Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Abstract

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-γ 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-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ 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.

Author Summary:
Human cytomegalovirus (hCMV) is a leading cause of birth defects and severe disease in people with compromised immunity. Disease caused by hCMV is frequently linked to inflammation, and the virus has been shown to induce numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the contributions of individual viral proteins to these changes in cellular transcription. We systematically analyzed the effects of the hCMV immediate-early 1 (IE1) protein, a major viral transcriptional activator, on expression of >28,000 human genes. Following expression under conditions mimicking the situation during hCMV infection, IE1 elicited a transcriptional response dominated by the up-regulation of pro-inflammatory and immune stimulatory genes normally induced by the secreted signaling protein interferon-γ. However, IE1-mediated gene expression was independent of interferon induction, yet required the activated form of signal transducer and activator of transcription 1 (STAT1), a central mediator of interferon signaling. Indeed, STAT1 moved to the nucleus and became associated with IE1 target genes upon expression of the viral protein. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host cell response via an unexpected mechanism and suggest that IE1 may contribute to hCMV disease in more direct ways than previously thought.