressed insulin pathway -delayed development, depleted fat reserves, and hyperglycemia. These observations led us to ask if the inhibition of insulin signaling improves host survival after infection. To test this, we challenged insulin pathway mutants with lethal doses of the enteric pathogen, Vibrio cholerae. We found that loss-of-function mutations in the insulin pathway extended viability and lowered bacterial loads, while gain-of-function mutations diminished viability and elevated bacterial loads. Combined, our results support a role for immune regulation of the insulin pathway in the survival of microbial challenges.

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Forkhead, a new cross regulator of metabolism and innate immunity downstream of TOR in Drosophila

Cited by 46 publications

References 27 publications

Antimicrobial peptides extend lifespan in Drosophila

Antimicrobial peptides extend lifespan in Drosophila

Ecdysone Titer Determined by 3DE-3β-Reductase Enhances the Immune Response in the Silkworm

The Immune Deficiency Pathway Regulates Metabolic Homeostasis inDrosophila

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