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

• Main Authors: Dan Xiong, Li Song, Shizhong Geng, Yang Jiao, Xiaohui Zhou, Hongqin Song, Xilong Kang, Yi Zhou, Xiulong Xu, Jun Sun, Zhiming Pan, Xinan Jiao
• Format: Article
• Language: English
• Published: Elsevier 2019-07-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719308216

Summary: 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. : 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. Keywords: Salmonella, coiled-coil, TIR, TcpS, TLR signaling, immune evasion, inflammation, therapeutic peptide