Toll-like receptor-2/6 and toll-like receptor-9 agonists suppress viral replication but not airway hyperreactivity in guinea pigs

Matthew G. Drake, Scott E. Evans, Burton F. Dickey, Allison D. Fryer, David B. Jacoby

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Respiratory virus infections cause airway hyperreactivity (AHR). Preventative strategies for virus-induced AHR remain limited. Toll-like receptors (TLRs) have been suggested as a therapeutic target because of their central role in triggering antiviral immune responses. Previous studies showed that concurrent treatment with TLR2/6 and TLR9 agonists reduced lethality and the microbial burden in murine models of bacterial and viral pneumonia. This study investigated the effects of TLR2/6 and TLR9 agonist pretreatment on parainfluenza virus pneumonia and virus-induced AHR in guinea pigs in vivo. Synthetic TLR2/6 lipopeptide agonist Pam2CSK4 and Class C oligodeoxynucleotide TLR9 agonist ODN2395, administered in combination 24 hours before virus infection, significantly reduced viral replication in the lung. Despite a fivefold reduction in viral titers, concurrent TLR2/6 and TLR9 agonist pretreatment did not prevent virus-induced AHR or virus-induced inhibitory M2 muscarinic receptor dysfunction. Interestingly, the TLR agonists independently caused non-M2-dependent AHR. These data confirm the therapeutic antiviral potential of TLR agonists, while suggesting that virus inhibition may be insufficient to prevent virus-induced airway pathophysiology. Furthermore, TLR agonists independently cause AHR, albeit through a distinctly differentmechanismfrom that of parainfluenza virus.

Original languageEnglish (US)
Pages (from-to)790-796
Number of pages7
JournalAmerican journal of respiratory cell and molecular biology
Volume48
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Airway hyperreactivity
  • Muscarinic receptor
  • Parainfluenza virus
  • Toll-like receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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