Defensive Mutualism Rescues NADPH Oxidase Inactivation in Gut Infection

Gratiela Pircalabioru, Gabriella Aviello, Malgorzata Kubica, Alexander Zhdanov, Marie-Helene Paclet, Lorraine Brennan, Rosanne Hertzberger, Dmitri Papkovsky, Billy Bourke, Ulla G Knaus

Research output: Contribution to journalArticle

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Abstract

NOX/DUOX family of NADPH oxidases are expressed in diverse tissues and are the primary enzymes for the generation of reactive oxygen species (ROS). The intestinal epithelium expresses NOX1, NOX4, and DUOX2, whose functions are not well understood. To address this, we generated mice with complete or epithelium-restricted deficiency in the obligatory NOX dimerization partner Cyba (p22(phox)). We discovered that NOX1 regulates DUOX2 expression in the intestinal epithelium, which magnified the epithelial ROS-deficiency. Unexpectedly, epithelial deficiency of Cyba resulted in protection from C. rodentium and L. monocytogenes infection. Microbiota analysis linked epithelial Cyba deficiency to an enrichment of H2O2-producing bacterial strains in the gut. In particular, elevated levels of lactobacilli physically displaced and attenuated C. rodentium virulence by H2O2-mediated suppression of the virulence-associated LEE pathogenicity island. This transmissible compensatory adaptation relied on environmental factors, an important consideration for prevention and therapy of enteric disease.

Original languageEnglish
Pages (from-to)651-63
Number of pages13
JournalCell Host & Microbe
Volume19
Issue number5
DOIs
Publication statusPublished - 11 May 2016

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Symbiosis
NADPH Oxidase
Intestinal Mucosa
Virulence
Reactive Oxygen Species
Genomic Islands
Microbiota
Dimerization
Lactobacillus
Infection
Epithelium
Enzymes
Therapeutics
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one
Hypoxia

Keywords

  • Journal Article

Cite this

Pircalabioru, G., Aviello, G., Kubica, M., Zhdanov, A., Paclet, M-H., Brennan, L., ... Knaus, U. G. (2016). Defensive Mutualism Rescues NADPH Oxidase Inactivation in Gut Infection. Cell Host & Microbe, 19(5), 651-63. https://doi.org/10.1016/j.chom.2016.04.007

Defensive Mutualism Rescues NADPH Oxidase Inactivation in Gut Infection. / Pircalabioru, Gratiela; Aviello, Gabriella; Kubica, Malgorzata; Zhdanov, Alexander; Paclet, Marie-Helene; Brennan, Lorraine; Hertzberger, Rosanne; Papkovsky, Dmitri; Bourke, Billy; Knaus, Ulla G.

In: Cell Host & Microbe, Vol. 19, No. 5, 11.05.2016, p. 651-63.

Research output: Contribution to journalArticle

Pircalabioru, G, Aviello, G, Kubica, M, Zhdanov, A, Paclet, M-H, Brennan, L, Hertzberger, R, Papkovsky, D, Bourke, B & Knaus, UG 2016, 'Defensive Mutualism Rescues NADPH Oxidase Inactivation in Gut Infection' Cell Host & Microbe, vol. 19, no. 5, pp. 651-63. https://doi.org/10.1016/j.chom.2016.04.007
Pircalabioru G, Aviello G, Kubica M, Zhdanov A, Paclet M-H, Brennan L et al. Defensive Mutualism Rescues NADPH Oxidase Inactivation in Gut Infection. Cell Host & Microbe. 2016 May 11;19(5):651-63. https://doi.org/10.1016/j.chom.2016.04.007
Pircalabioru, Gratiela ; Aviello, Gabriella ; Kubica, Malgorzata ; Zhdanov, Alexander ; Paclet, Marie-Helene ; Brennan, Lorraine ; Hertzberger, Rosanne ; Papkovsky, Dmitri ; Bourke, Billy ; Knaus, Ulla G. / Defensive Mutualism Rescues NADPH Oxidase Inactivation in Gut Infection. In: Cell Host & Microbe. 2016 ; Vol. 19, No. 5. pp. 651-63.
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abstract = "NOX/DUOX family of NADPH oxidases are expressed in diverse tissues and are the primary enzymes for the generation of reactive oxygen species (ROS). The intestinal epithelium expresses NOX1, NOX4, and DUOX2, whose functions are not well understood. To address this, we generated mice with complete or epithelium-restricted deficiency in the obligatory NOX dimerization partner Cyba (p22(phox)). We discovered that NOX1 regulates DUOX2 expression in the intestinal epithelium, which magnified the epithelial ROS-deficiency. Unexpectedly, epithelial deficiency of Cyba resulted in protection from C. rodentium and L. monocytogenes infection. Microbiota analysis linked epithelial Cyba deficiency to an enrichment of H2O2-producing bacterial strains in the gut. In particular, elevated levels of lactobacilli physically displaced and attenuated C. rodentium virulence by H2O2-mediated suppression of the virulence-associated LEE pathogenicity island. This transmissible compensatory adaptation relied on environmental factors, an important consideration for prevention and therapy of enteric disease.",
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N1 - We thank B. Vallance, P. Cossart, and P. O’Toole for reagents; D. Guttman, S. Donaldson, and A. Surendra for microbiota sequencing and bioinformatics analysis; and the staff of the UCD Biomedical facility for their assistance. The work was supported by Science Foundation Ireland (U.G.K. and D.P.) and the National Children’s Research Center (U.G.K. and B.B.).

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AB - NOX/DUOX family of NADPH oxidases are expressed in diverse tissues and are the primary enzymes for the generation of reactive oxygen species (ROS). The intestinal epithelium expresses NOX1, NOX4, and DUOX2, whose functions are not well understood. To address this, we generated mice with complete or epithelium-restricted deficiency in the obligatory NOX dimerization partner Cyba (p22(phox)). We discovered that NOX1 regulates DUOX2 expression in the intestinal epithelium, which magnified the epithelial ROS-deficiency. Unexpectedly, epithelial deficiency of Cyba resulted in protection from C. rodentium and L. monocytogenes infection. Microbiota analysis linked epithelial Cyba deficiency to an enrichment of H2O2-producing bacterial strains in the gut. In particular, elevated levels of lactobacilli physically displaced and attenuated C. rodentium virulence by H2O2-mediated suppression of the virulence-associated LEE pathogenicity island. This transmissible compensatory adaptation relied on environmental factors, an important consideration for prevention and therapy of enteric disease.

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