Coordination of multiple dual oxidase–regulatory pathways in responses to commensal and infectious microbes in drosophila gut

Ha, Eun Mi; Lee, Kyung Ah; Seo, Yongho; Kim, Sung Hee; Lim, Jae Hong; Oh, Byung Ha; Kim, Jaesang; Lee, Won Jae

doi:10.1038/ni.1765

Cited by 292 publications

(344 citation statements)

References 49 publications

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“…To date, the regulation of DUOX2/DUOXA2 expression has been mainly investigated in thyrocytes, as well as in airways and gut epithelial cells following bacterial infection [6,[27][28][29]. Our observation that DUOX2/ DUOXA2 were induced following SeV infection in three different AEC models, A549, ALI-Calu-3 and NHBEs, adds to the picture of the previously reported RV-induced DUOX2/DUOXA2 expression in primary AECs [6,[30][31][32].…”

Section: Rsv Interferes With the Expression Of Duox2supporting

confidence: 69%

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

et al. 2013

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Airway epithelial cells are key initial innate immune responders in the fight against respiratory viruses, primarily via the secretion of antiviral and proinflammatory cytokines that act in an autocrine/paracrine fashion to trigger the establishment of an antiviral state. It is currently thought that the early antiviral state in airway epithelial cells primarily relies on IFNβ secretion and the subsequent activation of the interferon-stimulated gene factor 3 (ISGF3) transcription factor complex, composed of STAT1, STAT2 and IRF9, which regulates the expression of a panoply of interferon-stimulated genes encoding proteins with antiviral activities. However, the specific pathways engaged by the synergistic action of different cytokines during viral infections, and the resulting physiological outcomes are still ill-defined. Here, we unveil a novel delayed antiviral response in the airways, which is initiated by the synergistic autocrine/paracrine action of IFNβ and TNFα, and signals through a non-canonical STAT2-and IRF9-dependent, but STAT1-independent cascade. This pathway ultimately leads to the late induction of the DUOX2 NADPH oxidase expression. Importantly, our study uncovers that the development of the antiviral state relies on DUOX2-dependent H 2 O 2 production. Key antiviral pathways are often targeted by evasion strategies evolved by various pathogenic viruses. In this regard, the importance of the novel DUOX2-dependent antiviral pathway is further underlined by the observation that the human respiratory syncytial virus is able to subvert DUOX2 induction.

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Section: Rsv Interferes With the Expression Of Duox2supporting

confidence: 69%

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

et al. 2013

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“…4B). Candidate genes regulated by TIR during this process include cyclin D1 (also regulated by the microbiota), Csda (also known as Zonab) (41), and Duox2 and Duoxa2 (42), the latter of which have been implicated in activation of stem cells after injury (43,44). These data include postnatal development within the spectrum of physiologic (tissue repair at the adult stage) (45,46) and pathophysiologic (tumorigenesis) (47) processes regulated by TIR signaling.…”

Section: Resultsmentioning

confidence: 99%

Analysis of gene–environment interactions in postnatal development of the mammalian intestine

Rakoff-Nahoum

Kong

Kleinstein

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Unlike mammalian embryogenesis, which takes place in the relatively predictable and stable environment of the uterus, postnatal development can be affected by a multitude of highly variable environmental factors, including diet, exposure to noxious substances, and microorganisms. Microbial colonization of the intestine is thought to play a particularly important role in postnatal development of the gastrointestinal, metabolic, and immune systems. Major changes in environmental exposure occur right after birth, upon weaning, and during pubertal maturation into adulthood. These transitions include dramatic changes in intestinal contents and require appropriate adaptations to meet changes in functional demands. Here, we attempt to both characterize and provide mechanistic insights into postnatal intestinal ontogeny. We investigated changes in global intestinal gene expression through postnatal developmental transitions. We report profound alterations in small and large intestinal transcriptional programs that accompany both weaning and puberty in WT mice. Using myeloid differentiation factor 88 (MyD88)/TIR-domain-containing adapter-inducing interferon-β (TRIF) double knockout littermates, we define the role of toll-like receptors (TLRs) and interleukin (IL)-1 receptor family member signaling in postnatal gene expression programs and select ontogeny-specific phenotypes, such as vascular and smooth muscle development and neonatal epithelial and mast cell homeostasis. Metaanalysis of the effect of the microbiota on intestinal gene expression allowed for mechanistic classification of developmentally regulated genes by TLR/IL-1R (TIR) signaling and/or indigenous microbes. We find that practically every aspect of intestinal physiology is affected by postnatal transitions. Developmental timing, microbial colonization, and TIR signaling seem to play distinct and specific roles in regulation of gene-expression programs throughout postnatal development.

