Inhibition of NF-κB Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disorder of unknown etiology. Several studies have demonstrated an association between pulmonary infection with a herpesvirus and IPF. Based on those observations, we have developed a mouse model in which interferon (IFN)γR−/− mice infected intranasally with murine gammaherpesvirus 68 (MHV68) develop lung fibrosis. We hypothesize that viral load was a critical factor for the development of fibrosis. Because nuclear factor (NF)-κB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNγR−/− mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-κB signaling pathway, called IκBαM. Striking differences were observed at the onset of the chronic infection, which correlated with a decreased virus load in mice infected with MHV68-IκBαM compared with mice infected with control MHV68 (MHV68-MR). IFNγR−/− mice infected with MHV68-IκBαM lacked vasculitis and fibrosis 15 to 120 days post infection. Inhibition of NF-κB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 (MCP-1) and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin αvβ6, which is implicated in the activation of the profibrotic factor TGF-β. Thus, the inhibition of NF-κB signaling in the infected lung cells of IFNγR−/− mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated pulmonary fibrosis.