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

• Published in: The Journal of immunology (1950) 2005-03, Vol.174 (5), p.3006-3014
• Main Authors: McCoy, Sharon L, Kurtz, Stephen E, MacArthur, Carol J, Trune, Dennis R, Hefeneider, Steven H
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Line; Cytokines - antagonists & inhibitors; Cytokines - metabolism; I-kappa B Proteins - antagonists & inhibitors; I-kappa B Proteins - metabolism; Inflammation Mediators - chemical synthesis; Inflammation Mediators - metabolism; Inflammation Mediators - physiology; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Molecular Sequence Data; NF-KappaB Inhibitor alpha; Otitis Media with Effusion - immunology; Otitis Media with Effusion - pathology; Otitis Media with Effusion - prevention & control; Peptide Fragments - chemical synthesis; Peptide Fragments - metabolism; Peptide Fragments - physiology; Phosphorylation; Pneumococcal Infections - immunology; Pneumococcal Infections - pathology; Pneumococcal Infections - prevention & control; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - physiology; Signal Transduction - immunology; Streptococcus pneumoniae; Tetradecanoylphorbol Acetate - pharmacology; Toll-Like Receptors; Tumor Necrosis Factor-alpha - pharmacology; Vaccinia virus; Vaccinia virus - immunology; Viral Proteins - chemical synthesis; Viral Proteins - metabolism; Viral Proteins - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.5.3006

TLRs recognize and respond to conserved motifs termed pathogen-associated molecular patterns. TLRs are characterized by an extracellular leucine-rich repeat motif and an intracellular Toll/IL-1R 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-1R 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 resulted 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.