Abstract
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 ΔTcpC 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-1β −/− mice and innate immune responses to ΔTcpC were increased, confirming that Trif and Il-1β 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.
Highlights
Toll-like receptors (TLRs) control innate host responses to mucosal and systemic infections and signaling involves the intracellular Toll/interleukin-1 receptor (TIR) domain [1]
We recently showed that the TIR homologous protein TcpC in the uropathogenic E. coli (UPEC) strain E. coli CFT073 acts as a virulence factor by suppressing innate host responses in the kidney, enhancing bacterial persistence and tissue damage [12]
The results show that bacterial TcpC modifies the innate host response broadly through inhibition of Tlr4, Myd88, Trif, IL-6/IL-1 and Irf3 dependent antibacterial effector functions
Summary
Toll-like receptors (TLRs) control innate host responses to mucosal and systemic infections and signaling involves the intracellular Toll/interleukin-1 receptor (TIR) domain [1]. Negative regulators of TLR signaling include SIGIRR, MyD88s and IRAK-M, which block MyD88 dependent activation, or Triad3A and SARM, which block the TRIF dependent pathway. TIR-TIR interactions between SIGIRR and TLR4 prevent the recruitment of IRAK and TRAF6 to MyD88 [6]. IRAK-M prevents IRAK and IRAK-4 dissociation from MyD88 and TRAF6 complex formation [8]; Triad3A interacts with TIR domains of TLRs, TRIF, TIRAP and RIP1 [9]; and SARM blocks gene induction downstream of TRIF [10]. Competition at the level of the TIR domain is used by host cells to modify TLR signaling in response to specific agonists [6,7,11,12]
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