RGD Reference Report - Inhibition of TIR domain signaling by TcpC: MyD88-dependent and independent effects on Escherichia coli virulence. - Rat Genome Database

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Inhibition of TIR domain signaling by TcpC: MyD88-dependent and independent effects on Escherichia coli virulence.

Authors: Yadav, M  Zhang, J  Fischer, H  Huang, W  Lutay, N  Cirl, C  Lum, J  Miethke, T  Svanborg, C 
Citation: Yadav M, etal., PLoS Pathog. 2010 Sep 23;6(9):e1001120.
RGD ID: 7175340
Pubmed: PMID:20886104   (View Abstract at PubMed)
PMCID: PMC2944809   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.ppat.1001120   (Journal Full-text)

Toll-like receptor signaling requires functional Toll/interleukin-1 (IL-1) receptor (TIR) domains to activate innate immunity. By producing TIR homologous proteins, microbes inhibit host response induction and improve their own survival. The TIR homologous protein TcpC was recently identified as a virulence factor in uropathogenic Escherichia coli (E. coli), suppressing innate immunity by binding to MyD88. This study examined how the host MyD88 genotype modifies the in vivo effects of TcpC and whether additional, TIR-domain containing proteins might be targeted by TcpC. In wild type mice (wt), TcpC enhanced bacterial virulence, increased acute mortality, bacterial persistence and tissue damage after infection with E. coli CFT073 (TcpC+), compared to a DeltaTcpC deletion mutant. These effects were attenuated in Myd88(-/-) and Tlr4(-/-) mice. Transcriptomic analysis confirmed that TcpC inhibits MYD88 dependent gene expression in CFT073 infected human uroepithelial cells but in addition the inhibitory effect included targets in the TRIF and IL-6/IL-1 signaling pathways, where MYD88 dependent and independent signaling may converge. The effects of TcpC on bacterial persistence were attenuated in Trif (-/-) or Il-1beta (-/-) mice and innate immune responses to DeltaTcpC were increased, confirming that Trif and Il-1beta dependent targets might be involved in vivo, in addition to Myd88. Furthermore, soluble TcpC inhibited Myd88 and Trif dependent TLR signaling in murine macrophages. Our results suggest that TcpC may promote UTI-associated pathology broadly, through inhibition of TIR domain signaling and downstream pathways. Dysregulation of the host response by microbial TcpC thus appears to impair the protective effects of innate immunity, while promoting inflammation and tissue damage.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
urinary tract infection  ISOIl1b (Mus musculus)7175340; 7175340 RGD 
urinary tract infection  IMP 7175340 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Il1b  (interleukin 1 beta)

Genes (Mus musculus)
Il1b  (interleukin 1 beta)

Genes (Homo sapiens)
IL1B  (interleukin 1 beta)


Additional Information