title: Poly I:C enhances susceptibility to secondary pulmonary infections by gram-positive bacteria.
abstract: Secondary bacterial pneumonias are a frequent complication of influenza and other respiratory viral infections, but the mechanisms underlying viral-induced susceptibility to bacterial infections are poorly understood. In particular, it is unclear whether the host's response against the viral infection, independent of the injury caused by the virus, results in impairment of antibacterial host defense. Here, we sought to determine whether the induction of an "antiviral" immune state using various viral recognition receptor ligands was sufficient to result in decreased ability to combat common bacterial pathogens of the lung. Using a mouse model, animals were administered polyinosine-polycytidylic acid (poly I:C) or Toll-like 7 ligand (imiquimod or gardiquimod) intranasally, followed by intratracheal challenge with Streptococcus pneumoniae. We found that animals pre-exposed to poly I:C displayed impaired bacterial clearance and increased mortality. Poly I:C-exposed animals also had decreased ability to clear methicillin-resistant Staphylococcus aureus. Furthermore, we showed that activation of Toll-like receptor (TLR)3 and Retinoic acid inducible gene (RIG-I)/Cardif pathways, which recognize viral nucleic acids in the form of dsRNA, both contribute to poly I:C mediated impairment of bacterial clearance. Finally, we determined that poly I:C administration resulted in significant induction of type I interferons (IFNs), whereas the elimination of type I IFN signaling improved clearance and survival following secondary bacterial pneumonia. Collectively, these results indicate that in the lung, poly I:C administration is sufficient to impair pulmonary host defense against clinically important gram-positive bacterial pathogens, which appears to be mediated by type I IFNs.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Tian
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Wing Yi
authors.initials: WY
authors.lastname: Lung
authors.forename: Cherise
authors.initials: C
authors.lastname: Meyerson
authors.forename: Amir Ali
authors.initials: AA
authors.lastname: Ghaffari
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Jane C
authors.initials: JC
authors.lastname: Deng
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000956:Antigens, Viral / Q000008:administration & dosage / Q000276:immunology*; D004198:Disease Susceptibility; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D000077271:Imiquimod; D007369:Interferon Inducers / Q000494:pharmacology; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D011070:Poly I-C / Q000008:administration & dosage / Q000276:immunology*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D013296:Streptococcus pneumoniae / Q000276:immunology; D015996:Survival Rate; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology; D000097905:Roundabout Proteins
chemical_list: D000634:Aminoquinolines; D000906:Antibodies; D000956:Antigens, Viral; D007093:Imidazoles; D000077271:Imiquimod; D007369:Interferon Inducers; D007370:Interferon Type I; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011070:Poly I-C; D053633:Receptor, Interferon alpha-beta; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C519703:TLR3 protein, mouse; C546771:gardiquimod