Direct bacterial killing in vitro by recombinant Nod2 is compromised by Crohn's disease-associated mutations.

<h4>Background</h4>A homeostatic relationship with the intestinal microflora is increasingly appreciated as essential for human health and wellbeing. Mutations in the leucine-rich repeat (LRR) domain of Nod2, a bacterial recognition protein, are associated with development of the inflamm...

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Autores principales: Laurent-Herve Perez, Matt Butler, Tammy Creasey, JoAnn Dzink-Fox, John Gounarides, Stephanie Petit, Anna Ropenga, Neil Ryder, Kathryn Smith, Philip Smith, Scott J Parkinson
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Publicado: Public Library of Science (PLoS) 2010
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spelling oai:doaj.org-article:1133fe159fb844d2877b522597347e562021-12-02T20:21:14ZDirect bacterial killing in vitro by recombinant Nod2 is compromised by Crohn's disease-associated mutations.1932-620310.1371/journal.pone.0010915https://doaj.org/article/1133fe159fb844d2877b522597347e562010-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20531959/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>A homeostatic relationship with the intestinal microflora is increasingly appreciated as essential for human health and wellbeing. Mutations in the leucine-rich repeat (LRR) domain of Nod2, a bacterial recognition protein, are associated with development of the inflammatory bowel disorder, Crohn's disease. We investigated the molecular mechanisms underlying disruption of intestinal symbiosis in patients carrying Nod2 mutations.<h4>Methodology/principal findings</h4>In this study, using purified recombinant LRR domains, we demonstrate that Nod2 is a direct antimicrobial agent and this activity is generally deficient in proteins carrying Crohn's-associated mutations. Wild-type, but not Crohn's-associated, Nod2 LRR domains directly interacted with bacteria in vitro, altered their metabolism and disrupted the integrity of the plasma membrane. Antibiotic activity was also expressed by the LRR domains of Nod1 and other pattern recognition receptors suggesting that the LRR domain is a conserved anti-microbial motif supporting innate cellular immunity.<h4>Conclusions/significance</h4>The lack of anti-bacterial activity demonstrated with Crohn's-associated Nod2 mutations in vitro, supports the hypothesis that a deficiency in direct bacterial killing contributes to the association of Nod2 polymorphisms with the disease.Laurent-Herve PerezMatt ButlerTammy CreaseyJoAnn Dzink-FoxJohn GounaridesStephanie PetitAnna RopengaNeil RyderKathryn SmithPhilip SmithScott J ParkinsonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 6, p e10915 (2010)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Laurent-Herve Perez
Matt Butler
Tammy Creasey
JoAnn Dzink-Fox
John Gounarides
Stephanie Petit
Anna Ropenga
Neil Ryder
Kathryn Smith
Philip Smith
Scott J Parkinson
Direct bacterial killing in vitro by recombinant Nod2 is compromised by Crohn's disease-associated mutations.
description <h4>Background</h4>A homeostatic relationship with the intestinal microflora is increasingly appreciated as essential for human health and wellbeing. Mutations in the leucine-rich repeat (LRR) domain of Nod2, a bacterial recognition protein, are associated with development of the inflammatory bowel disorder, Crohn's disease. We investigated the molecular mechanisms underlying disruption of intestinal symbiosis in patients carrying Nod2 mutations.<h4>Methodology/principal findings</h4>In this study, using purified recombinant LRR domains, we demonstrate that Nod2 is a direct antimicrobial agent and this activity is generally deficient in proteins carrying Crohn's-associated mutations. Wild-type, but not Crohn's-associated, Nod2 LRR domains directly interacted with bacteria in vitro, altered their metabolism and disrupted the integrity of the plasma membrane. Antibiotic activity was also expressed by the LRR domains of Nod1 and other pattern recognition receptors suggesting that the LRR domain is a conserved anti-microbial motif supporting innate cellular immunity.<h4>Conclusions/significance</h4>The lack of anti-bacterial activity demonstrated with Crohn's-associated Nod2 mutations in vitro, supports the hypothesis that a deficiency in direct bacterial killing contributes to the association of Nod2 polymorphisms with the disease.
format article
author Laurent-Herve Perez
Matt Butler
Tammy Creasey
JoAnn Dzink-Fox
John Gounarides
Stephanie Petit
Anna Ropenga
Neil Ryder
Kathryn Smith
Philip Smith
Scott J Parkinson
author_facet Laurent-Herve Perez
Matt Butler
Tammy Creasey
JoAnn Dzink-Fox
John Gounarides
Stephanie Petit
Anna Ropenga
Neil Ryder
Kathryn Smith
Philip Smith
Scott J Parkinson
author_sort Laurent-Herve Perez
title Direct bacterial killing in vitro by recombinant Nod2 is compromised by Crohn's disease-associated mutations.
title_short Direct bacterial killing in vitro by recombinant Nod2 is compromised by Crohn's disease-associated mutations.
title_full Direct bacterial killing in vitro by recombinant Nod2 is compromised by Crohn's disease-associated mutations.
title_fullStr Direct bacterial killing in vitro by recombinant Nod2 is compromised by Crohn's disease-associated mutations.
title_full_unstemmed Direct bacterial killing in vitro by recombinant Nod2 is compromised by Crohn's disease-associated mutations.
title_sort direct bacterial killing in vitro by recombinant nod2 is compromised by crohn's disease-associated mutations.
publisher Public Library of Science (PLoS)
publishDate 2010
url https://doaj.org/article/1133fe159fb844d2877b522597347e56
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