RESUMO
Glial cells function as sensors for infection within the brain and produce cytokines to limit viral replication and spread. We examined both cytokine (TNF-alpha, IL-1beta, and IL-6) and chemokine (MCP-1, MIP-1alpha, RANTES, and IL-8) production by primary human glial cells in response to cytomegalovirus (CMV). Although CMV-infected astrocytes did not produce antiviral cytokines, they generated significant quantities of the chemokines MCP-1 and IL-8 in response to viral infection. On the other hand, supernatants from CMV-stimulated purified microglial cell cultures showed a marked increase in the production of TNF-alpha and IL-6, as well as chemokines. Supernatants from CMV-infected astrocyte cultures induced the migration of microglia towards chemotactic signals generated from infected astrocytes. Antibodies to MCP-1, but not to MIP-1alpha, RANTES, or IL-8, inhibited this migratory activity. These findings suggest that infected astrocytes may use MCP-1 to recruit antiviral cytokine-producing microglial cells to foci of infection. To test this hypothesis, cocultures of astrocytes and microglial cells were infected with CMV. Viral gene expression in these cocultures was 60% lower than in CMV infected purified astrocyte cultures lacking microglia. These results support the hypothesis that microglia play an important antiviral role in defense of the brain against CMV. The host defense function of microglial cells may be directed in part by chemokines, such as MCP-1, produced by infected astrocytes.
Assuntos
Astrócitos/virologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Encefalite Viral/imunologia , Microglia/virologia , Astrócitos/citologia , Astrócitos/imunologia , Encéfalo/citologia , Encéfalo/virologia , Células Cultivadas , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Quimiotaxia/imunologia , Técnicas de Cocultura , Citomegalovirus/crescimento & desenvolvimento , Encefalite Viral/virologia , Feto/citologia , Regulação Viral da Expressão Gênica/imunologia , Humanos , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Proteínas Inflamatórias de Macrófagos/genética , Proteínas Inflamatórias de Macrófagos/imunologia , Microglia/citologia , Microglia/imunologia , RNA Mensageiro/análise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Replicação ViralRESUMO
Cytomegalovirus-stimulated CD4(+) lymphocytes from seropositive but not seronegative donors suppressed viral gene expression in primary human astrocytes. This suppressive activity was mediated through soluble factors. These findings suggest that CD4(+) lymphocytes play a role in defense of the brain against cytomegalovirus.
