Pathogen Specific, IRF3-Dependent Signaling and Innate Resistance to Human Kidney Infection

PLoS Pathogens

Ahmed Al Hadad¹  Petter Storm¹  Manisha Yadav¹  Nataliya Lutay¹  Hans Fischer¹  Bryndís Ragnarsdóttir¹  Catharina Svanborg¹  Sebastian Rämisch¹  Diana Karpman²  Ellaine Salvador³  Ulrich Dobrindt³  Ulf Jodal⁴  Klas Jönsson⁵  Alexander Urbano⁵ 

[1] Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden;Department of Pediatrics, Clinical Sciences Lund, Lund University, and Lund University Hospital, Lund, Sweden;Institute for Molecular Biology of Infectious Diseases, Julius-Maximilians-University Würzburg, Würzburg, Germany;Pediatric-Uronephrology Center, Queen Silvia Children's Hospital, University of Gothenburg, Sweden;Singapore Immunology Network (SIgN), Biomedical Sciences Institutes, Agency for Science, Technology, and Research (A*STAR), Immunos, BIOPOLIS, Singapore, Singapore

关键词: Bacterial pathogens;    Phosphorylation;    Kidneys;    Immune receptor signaling;    Transcription factors;    Small interfering RNAs;    Epithelial cells;    Urinary tract infections;   

DOI  :  10.1371/journal.ppat.1001109

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY