Identification of a peptide derived from vaccinia virus A52R protein that inhibits cytokine secretion in response to TLR-dependent signaling and reduces in vivo bacterial-induced inflammation

Sharon L. McCoy, Stephen E. Kurtz, Carol Macarthur, Dennis Trune, Steven Hefeneider

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45 Citations (Scopus)

Abstract

TLRs recognize and respond to conserved motifs termed athogen-associated molecular patterns. TLRs are characterized by an extracellular leucine-rich repeat motif and an intracellular Toll/IL-IR domain. Triggering of TLRs by pathogen-associated molecular patterns initiates a series of intracellular signaling events resulting in an inflammatory immune response designed to contain and eliminate the pathogen. Vaccinia virus encodes immunoregulatory proteins, such as A52R, that can effectively inhibit intracellular Toll/IL-IR signaling, resulting in a diminished host immune response and enhancing viral survival. In this study, we report the identification and characterization of a peptide derived from the A52R protein (sequence DIVKLTVYDCI) that, when linked to the nine-arginine cell transduction sequence, effectively inhibits cytokine secretion in response to TLR activation. The peptide had no effect on cytokine secretion resulting from cell activation that was initiated independent of TLR stimulation. Using a mouse model of otitis media with effusion, administration of heat-inactivated Streptococcus pneumoniae into the middle ears of BALB/c mice resetted in a significant inflammatory response that was dramatically reduced with peptide treatment. The identification of this peptide that selectively targets TLR-dependent signaling may have application in the treatment of chronic inflammation initiated by bacterial or viral infections.

Original languageEnglish (US)
Pages (from-to)3006-3014
Number of pages9
JournalJournal of Immunology
Volume174
Issue number5
StatePublished - Mar 1 2005

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Cytokines
Inflammation
Peptides
Otitis Media with Effusion
Vaccinia virus
Middle Ear
Virus Diseases
Streptococcus pneumoniae
Bacterial Infections
Leucine
Arginine
Proteins
Hot Temperature
vaccinia virus A52R protein
Pathogen-Associated Molecular Pattern Molecules

ASJC Scopus subject areas

  • Immunology

Cite this

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abstract = "TLRs recognize and respond to conserved motifs termed athogen-associated molecular patterns. TLRs are characterized by an extracellular leucine-rich repeat motif and an intracellular Toll/IL-IR domain. Triggering of TLRs by pathogen-associated molecular patterns initiates a series of intracellular signaling events resulting in an inflammatory immune response designed to contain and eliminate the pathogen. Vaccinia virus encodes immunoregulatory proteins, such as A52R, that can effectively inhibit intracellular Toll/IL-IR signaling, resulting in a diminished host immune response and enhancing viral survival. In this study, we report the identification and characterization of a peptide derived from the A52R protein (sequence DIVKLTVYDCI) that, when linked to the nine-arginine cell transduction sequence, effectively inhibits cytokine secretion in response to TLR activation. The peptide had no effect on cytokine secretion resulting from cell activation that was initiated independent of TLR stimulation. Using a mouse model of otitis media with effusion, administration of heat-inactivated Streptococcus pneumoniae into the middle ears of BALB/c mice resetted in a significant inflammatory response that was dramatically reduced with peptide treatment. The identification of this peptide that selectively targets TLR-dependent signaling may have application in the treatment of chronic inflammation initiated by bacterial or viral infections.",
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AU - Trune, Dennis

AU - Hefeneider, Steven

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