Murine gammaherpesvirus-68 infection causes multi-organ fibrosis and alters leukocyte trafficking in interferon-gamma receptor knockout mice

Murine gammaherpesvirus-68 (MHV-68) infection in interferon-gamma receptor knockout mice (IFN-gammaR(-)/(-)) results in splenic fibrosis and excessive loss of splenocytes, In our present study we found that MHV-68 infection i n IFN-gammaR(-)/(-) mice also resulted in fibrosis and atrophy of the media stinal lymph nodes, interstitial pulmonary fibrosis and fibrotic changes in the Liver. Atrophy and cellular depletion of the spleen in IFN-gammaR(-)/( -) was not the result of increased cell death. The loss of splenocytes in I FN-gammaR(-)/(-) mice, which was most evident on day 23 after infection, co rrelated with an increase in the number of leukocytes in peripheral blood. At the peak of leukocytosis, on day 23 after infection, peripheral blood ce lls from infected IFN-gammaR(-)/(-) mice were unable to traffic through the fibrosed spleens of IFN-gammaR(-)/(-) mice but were able to enter the sple ens of wild-type mice. This indicates that leukocytosis was in part the res ult of emigration of cells from the spleen and their subsequent exclusion o f re-entry at the height of fibrosis. Significant cytokine and chemokine ch anges were observed in spleens of IFN-gammaR(-)/(-) mice. IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), TNF-beta, interleukin-1 beta (IL-1 beta) , transforming growth factor-pr (TGF-beta1), lymphotactin, and MIP-1 beta w ere elevated on day 14 after infection whereas chemokines IP-10 and MIG wer e significantly reduced. These changes suggest a role for dysregulated cyto kines and chemokines in severe organ-specific fibrosis with implications fo r immune-mediated fibrotic disorders.