title: TLR9-induced interferon β is associated with protection from gammaherpesvirus-induced exacerbation of lung fibrosis.
abstract: BACKGROUND
  We have shown previously that murine gammaherpesvirus 68 (γHV68) infection exacerbates established pulmonary fibrosis. Because Toll-like receptor (TLR)-9 may be important in controlling the immune response to γHV68 infection, we examined how TLR-9 signaling effects exacerbation of fibrosis in response to viral infection, using models of bleomycin- and fluorescein isothiocyanate-induced pulmonary fibrosis in wild-type (Balb/c) and TLR-9-/- mice.
  
  
  RESULTS
  We found that in the absence of TLR-9 signaling, there was a significant increase in collagen deposition following viral exacerbation of fibrosis. This was not associated with increased viral load in TLR-9-/- mice or with major alterations in T helper (Th)1 and Th2 cytokines. We examined alveolar epithelial-cell apoptosis in both strains, but this could not explain the altered fibrotic outcomes. As expected, TLR-9-/- mice had a defect in the production of interferon (IFN)-β after viral infection. Balb/c fibroblasts infected with γHV68 in vitro produced more IFN-β than did infected TLR-9-/- fibroblasts. Accordingly, in vitro infection of Balb/c fibroblasts resulted in reduced proliferation rates whereas infection of TLR-9-/- fibroblasts did not. Finally, therapeutic administration of CpG oligodeoxynucleotides ameliorated bleomycin-induced fibrosis in wild-type mice.
  
  
  CONCLUSIONS
  These results show a protective role for TLR-9 signaling in murine models of lung fibrosis, and highlight differences in the biology of TLR-9 between mice and humans.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, University of Alabama at Birmingham Medical School, Birmingham, AL, USA. tluck@uab.edu.
authors.forename: Tracy R
authors.initials: TR
authors.lastname: Luckhardt
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Coomes
authors.forename: Glenda
authors.initials: G
authors.lastname: Trujillo
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Stoolman
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Vannella
authors.forename: Urvashi
authors.initials: U
authors.lastname: Bhan
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wilke
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Moore
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Cory
authors.initials: C
authors.lastname: Hogaboam
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore