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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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Lancet

2

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