Bacterial TIR Domains

Abstract

Bacteria need to evade the first line of immune defense, the innate immune response, to survive in their hosts. Signaling in response to foreign molecules by Toll-like receptors (TLRs) is an important part of the innate immune response, so pathogens have evolved mechanisms to disrupt this pathway (see O’Neill). Cirl et al . identified proteins containing the Toll/interleukin-1 receptor (TIR) domains in several human bacterial pathogens, including Escherichia coli strain CFT073, which causes urinary tract infections, and Brucella melitensis , which causes brucellosis, a disease with symptoms similar to those associated with flu. The authors named these proteins Tcps, for TIR domain-containing proteins; the E. coli protein was named TcpC, and the B. melitensis protein was named TcpB. Cells infected with a TcpC-deficient mutant of CFT073 showed greater production of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) and increased bacterial load compared to cells infected with wild-type CFT073. Cells transfected with plasmids encoding TLR signaling components and the TcpC or TcpB proteins, along with reporter plasmids, exhibited decreased signaling through TLRs that are coupled to the adaptor MyD88--TLR4 and TLR2--but not those coupled to other adaptors. CFT073 infection of MyD88-deficient cells did not show a decrease in TNF secretion. Thus, TcpC and TcpB appear to selectively interfere with MyD88-dependent TLR pathways. The TIR domain of TcpC or full-length TcpB bound to MyD88 in pull-down assays. TcpC was secreted from the bacteria and was detectable inside bone marrow-derived macrophages even when the macrophages were separated from the bacteria in a transwell system. Uptake of a purified peptide of the TIR domain of TcpC was inhibited if cholesterol was depleted from the membranes of the host cells, which suggests that lipid rafts may be important for uptake. Finally, the importance of TcpC in disease was determined by infecting mice with the wild-type CFT073 or the TcpC-deficient strain, and those with the wild-type strain had more aggressive disease. In human urinary tract isolates, more severe disease (acute pyelonephritis) was associated with a higher frequency of the presence of the TcpC-positive strains, whereas TcpC-positive strains were less frequently detected in samples from patients with less serious (cystitis) or asymptomatic infection. Thus, as with some viral pathogens, bacteria also appear to target TLR signaling to enhance virulence. C. Cirl, A. Wieser, M. Yadav, S. Duerr, S. Schubert, H. Fischer, D. Stappert, N. Wantia, N. Rodriguez, H. Wagner, C. Svanborg, T. Miethke, Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat. Med. 14 , 399-406 (2008). [PubMed] L. A. J. O’Neill, Bacteria fight back against Toll-like receptors. Nat. Med. 14 , 370-372 (2008). [PubMed]