Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225009, China; Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Yangzhou, Jiangsu 225009, China; Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China, Yangzhou University, Yangzhou, Jiangsu 225009, China.
Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT 06269, USA.
Cell Rep. 2019 Jul 16;28(3):804-818.e7. 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.
Toll 样受体（TLRs）通过其 Toll/白细胞介素-1（IL-1）受体（TIR）结构域与下游衔接蛋白之间的相互作用激活固有免疫。在这里，我们报告肠炎沙门氏菌产生一种分泌蛋白（TcpS），该蛋白含有 TIR 结构域和卷曲螺旋结构域。TcpS 阻断 MyD88 和 TRIF 介导的 TLR 信号转导，抑制炎症反应，并促进细菌存活。TcpS 的早期免疫逃避导致感染后期严重的组织损伤，并有助于沙门氏菌的毒力。TcpS 衍生肽抑制核因子 κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）的激活，并减少脂多糖（LPS）引起的全身炎症。治疗性肽给药可减轻感染 H1N1 流感的小鼠的体重减轻。重要的是，TcpS 介导的 TLR 抑制的最大程度需要关键的 TIR-TcpS 残基 Y191 和 I284 以及其 N 端卷曲螺旋结构域的 TcpS 同源二聚化。我们的研究揭示了一种机制，即 TcpS 通过同源二聚化和与 MyD88 的相互作用来抑制固有免疫。TcpS 也是一种用于炎症相关疾病的潜在治疗剂。
