title: Double-stranded RNA induces similar pulmonary dysfunction to respiratory syncytial virus in BALB/c mice.
abstract: Both respiratory syncytial virus (RSV) and influenza A virus induce nucleotide/P2Y purinergic receptor-mediated impairment of alveolar fluid clearance (AFC), which contributes to formation of lung edema. Although genetically dissimilar, both viruses generate double-stranded RNA replication intermediates, which act as Toll-like receptor (TLR)-3 ligands. We hypothesized that double-stranded RNA/TLR-3 signaling underlies nucleotide-mediated inhibition of amiloride-sensitive AFC in both infections. We found that addition of the synthetic double-stranded RNA analog poly-inosinic-cytidylic acid [poly(I:C)] (500 ng/ml) to the AFC instillate resulted in nucleotide/P2Y purinergic receptor-mediated inhibition of amiloride-sensitive AFC in BALB/c mice but had no effect on cystic fibrosis transmembrane regulator (CFTR)-mediated Cl(-) transport. Poly(I:C) also induced acute keratinocyte cytokine-mediated AFC insensitivity to stimulation by the β-adrenergic agonist terbutaline. Inhibitory effects of poly(I:C) on AFC were absent in TLR-3(-/-) mice and were not replicated by addition to the AFC instillate of ligands for other TLRs except TLR-2. Intranasal poly(I:C) administration (250 μg/mouse) similarly induced nucleotide-dependent AFC inhibition 2-3 days later, together with increased lung water content and neutrophilic inflammation. Intranasal treatment of BALB/c mice with poly(I:C) did not induce airway hyperresponsiveness at day 2 but did result in insensitivity to airway bronchodilation by β-adrenergic agonists. These findings suggest that viral double-stranded RNA replication intermediates induce nucleotide-mediated impairment of amiloride-sensitive AFC in both infections, together with β-adrenergic agonist insensitivity. Both of these effects also occur in RSV infection. However, double-stranded RNA replication intermediates do not appear to be sufficient to induce either adenosine-mediated, CFTR-dependent Cl(-) secretion in the lung or severe, lethal hypoxemia, both of which are features of influenza infection.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Famke
authors.initials: F
authors.lastname: Aeffner
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Traylor
authors.forename: Erin N Z
authors.initials: EN
authors.lastname: Yu
authors.forename: Ian C
authors.initials: IC
authors.lastname: Davis
mesh_terms: D000281:Administration, Intranasal; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001826:Body Fluids / Q000187:drug effects; D019570:Inhalation Exposure; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000503:physiopathology* / Q000821:virology*; D055370:Lung Injury / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D058470:Receptors, Purinergic P2Y / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000150:complications / Q000503:physiopathology* / Q000821:virology*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D008024:Ligands; D012330:RNA, Double-Stranded; D058470:Receptors, Purinergic P2Y; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C