Murine Gammaherpesvirus-68 Infection Causes Multi-Organ Fibrosis and Alters Leukocyte Trafficking in Interferon-γ Receptor Knockout Mice

Infectious disease, the innate immune response, and fibrosis

“…This scenario can be observed in the context of a secondary viral insult in the form of a herpesvirus. Experimentally, MHV-68 markedly enhanced fibrosis in a Th1-deficient environment (73). Current data suggests that MHV-68 exacerbates the tissue fibrotic response in mice by contributing gene products that can neutralize necessary innate immune cytokines (through cytokine-binding proteins such as M3) or induce rapid cell proliferation (through the viral chemokine receptor vGPCR) (our unpublished observations).…”

“…Interestingly, alveolar content samples from patients with IPF contain M2 macrophages (71,72), and it has been suggested that the upregulation of the alternative activation pathway in these cells might contribute to the fibrotic process because these cells inhibit the pulmonary antiviral response (72). When mice lacking the receptor for IFN-γ (Ifngr -/-mice) were challenged with the murine homolog of HHV8, murine γ-herpesvirus-68 (MHV-68), they exhibited multi-organ fibrosis (73). The development of multi-organ fibrosis in these mice might reflect the persistence and dissemination of this virus within this knockout mouse, which has an immune response heavily skewed toward a Th2-type cytokine response.…”

Right place, right time: the evolving role of herpesvirus infection as a “second hit” in idiopathic pulmonary fibrosis

“…MHV-68-infected IFN␥R-deficient mice, which progress to a fibrotic phenotype, have more inflammatory cells, higher levels of proinflammatory cytokines, and delayed resolution of inflammation compared with MHV-68-infected wild-type controls (23,24), a pattern also seen with MHV-68-infected/FITC-treated wild-type mice (20,34). Following MHV-68 infection, IFN␥R-deficient mice infected with MHV-68 also develop fibrosis in the liver and spleen (5). In this model, herpesvirus infection increased the number of alternatively activated macrophages, which are thought to participate in tissue remodeling (22).…”

Toll-like Receptors, Notch Ligands, and Cytokines Drive the Chronicity of Lung Inflammation

“…Wild-type mice infected via the respiratory route with MuHV-68 exhibited a lytic infection of alveolar epithelial cells with a subsequent latent infection of B cells and an elevation of CD8 1 T cells (24). Immunocompetent wild-type mice challenged with MuHV-68 did not exhibit pronounced chronic changes in the lung, which is quite different from mice with a type 2 cytokine bias (25,26). Intranasal challenge with MuHV-68 in IFN-g receptor knockout mice induced a type 2 cytokine bias and a striking pathologic picture, characterized by an altered cytokine profile and significant fibrosis of the lungs.…”