title: A Decoy Peptide that Disrupts TIRAP Recruitment to TLRs Is Protective in a Murine Model of Influenza.
abstract: Toll-like receptors (TLRs) activate distinct, yet overlapping sets of signaling molecules, leading to inflammatory responses to pathogens. Toll/interleukin-1 receptor (TIR) domains, present in all TLRs and TLR adapters, mediate protein interactions downstream of activated TLRs. A peptide library derived from TLR2 TIR was screened for inhibition of TLR2 signaling. Cell-permeable peptides derived from the D helix and the segment immediately N-terminal to the TLR2 TIR domain potently inhibited TLR2-mediated cytokine production. The D-helix peptide, 2R9, also potently inhibited TLR4, TLR7, and TLR9, but not TLR3 or TNF-α signaling. Cell imaging, co-immunoprecipitation, and in vitro studies demonstrated that 2R9 preferentially targets TIRAP. 2R9 diminished systemic cytokine responses elicited in vivo by synthetic TLR2 and TLR7 agonists; it inhibited the activation of macrophages infected with influenza strain A/PR/8/34 (PR8) and significantly improved the survival of PR8-infected mice. Thus, 2R9 represents a TLR-targeting agent that blocks protein interactions downstream of activated TLRs.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Wenji
authors.initials: W
authors.lastname: Piao
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Ru
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lai
authors.affiliation: Department of Biochemistry and Molecular Biology and Center for Fluorescence Spectroscopy, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Henryk
authors.initials: H
authors.lastname: Szmacinski
authors.affiliation: Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Snyder
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sundberg
authors.affiliation: Department of Biochemistry and Molecular Biology and Center for Fluorescence Spectroscopy, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Lakowicz
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: vtoshchakov@som.umaryland.edu.
authors.forename: Vladimir Y
authors.initials: VY
authors.lastname: Toshchakov
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007251:Influenza, Human / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010455:Peptides; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; C499045:TIRAP protein, mouse; C546114:TLR4 decoy; C493486:Tlr2 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9