Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.

The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-...

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Autores principales:	Hans Fischer, Nataliya Lutay, Bryndís Ragnarsdóttir, Manisha Yadav, Klas Jönsson, Alexander Urbano, Ahmed Al Hadad, Sebastian Rämisch, Petter Storm, Ulrich Dobrindt, Ellaine Salvador, Diana Karpman, Ulf Jodal, Catharina Svanborg
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5e7bfc5267f147b6ba2d183cd497fd21
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spelling	oai:doaj.org-article:5e7bfc5267f147b6ba2d183cd497fd212021-11-18T06:01:36ZPathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.1553-73661553-737410.1371/journal.ppat.1001109https://doaj.org/article/5e7bfc5267f147b6ba2d183cd497fd212010-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20886096/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3(-/-) mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFNβ-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3(-/-) mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response.Hans FischerNataliya LutayBryndís RagnarsdóttirManisha YadavKlas JönssonAlexander UrbanoAhmed Al HadadSebastian RämischPetter StormUlrich DobrindtEllaine SalvadorDiana KarpmanUlf JodalCatharina SvanborgPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 9, p e1001109 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Hans Fischer Nataliya Lutay Bryndís Ragnarsdóttir Manisha Yadav Klas Jönsson Alexander Urbano Ahmed Al Hadad Sebastian Rämisch Petter Storm Ulrich Dobrindt Ellaine Salvador Diana Karpman Ulf Jodal Catharina Svanborg Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.
description	The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3(-/-) mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFNβ-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3(-/-) mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response.
format	article
author	Hans Fischer Nataliya Lutay Bryndís Ragnarsdóttir Manisha Yadav Klas Jönsson Alexander Urbano Ahmed Al Hadad Sebastian Rämisch Petter Storm Ulrich Dobrindt Ellaine Salvador Diana Karpman Ulf Jodal Catharina Svanborg
author_facet	Hans Fischer Nataliya Lutay Bryndís Ragnarsdóttir Manisha Yadav Klas Jönsson Alexander Urbano Ahmed Al Hadad Sebastian Rämisch Petter Storm Ulrich Dobrindt Ellaine Salvador Diana Karpman Ulf Jodal Catharina Svanborg
author_sort	Hans Fischer
title	Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.
title_short	Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.
title_full	Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.
title_fullStr	Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.
title_full_unstemmed	Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.
title_sort	pathogen specific, irf3-dependent signaling and innate resistance to human kidney infection.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/5e7bfc5267f147b6ba2d183cd497fd21
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Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.

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