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

• Published in: PLoS pathogens Vol. 6; no. 9; p. e1001109
• Main Authors: Fischer, Hans, Lutay, Nataliya, Ragnarsdóttir, Bryndís, Yadav, Manisha, Jönsson, Klas, Urbano, Alexander, Al Hadad, Ahmed, Rämisch, Sebastian, Storm, Petter, Dobrindt, Ulrich, Salvador, Ellaine, Karpman, Diana, Jodal, Ulf, Svanborg, Catharina
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-09-2010; Public Library of Science (PLoS)
• Subjects: Adult; Animals; Bacterial infections; Basic Medicine; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting; Blotting, Western; Case-Control Studies; Cell Nucleus; Cell Nucleus - metabolism; Cellular signal transduction; Ceramides; Ceramides - metabolism; Child; E coli; Escherichia coli; Escherichia coli - pathogenicity; Escherichia coli Infections; Escherichia coli Infections - etiology; Escherichia coli Infections - mortality; Escherichia coli Infections - prevention & control; etiology; Experiments; Fimbriae, Bacterial; Gene Expression Profiling; Genetic aspects; Humans; Immune response; Immune system; Immunity, Innate - physiology; Immunology/Immune Response; Infections; Infectious Diseases/Urological Infections; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Interferon Regulatory Factor-3 - physiology; Kidney - metabolism; Kidney - pathology; Kidney - virology; Kidney Neoplasms - etiology; Kidney Neoplasms - mortality; Kidney Neoplasms - prevention & control; Ligands; Lung Neoplasms - etiology; Lung Neoplasms - mortality; Lung Neoplasms - prevention & control; Medical and Health Sciences; Medical research; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology in the medical area; Microbiology/Innate Immunity; Mikrobiologi inom det medicinska området; Mortality; Observations; Oligonucleotide Array Sequence Analysis; pathogenicity; Pediatrics; Pediatrik; Phosphorylation; Polymorphism, Genetic - genetics; Promoter Regions, Genetic - genetics; Properties; Prospective Studies; Protein Transport; Pyelonephritis - etiology; Pyelonephritis - mortality; Pyelonephritis - pathology; Reverse Transcriptase Polymerase Chain Reaction; Risk assessment; RNA, Messenger - genetics; Rodents; Signal Transduction; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Tumor Cells, Cultured; Urinary Tract Infections - etiology; Urinary Tract Infections - mortality; Urinary Tract Infections - prevention & control; Urogenital system; Western; Sweden
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1001109

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.