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Fibroblast cells immediate-early after human cytomegalovirus infection

ABSTRACT: Human cytomegalovirus (HCMV) has been shown to have the potential to alter cellular gene expression early after infection. However, one-gene approaches and the use of closed system gene expression technologies have identified only few cellular genes whose activity changed immediate-early. We therefore used serial analysis of gene expression (SAGE) to investigate the transcriptional program of human fibroblasts in response to HCMV in the immediate-early phase of infection. Differential expression of various cellular genes was monitored. Transcriptional expression changes of genes coding for ribosomal proteins reflected a general cellular response to starvation and stress. But differential regulation of genes coding for transcription factors and proteins associated with cellular metabolism, homeostasis and cell structure may represent transcriptional alterations in response to HCMV infection. Expression kinetics by 5' nuclease fluorigenic real-time PCR of selected genes revealed partial protection of infected cells against initial stress-associated alterations of gene expression and indicated fluctuations of transcriptional levels over time. Additionally, agreement with the quantitative results obtained by SAGE was observed only for genes up-regulated in HCMV-infected cells. This finding pointed to various technical and statistical parameters that all may be critical for quantitative transcriptome studies using global approaches, especially when exploring biological systems in a critical phase of cellular physiology. Keywords: other

ORGANISM(S): Homo sapiens

PROVIDER: GSE506 | GEO | 2003/07/16

SECONDARY ACCESSION(S): PRJNA85223

REPOSITORIES: GEO

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Project description:Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-gamma and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-gamma-responsive promoters. However, neither synthesis nor secretion of IFN-gamma or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity. We used a total of 18 microarrays for analyzing triplicate samples each of IE1-negative control fibroblasts (TetR cells) without induction (3 arrays), fibroblasts containing inducible IE1 (TetR-IE1 cells) without induction (3 arrays), TetR cells induced for 24 h (3 arrays), TetR-IE1 cells induced for 24 h (3 arrays), TetR cells induced for 72 h (3 arrays), and TetR-IE1 cells induced for 72 h (3 arrays)

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Fibroblast cells immediate-early after human cytomegalovirus infection

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