Salmonella Coiled-Coil- and TIR-Containing TcpS Evades the Innate Immune System and Subdues Inflammation

• Published in: Cell reports (Cambridge) Vol. 28; no. 3; pp. 804 - 818.e7
• Main Authors: Xiong, Dan, Song, Li, Geng, Shizhong, Jiao, Yang, Zhou, Xiaohui, Song, Hongqin, Kang, Xilong, Zhou, Yi, Xu, Xiulong, Sun, Jun, Pan, Zhiming, Jiao, Xinan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-07-2019; Elsevier
• Subjects: coiled-coil; immune evasion; inflammation; Salmonella; TcpS; therapeutic peptide; TIR; TLR signaling; TLR signaling; Salmonella; coiled-coil; immune evasion; TcpS; inflammation; TIR; therapeutic peptide
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.06.048

Toll-like receptors (TLRs) activate innate immunity via interactions between their Toll/interleukin-1 (IL-1) receptor (TIR) domain and downstream adaptor proteins. Here we report that Salmonella Enteritidis produces a secreted protein (TcpS) that contains both a TIR domain and a coiled-coil domain. TcpS blocks MyD88- and TRIF-mediated TLR signaling, inhibits inflammatory responses, and promotes bacterial survival. Early-stage immune evasion by TcpS results in severe tissue damage in the late stage of infection and contributes to Salmonella virulence. TcpS-derived peptides inhibit nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) activation and reduce lipopolysaccharide (LPS)-elicited systemic inflammation. Therapeutic peptide administration alleviates weight loss of mice infected with H1N1 influenza. Importantly, maximal TcpS-mediated TLR inhibition requires the critical TIR-TcpS residues Y191 and I284, as well as TcpS homodimerization via its N-terminal coiled-coil domain. Our study unveils a mechanism in which TcpS suppresses innate immunity via both its homodimerization and interaction with MyD88. TcpS is also a potential therapeutic agent for inflammation-associated diseases.
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•Salmonella TcpS blocks TLR-induced innate immunity to promote infection via a TIR domain•Immune evasion by TcpS results in inflammation storm and enhances bacterial virulence•TIR-TcpS-derived bait peptides reduce excessive inflammation and influenza pathologies•TcpS homodimerization via its coiled-coil domain is required for efficient TLR inhibition
Xiong et al. show that Salmonella subverts host TLR signaling by delivering a protein containing a TIR domain and a coiled-coil domain, TcpS. Immune evasion by TcpS supports early bacterial infection, which enables late-stage virulence and inflammation storm. TcpS-derived peptides reduce LPS-elicited systemic inflammation and are protective against influenza challenge in mice.