Inhibition of TLR4 signaling by Brucella TIR-containing protein TcpB-derived decoy peptides.
Brucella spp. avoid host immune recognition and thus, weaken the immune response to infection. The Toll/interleukin-1 receptor (TIR) domain-containing protein (TcpB/Btp1) of Brucella spp. is thought to be involved in blocking host innate immune responses by binding to adaptors downstream of Toll-like receptors. In this study, based on the observation that TcpB binds to the host target proteins, MAL, through the TIR domain, we examined decoy peptides from TcpB TIR domains and found that TB-8 and TB-9 substantially inhibit lipopolysaccharide (LPS)-induced signaling in vitro and in vivo. Both these peptides share a common loop, the DD loop, indicating a novel structural region mediating TIR interactions. The inhibition of LPS signaling by TB-8 and TB-9 shows no preference to MyD88-dependent cytokines, such as TNF-α and IL-1β or TRIF-dependent cytokines including IFN-β and IL-6. Furthermore, these two peptides rescue the virulence of Brucella ΔtcpB mutants at the cellular level, indicating key roles of the DD loop in Brucella pathogenesis. In conclusion, identification of inhibitors from the bacterial TIR domains is helpful not only for illustrating interacting mechanisms between TIR domains and bacterial pathogenesis, but also for developing novel signaling inhibitors and therapeutics for human inflammatory diseases.
Institute of Disease Control and Prevention, AMMS, Beijing 100071, People's Republic of China.
Yuehua
Y
Ke
Institute of Disease Control and Prevention, AMMS, Beijing 100071, People's Republic of China; School of Public Health, Jilin University, Changchun 130021, People's Republic of China.
Wenna
W
Li
General Hospital of People's Armed Police Forces, Beijing 100039, People's Republic of China.
Yufei
Y
Wang
Institute of Disease Control and Prevention, AMMS, Beijing 100071, People's Republic of China.
Mingjuan
M
Yang
Institute of Disease Control and Prevention, AMMS, Beijing 100071, People's Republic of China.
Jinpeng
J
Guo
Institute of Disease Control and Prevention, AMMS, Beijing 100071, People's Republic of China.
Shaoxia
S
Zhan
Institute of Disease Control and Prevention, AMMS, Beijing 100071, People's Republic of China.
Xinying
X
Du
Institute of Disease Control and Prevention, AMMS, Beijing 100071, People's Republic of China.
Zhoujia
Z
Wang
Construction Engineering Research Institute, Xi'an 71000, Shanxi Province, People's Republic of China.
Min
M
Yang
School of Public Health, Jilin University, Changchun 130021, People's Republic of China. Electronic address: li_juan@jlu.edu.cn.
Juan
J
Li
Department of Orthopedics, The First Affiliated Hospital of General Hospital of People's Liberation Army, Beijing 100048, People's Republic of China. Electronic address: lwf304@163.com.
Wenfeng
W
Li
Institute of Disease Control and Prevention, AMMS, Beijing 100071, People's Republic of China; College of Medicine, Shihezi University, Shihezi, People's Republic of China; Research Center of Molecular Biology, Inner Mongolia Medical University, Hohhot, People's Republic of China. Electronic address: zeliangchen@yahoo.com.
Zeliang
Z
Chen
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D037521:Virulence Factors / Q000378:metabolism*
D001426:Bacterial Proteins; D010455:Peptides; C495345:TLR4 protein, human; C587630:TcpB protein, Brucella melitensis; D051197:Toll-Like Receptor 4; D037521:Virulence Factors
Brucella; Decoy peptides; Innate immunity; Signaling pathway; TIR domain