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

Abstract

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.

Innate Transcriptional Networks Activated in Bladder in Response to Uropathogenic Escherichia coli Drive Diverse Biological Pathways and Rapid Synthesis of IL-10 for Defense against Bacterial Urinary Tract Infection

“…Included among the the most activated cytokine genes were IL-10 and its receptor IL-10ra (boxed). strated in the context of pathogen-specific signaling in murine pyelonephritis (55), and the danger-associated molecular pattern S100A8/A9 was shown to be unnecessary for effective host defense against UTI (56). The overall innate response of bladder in UPEC cystitis in the murine UTI model, however, remains largely uncharacterized.…”

Bacterial control of host gene expression through RNA polymerase II

“…Uropathogenic E. coli activate a pathogen-specific, TLR4/CREB/ IRF3/7-dependent innate immune response, which is crucial for host resistance to acute pyelonephritis (9,44). P fimbriae bind to glycosphingolipids, and ceramide release activates TLR4 signaling (44).…”

“…Bacterial pathogens, in contrast, gain a short-term advantage at these sites by expressing virulence factors that can dysregulate a range of host signaling pathways (5). Their virulence repertoire includes a diverse array of molecules that trigger specific host cell receptors and signaling pathways or inactivate the host defense, including capsules, complement inactivators (6,7), and secreted inhibitors of Toll-like receptor (TLR) and MyD88 signaling (8,9). The failure of asymptomatic carrier strains to trigger disease-associated signaling pathways and pathology has generally been attributed to their lack of virulence (5,10,11).…”

The role of bacterial virulence factors in the clinical course of urinary tract infections

“…Innate immunity controls many aspects of the host response to acute UTI and variation on the efficiency of this response has been shown to affect the degree of tissue damage and the clearance of infection [41]. As a consequence, host genetic variants that modify the innate immune response have been associated with different forms of UTI [42,43]. In patients with recurrent UTI, which mostly denotes cystitis, several genetic screens have proposed gene associations, including promoter polymorphisms in LTA and TNFa [44], in the coding regions of TLR1, TLR4 and TLR5 [45].…”

“…The expression of α-hemolysin was shown to increase the clinical severity of urinary tract infections [40]. In high concentrations, α-hemolysin leads to cell lysis [41,42], however, sublytic concentrations seem to be more physiologically relevant, when α-hemolysin was proposed to inhibit chemotaxis and phagocytosis as well as stimulation of host apoptotic and inflammatory pathways [37,43,44].…”