title: Toll-like receptor-2/6 and Toll-like receptor-9 agonists suppress viral replication but not airway hyperreactivity in guinea pigs.
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 different mechanism from that of parainfluenza virus.
authors: Department of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR 97239, USA. drakem@ohsu.edu
authors: Matthew G
authors: MG
authors: Drake
authors: Scott E
authors: SE
authors: Evans
authors: Burton F
authors: BF
authors: Dickey
authors: Allison D
authors: AD
authors: Fryer
authors: David B
authors: DB
authors: Jacoby
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000503:physiopathology / Q000821:virology*; D016084:Bronchoconstriction; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D007958:Leukocyte Count; D055666:Lipopeptides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000821:virology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D043587:Receptor, Muscarinic M3 / Q000187:drug effects / Q000276:immunology; D010253:Respirovirus Infections / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D029082:Sendai virus / Q000276:immunology / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000819:agonists* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C527702:CpG ODN 2395; D055666:Lipopeptides; D009838:Oligodeoxyribonucleotides; C560312:Pam2CSK4 lipopeptide; D043587:Receptor, Muscarinic M3; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051217:Toll-Like Receptor 9; D000109:Acetylcholine