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Cytomegalovirus production by infected astrocytes correlates with transforming growth factor-beta release
Thomas Kossmann1, M Cristina Morganti-Kossmann, Jan M Orenstein
1Oral Infection and Immunity Branch, National Institute of Dental and Crainofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
Cytomegalovirus (CMV) encephalitis is well documented in immunosuppressed persons, but its pathogenesis has received little investigative attention. The examination of brain tissue from 2 patients with acquired immunodeficiency syndrome who had CMV encephalitis showed colocalization of CMV inclusions and transforming growth factor (TGF)-beta in cells that contained astrocyte-specific glial filaments. To investigate the relationship between CMV and TGF-beta in the brain, an ex vivo murine model of CMV-infected astrocytes was established. Cultures of primary murine (strain FVB/N) astrocytes inoculated with murine (Smith strain) CMV expressed, over time, increasing amounts of infectious CMV in parallel with increasing levels of TGF-beta mRNA and peptide. Astrocyte release of CMV declined in the presence of antibody to TGF-beta and increased substantially after the addition of exogenous TGF-beta. These findings suggest that CMV infection of astrocytes induces the production of TGF-beta, which in turn enhances productive CMV expression.
Insights
Cytomegalovirus (CMV) encephalitis pathogenesis involves astrocytes producing transforming growth factor-beta (TGF-beta). This TGF-beta enhances CMV replication in brain cells, suggesting a key mechanism in CMV encephalitis.
Area of Science:
- Neurovirology
- Immunology
- Cellular Biology
Background:
- Cytomegalovirus (CMV) encephalitis is a known complication in immunosuppressed individuals, particularly those with acquired immunodeficiency syndrome (AIDS).
- The precise mechanisms driving CMV encephalitis pathogenesis remain largely unexplored.
- Initial observations linked CMV inclusions and TGF-beta to astrocytes in patient brain tissue.
Purpose of the Study:
- To investigate the relationship between Cytomegalovirus (CMV) and transforming growth factor-beta (TGF-beta) in the context of brain infection.
- To elucidate the role of astrocytes in CMV encephalitis pathogenesis.
Main Methods:
- Establishment of an ex vivo murine model using primary astrocyte cultures.
- Inoculation of murine astrocytes with murine CMV (Smith strain).
- Quantification of infectious CMV, TGF-beta mRNA, and TGF-beta peptide levels over time.
- Assessment of CMV release in response to TGF-beta modulation (antibody and exogenous addition).
Main Results:
- CMV-infected astrocytes showed a time-dependent increase in both infectious CMV and TGF-beta mRNA/peptide levels.
- Astrocyte release of CMV was inhibited by antibodies targeting TGF-beta.
- Exogenous TGF-beta significantly enhanced CMV release from infected astrocytes.
Conclusions:
- CMV infection in astrocytes stimulates the production of TGF-beta.
- TGF-beta plays a crucial role in promoting productive CMV replication and release from astrocytes.
- This interaction highlights a potential therapeutic target for managing CMV encephalitis.