TLR9-induced interferon [beta] is associated with protection from gammaherpesvirus-induced exacerbation of lung fibrosis

Background We have shown previously that murine gammaherpesvirus 68 ([gamma]HV68) infection exacerbates established pulmonary fibrosis. Because Toll-like receptor (TLR)-9 may be important in controlling the immune response to [gamma]HV68 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.sup.-/- .sup.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.sup.-/- .sup.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.sup.-/- .sup.mice had a defect in the production of interferon (IFN)-[beta] after viral infection. Balb/c fibroblasts infected with [gamma]HV68 in vitro produced more IFN-[beta] than did infected TLR-9.sup.-/- .sup.fibroblasts. Accordingly, in vitro infection of Balb/c fibroblasts resulted in reduced proliferation rates whereas infection of TLR-9.sup.-/- .sup.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.