Research Article The TIR Domain Containing Locus of Enterococcus faecalis Is Predominant among Urinary Tract Infection Isolates and Downregulates Host Inflammatory Response Thomas Daniel Kraemer, 1 Orlando Daniel Quintanar Haro, 1,2 Eugen Domann, 1 Trinad Chakraborty, 1 and Svetlin Tchatalbachev 1 1 Institute of Medical Microbiology, Justus Liebig University, Schubertstraße 81, 35392 Giessen, Germany 2 Iztacala Superior Studies Faculty, National Autonomous University of Mexico, Avenida de los Barrios 1, Los Reyes Iztacala, 54090 Tlalnepantla, MEX, Mexico Correspondence should be addressed to Svetlin Tchatalbachev; svetlin.tchatalbachev@mikrobio.med.uni-giessen.de Received 3 April 2014; Revised 11 June 2014; Accepted 30 June 2014; Published 24 July 2014 Academic Editor: Michael McClelland Copyright © 2014 homas Daniel Kraemer et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Based on Toll/interleukin-1 receptor (TIR) domain structure homology, we detected a previously uncharacterized gene encoding for a TIR domain containing protein (Tcp) in the genome of Enterococcus faecalis. We assigned this gene the name tcpF (as in Tcp of E. faecalis). Screening of E. faecalis samples revealed that tcpF is more common in isolates from urinary tract infections (UTIs) than in human faecal lora. tcpF alleles showed moderate single nucleotide polymorphism (SNP) among UTI isolates. Infection of mouse RAW264.7 macrophages with a tcpF knock-out mutant led to elevated cytokine response compared to the isogenic wild type E. faecalis strain. In silico analysis predicted signiicant tertiary structure homology to the TIR domain of human TLR1 (TLR1-TIR). When transiently expressed in cultured eukaryotic cells, TcpF caused suppression of TLR2-dependent NF-B activation suggesting for TcpF a role as a factor in E. faecalis that beneits colonization by modulating the host’s immune responses. 1. Introduction Signaling via Toll-like receptors (TLRs) requires the homo- or heterodimerization of the receptors. he process is initiated by their extracellular leucine-rich repeats (LRRs) regions and leads to dimerization of the receptor’s cytoplasmic Toll/interleukin-1 receptor (TIR) domains which form a TIR- TIR structure [1]. his TIR-TIR structure provides the site of association with proteins of the TIR domain-containing adapter family [2, 3]. Activation of TLR pathways leads to the release of inlammatory cytokines like tumor necrosis factor  (TNF-) and interleukin 6 (IL6), type I interferons (IFNs), and chemokines, which in turn control the recruitment of inlammatory cells to the infected tissues [4]. he central role of TLR signaling in innate immunity makes it a target for bacterial induced immune subversion. In 2006 the TIR-like protein, TlpA, from Salmonella enterica, was reported as a novel prokaryotic modulator of NF-B activity and interleukin 1 beta (IL-1) secretion that con- tributes to serovar Enteritidis virulence by interfering with TLR4 and MyD88 signaling [5]. Similar observations were also made with the TIR domain containing proteins TcpC of Escherichia coli and TcpB of Brucella melitensis [6]. TcpC was found to impair the signaling of TLRs and the secretion of proinlammatory cytokines IL6 and TNF-. Furthermore, tcpC was associated with the severity of urinary tract infec- tions (UTIs) [6]. It was demonstrated that the TIR domain of TcpC was directly associated with MyD88 and TLR4 [7] and TcpB targeted the Toll/IL-1 receptor domain-containing adaptor protein (TIRAP) dependent pathway by mimick- ing TIRAP’s ainity towards phosphatidylinositol phosphate (PIP) resulting in inhibition of TLR2- and TLR4-mediated signaling [8, 9]. Another TIR domain containing protein Btp1 from Brucella abortus downmodulates maturation of infected dendritic cells by interfering with the TLR2 signaling pathway [10]. Very recently a TcpC homolog protein (TirS) in Hindawi Publishing Corporation International Journal of Microbiology Volume 2014, Article ID 918143, 9 pages http://dx.doi.org/10.1155/2014/918143