title: Virus-inducible expression of a host chemokine gene relies on replication-linked mRNA stabilization.
abstract: Analysis of the host response to viral infection generally has focused on the capacity of viruses to activate or repress transcription of cellular genes, and this approach is also characteristic of work on RNA viruses such as respiratory syncytial virus (RSV). In the present study, it appeared initially that RSV-driven expression of a critical immune regulator, the beta-chemokine RANTES (regulated upon activation, normal T cell expressed and secreted), in primary-culture airway epithelial cells also depended on inducible gene transcription because expression was accompanied by coordinate increases in transcriptional initiation rate and gene promoter activity. However, RSV-driven increases in RANTES gene transcription and promoter activity were small and transient relative to RANTES expression, and they were no different in size and duration than for inactivated RSV that was incapable of fully inducing RANTES expression. These findings suggested that the increase in RANTES gene transcription was not sufficient for inducible expression and that critical regulatory effects occurred at a posttranscriptional level. This type of mechanism for virus-inducible expression of RANTES was established when we found that replicating (but not inactivated) RSV markedly increased RANTES mRNA half-life (from 0.8 to 6.8 h). In addition, RNase protection assays of heterologous promoter/reporter plasmids indicate that basal instability of RANTES mRNA is mediated at least in part by nucleotides 11-389 of the RANTES gene, and this region is also the target for induction by virus. The distinct pathway for production of RANTES (in combination with cytokine-dependent expression of RANTES and related immune-response genes) may more effectively coordinate immune cell interaction with epithelial barrier cells to mediate host defense.
mesh_terms: D001980:Bronchi / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007700:Kinetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D012136:Respiratory Syncytial Viruses / Q000235:genetics* / Q000276:immunology; D014132:Trachea / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic; D014779:Virus Replication / Q000235:genetics*