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“…The pathway that regulates Duox gene expression has been characterized as requiring Mekk1 and p38c (Ha et al, 2009b;Chakrabarti et al, 2014). Whereas it was initially thought that Duox gene expression was regulated by peptidoglycan via the pattern recognition receptor PGRP-LC (Ha et al, 2009b), Duox expression remained similar to wild-type levels in PGRP-LC mutants (Chakrabarti et al, 2014). These results suggest that Duox expression is activated by another mechanism.…”

Section: Discussionmentioning

confidence: 98%

“…It is a delicate task for the host to mount potent gut immune responses to combat infectious microbes while maintaining the proper number of symbiotic microorganisms needed for healthy gut-microbe interactions (Ha et al, 2009b;Bae et al, 2010). In contrast to the systemic response including melanization, coagulation, phagocytosis and AMP production that ensures the sterility of the body cavity and hemolymph (Buchon et al, 2013), the intestinal immune responses must tolerate the presence of the gut microbiota and dietary microorganisms while responding to and eliminating potential pathogens.…”

Section: Discussionmentioning

confidence: 99%

“…The p38 mitogenactivated protein (MAP) kinase is a signaling pathway that is involved in both stress and immunity in various species from yeast to humans, and each MAP kinase pathway contains a three-tiered kinase cascade consisting of a MAP kinase kinase kinase (MEKK), a MAP kinase kinase (MKK) and MAP kinase (Qi and Elion, 2005). The pathway that regulates Duox gene expression has been characterized as requiring Mekk1 and p38c (Ha et al, 2009b;Chakrabarti et al, 2014). Whereas it was initially thought that Duox gene expression was regulated by peptidoglycan via the pattern recognition receptor PGRP-LC (Ha et al, 2009b), Duox expression remained similar to wild-type levels in PGRP-LC mutants (Chakrabarti et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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The dual oxidase gene BdDuox regulates the intestinal bacterial community homeostasis of Bactrocera dorsalis

Yao¹,

Wang²,

Li³

et al. 2015

The ISME Journal

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The guts of metazoans are in permanent contact with the microbial realm that includes beneficial symbionts, nonsymbionts, food-borne microbes and life-threatening pathogens. However, little is known concerning how host immunity affects gut bacterial community. Here, we analyze the role of a dual oxidase gene (BdDuox) in regulating the intestinal bacterial community homeostasis of the oriental fruit fly Bactrocera dorsalis. The results showed that knockdown of BdDuox led to an increased bacterial load, and to a decrease in the relative abundance of Enterobacteriaceae and Leuconostocaceae bacterial symbionts in the gut. The resulting dysbiosis, in turn, stimulates an immune response by activating BdDuox and promoting reactive oxygen species (ROS) production that regulates the composition and structure of the gut bacterial community to normal status by repressing the overgrowth of minor pathobionts. Our results suggest that BdDuox plays a pivotal role in regulating the homeostasis of the gut bacterial community in B. dorsalis.

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Coordination of multiple dual oxidase–regulatory pathways in responses to commensal and infectious microbes in drosophila gut

Cited by 292 publications

References 49 publications

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

Analysis of gene–environment interactions in postnatal development of the mammalian intestine

The dual oxidase gene BdDuox regulates the intestinal bacterial community homeostasis of Bactrocera dorsalis

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