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-...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20886096/?tool=EBI |
| _version_ | 1818435868343402496 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T16:59:43Z |
| format | Article |
| id | doaj.art-5e7bfc5267f147b6ba2d183cd497fd21 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-14T16:59:43Z |
| publishDate | 2010-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-5e7bfc5267f147b6ba2d183cd497fd212022-12-21T22:53:52ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742010-09-0169e100110910.1371/journal.ppat.1001109Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.Hans FischerNataliya LutayBryndís RagnarsdóttirManisha YadavKlas JönssonAlexander UrbanoAhmed Al HadadSebastian RämischPetter StormUlrich DobrindtEllaine SalvadorDiana KarpmanUlf JodalCatharina SvanborgThe 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20886096/?tool=EBI |
| spellingShingle | 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. PLoS Pathogens |
| title | 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_short | 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20886096/?tool=EBI |
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