title: Inhibition of NF-kappaB signaling reduces virus load and gammaherpesvirus-induced pulmonary fibrosis.
abstract: 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)gammaR(-/-) 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)-kappaB signaling is required to efficiently establish gammaherpesvirus, latency we infected IFNgammaR(-/-) mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NF-kappaB signaling pathway, called IkappaBalphaM. Striking differences were observed at the onset of the chronic infection, which correlated with a decreased virus load in mice infected with MHV68-IkappaBalphaM compared with mice infected with control MHV68 (MHV68-MR). IFNgammaR(-/-) mice infected with MHV68-IkappaBalphaM lacked vasculitis and fibrosis 15 to 120 days post infection. Inhibition of NF-kappaB 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 alphavbeta6, which is implicated in the activation of the profibrotic factor TGF-beta. Thus, the inhibition of NF-kappaB signaling in the infected lung cells of IFNgammaR(-/-) mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated pulmonary fibrosis.
authors.affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.
authors.forename: Laurie T
authors.initials: LT
authors.lastname: Krug
authors.forename: Edilson
authors.initials: E
authors.lastname: Torres-González
authors.forename: Qianhong
authors.initials: Q
authors.lastname: Qin
authors.forename: Dan
authors.initials: D
authors.lastname: Sorescu
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: Arlene
authors.initials: A
authors.lastname: Stecenko
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Speck
authors.forename: Ana L
authors.initials: AL
authors.lastname: Mora
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018142:Gammaherpesvirinae / Q000472:pathogenicity / Q000502:physiology*; D006566:Herpesviridae Infections / Q000473:pathology*; D007249:Inflammation / Q000473:pathology / Q000821:virology; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000473:pathology / Q000821:virology*; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D019562:Viral Load; D014779:Virus Replication; D000096743:Interferon gamma Receptor
chemical_list: D016328:NF-kappa B; D017471:Receptors, Interferon; D053773:Transforming Growth Factor beta1; D000096743:Interferon gamma Receptor