A Decoy Peptide that Disrupts TIRAP Recruitment to TLRs Is Protective in a Murine Model of Influenza

Wenji Piao; Kari Ann Shirey; Lisa W Ru; Wendy Lai; Henryk Szmacinski; Greg A Snyder; Eric J Sundberg; Joseph R Lakowicz; Stefanie N Vogel; Vladimir Y Toshchakov

doi:10.1016/j.celrep.2015.05.035

A Decoy Peptide that Disrupts TIRAP Recruitment to TLRs Is Protective in a Murine Model of Influenza

Cell Rep. 2015 Jun 30;11(12):1941-52. doi: 10.1016/j.celrep.2015.05.035. Epub 2015 Jun 18.

Authors

Affiliations

¹ Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
² Department of Biochemistry and Molecular Biology and Center for Fluorescence Spectroscopy, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³ Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁴ 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.
⁵ Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cytokines / metabolism
Disease Models, Animal
Humans
Inflammation / genetics
Inflammation / metabolism
Inflammation / pathology
Influenza, Human / genetics*
Influenza, Human / metabolism
Influenza, Human / pathology
Macrophages / metabolism
Macrophages / pathology
Membrane Glycoproteins / antagonists & inhibitors
Membrane Glycoproteins / chemistry*
Membrane Glycoproteins / genetics*
Membrane Glycoproteins / metabolism
Mice
NF-kappa B / metabolism
Peptides / chemistry
Peptides / pharmacology
Receptors, Interleukin-1 / chemistry*
Receptors, Interleukin-1 / metabolism
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / genetics*
Signal Transduction / drug effects
Toll-Like Receptor 2 / antagonists & inhibitors
Toll-Like Receptor 2 / chemistry
Toll-Like Receptor 2 / genetics*
Toll-Like Receptor 7 / antagonists & inhibitors
Toll-Like Receptor 7 / chemistry
Toll-Like Receptor 7 / genetics*
Toll-Like Receptor 9 / antagonists & inhibitors
Toll-Like Receptor 9 / chemistry
Toll-Like Receptor 9 / genetics*

Substances

Cytokines
Membrane Glycoproteins
NF-kappa B
Peptides
Receptors, Interleukin-1
Recombinant Fusion Proteins
TIRAP protein, mouse
TLR4 decoy
Tlr2 protein, mouse
Tlr7 protein, mouse
Tlr9 protein, mouse
Toll-Like Receptor 2
Toll-Like Receptor 7
Toll-Like Receptor 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding