Abstract
The antiviral activity of type I interferons (IFNs) is primarily mediated by interferon-stimulated genes (ISGs). Induction of ISG transcription is achieved when type I IFNs bind to their cognate receptor and activate the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathways. Recently it has become clear that a number of viruses are capable of directly upregulating a subset of ISGs in the absence of type I IFN production. Using cells engineered to block either the response to, or production of type I IFN, the regulation of IFN-independent ISGs was examined in the context of human cytomegalovirus (HCMV) infection. Several ISGs, including IFIT1, IFIT2, IFIT3, Mx1, Mx2, CXCL10 and ISG15 were found to be upregulated transcriptionally following HCMV infection independently of type I IFN-initiated JAK-STAT signaling, but dependent on intact IRF3 signaling. ISG15 protein regulation mirrored that of its transcript with IFNβ neutralization failing to completely inhibit ISG15 expression post HCMV infection. In addition, no detectable ISG15 protein expression was observed following HCMV infection in IRF3 knockdown CRISPR/Cas-9 clones indicating that IFN-independent control of ISG expression during HCMV infection of human fibroblasts is absolutely dependent on IRF3 expression.
Highlights
Human cytomegalovirus (HCMV) is a betaherpesvirus with a 40–90% seroprevalence worldwide [1,2,3,4,5,6]
We extended our analysis to a range of interferonstimulated genes (ISGs) that have previously been identified as being regulated directly by virus infection in an IFN-independent manner i.e., IFIT1, IFIT2, IFIT3, ISG15, CXCL10, Mx1 and Mx2 [20,33,34,35,36,37]
ISG15 protein expression in all cells tested indicating that cells lacking interferon regulatory factor 3 (IRF3) expression retain the capacity to upregulate ISG15. Together these results directly demonstrate the essential role IRF3 plays in HCMV-induced ISG15 upregulation in both an IFN-dependent and IFN-independent manner
Summary
Human cytomegalovirus (HCMV) is a betaherpesvirus with a 40–90% seroprevalence worldwide [1,2,3,4,5,6]. Type I interferons (IFNα and IFNβ) play a crucial role in the innate immune response to HCMV, with viral replication inhibited following pre-treatment with type I IFN [13,14,15]. Initiation of the type I IFN response to HCMV is multifaceted. It begins when the viral envelope glycoproteins (gB, gL and gH) that initiate virion attachment are detected by Toll-like receptor 2. (TLR-2) [17,18]. TLR-2 stimulation activates a signaling cascade that culminates in initiation of type
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