Latent infection by γherpesvirus stimulates profibrotic mediator release from multiple cell types

Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L274-85. doi: 10.1152/ajplung.00028.2010. Epub 2010 Oct 29.

Abstract

Although γherpesvirus infections are associated with enhanced lung fibrosis in both clinical and animal studies, there is limited understanding about fibrotic effects of γherpesviruses on cell types present in the lung, particularly during latent infection. Wild-type mice were intranasally infected with a murine γherpesvirus (γHV-68) or mock-infected with saline. Twenty-eight days postinfection (dpi), ∼14 days following clearance of the lytic infection, alveolar macrophages (AMs), mesenchymal cells, and CD19-enriched cell populations from the lung and spleen express M(3) and/or glycoprotein B (gB) viral mRNA and harbor viral genome. AMs from infected mice express more transforming growth factor (TGF)-β(1), CCL2, CCL12, TNF-α, and IFN-γ than AMs from mock-infected mice. Mesenchymal cells express more total TGF-β(1), CCL12, and TNF-α than mesenchymal cells from mock-infected mice. Lung and spleen CD19-enriched cells express more total TGF-β(1) 28 dpi compared with controls. The CD19-negative fraction of the spleen overexpresses TGF-β(1) and harbors viral genome, but this likely represents infection of monocytes. Purified T cells from the lung harbor almost no viral genome. Purified T cells overexpress IL-10 but not TGF-β(1). Intracellular cytokine staining demonstrated that lung T cells at 28 dpi produce IFN-γ but not IL-4. Thus infection with a murine γherpesvirus is sufficient to upregulate profibrotic and proinflammatory factors in a variety of lung resident and circulating cell types 28 dpi. Our results provide new information about possible contributions of these cells to fibrogenesis in the lungs of individuals harboring a γherpesvirus infection and may help explain why γHV-68 infection can augment or exacerbate fibrotic responses in mice.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Chemokine CCL2 / biosynthesis
  • Cytokines / biosynthesis*
  • DNA Primers / genetics
  • DNA, Viral / genetics
  • Disease Models, Animal
  • Herpesviridae Infections / genetics
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / virology
  • Interferon-gamma / biosynthesis
  • Interleukin-10 / biosynthesis
  • Lung / immunology
  • Lung / virology
  • Macrophage Activation
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / virology
  • Male
  • Mesoderm / immunology
  • Mesoderm / virology
  • Mice
  • Mice, Inbred C57BL
  • Monocyte Chemoattractant Proteins / biosynthesis
  • Pulmonary Fibrosis / etiology*
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / immunology
  • Pulmonary Fibrosis / virology
  • Rhadinovirus / pathogenicity*
  • Spleen / immunology
  • Spleen / virology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / virology
  • Transforming Growth Factor beta1 / biosynthesis
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Virus Infections / genetics
  • Tumor Virus Infections / immunology*
  • Tumor Virus Infections / virology
  • Viral Load

Substances

  • Ccl12 protein, mouse
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Cytokines
  • DNA Primers
  • DNA, Viral
  • IL10 protein, mouse
  • Monocyte Chemoattractant Proteins
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma