Macrophage activation associated with chronic murine cytomegalovirus infection results in more severe experimental choroidal neovascularization

Scott W. Cousins, Diego G. Espinosa-Heidmann, Daniel M. Miller, Simone Pereira-Simon, Eleut P. Hernandez, Hsin Chien, Courtney Meier-Jewett, Richard D. Dix

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The neovascular (wet) form of age-related macular degeneration (AMD) leads to vision loss due to choroidal neovascularization (CNV). Since macrophages are important in CNV development, and cytomegalovirus (CMV)-specific IgG serum titers in patients with wet AMD are elevated, we hypothesized that chronic CMV infection contributes to wet AMD, possibly by pro-angiogenic macrophage activation. This hypothesis was tested using an established mouse model of experimental CNV. At 6 days, 6 weeks, or 12 weeks after infection with murine CMV (MCMV), laser-induced CNV was performed, and CNV severity was determined 4 weeks later by analysis of choroidal flatmounts. Although all MCMV-infected mice exhibited more severe CNV when compared with control mice, the most severe CNV developed in mice with chronic infection, a time when MCMV-specific gene sequences could not be detected within choroidal tissues. Splenic macrophages collected from mice with chronic MCMV infection, however, expressed significantly greater levels of TNF-α, COX-2, MMP-9, and, most significantly, VEGF transcripts by quantitative RT-PCR assay when compared to splenic macrophages from control mice. Direct MCMV infection of monolayers of IC-21 mouse macrophages confirmed significant stimulation of VEGF mRNA and VEGF protein as determined by quantitative RT-PCR assay, ELISA, and immunostaining. Stimulation of VEGF production in vivo and in vitro was sensitive to the antiviral ganciclovir. These studies suggest that chronic CMV infection may serve as a heretofore unrecognized risk factor in the pathogenesis of wet AMD. One mechanism by which chronic CMV infection might promote increased CNV severity is via stimulation of macrophages to make pro-angiogenic factors (VEGF), an outcome that requires active virus replication.

Original languageEnglish (US)
Article numbere1002671
JournalPLoS Pathogens
Volume8
Issue number4
DOIs
StatePublished - Apr 1 2012

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Muromegalovirus
Choroidal Neovascularization
Macrophage Activation
Cytomegalovirus Infections
Vascular Endothelial Growth Factor A
Macular Degeneration
Macrophages
Infection
Polymerase Chain Reaction
Ganciclovir
Angiogenesis Inducing Agents
Virus Replication
Matrix Metalloproteinases
Cytomegalovirus
Antiviral Agents
Lasers
Theoretical Models
Immunoglobulin G
Enzyme-Linked Immunosorbent Assay
Messenger RNA

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Macrophage activation associated with chronic murine cytomegalovirus infection results in more severe experimental choroidal neovascularization. / Cousins, Scott W.; Espinosa-Heidmann, Diego G.; Miller, Daniel M.; Pereira-Simon, Simone; Hernandez, Eleut P.; Chien, Hsin; Meier-Jewett, Courtney; Dix, Richard D.

In: PLoS Pathogens, Vol. 8, No. 4, e1002671, 01.04.2012.

Research output: Contribution to journalArticle

Cousins, Scott W. ; Espinosa-Heidmann, Diego G. ; Miller, Daniel M. ; Pereira-Simon, Simone ; Hernandez, Eleut P. ; Chien, Hsin ; Meier-Jewett, Courtney ; Dix, Richard D. / Macrophage activation associated with chronic murine cytomegalovirus infection results in more severe experimental choroidal neovascularization. In: PLoS Pathogens. 2012 ; Vol. 8, No. 4.
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