Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like
Host Cell Response That Depends on Activated STAT1 but Not
Interferon-γ
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.
Vyšlo v časopise:
Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like
Host Cell Response That Depends on Activated STAT1 but Not
Interferon-γ. PLoS Pathog 7(4): e32767. doi:10.1371/journal.ppat.1002016
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002016
Souhrn
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.
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