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-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.
Fischer
Hans
H
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden.
Lutay
Nataliya
N
Ragnarsdóttir
Bryndís
B
Yadav
Manisha
M
Jönsson
Klas
K
Urbano
Alexander
A
Al Hadad
Ahmed
A
Rämisch
Sebastian
S
Storm
Petter
P
Dobrindt
Ulrich
U
Salvador
Ellaine
E
Karpman
Diana
D
Jodal
Ulf
U
Svanborg
Catharina
C
D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D002648:Child; D004926:Escherichia coli / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000209:etiology / Q000401:mortality / Q000517:prevention & control; D010861:Fimbriae, Bacterial; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000821:virology; D007680:Kidney Neoplasms / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control; D008175:Lung Neoplasms / Q000209:etiology / Q000401:mortality / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D021381:Protein Transport; D011704:Pyelonephritis / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014552:Urinary Tract Infections / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control
D014408:Biomarkers, Tumor; D002518:Ceramides; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4