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Abstract
The critical role of interferons (IFNs) in mediating the innate immune response to cytomegalovirus (CMV) infection is well established. However, in recent years the functional importance of the IFN-independent antiviral response has become clearer. IFN-independent, IFN regulatory factor 3 (IRF3)-dependent interferon-stimulated gene (ISG) regulation in the context of CMV infection was first documented 20 years ago. Since then several IFN-independent, IRF3-dependent ISGs have been characterized and found to be among the most influential in the innate response to CMV. These include virus inhibitory protein, endoplasmic reticulum-associated IFN-inducible (viperin), ISG15, members of the interferon inducible protein with tetratricopeptide repeats (IFIT) family, interferon-inducible transmembrane (IFITM) proteins and myxovirus resistance proteins A and B (MxA, MxB). IRF3-independent, IFN-independent activation of canonically IFN-dependent signaling pathways has also been documented, such as IFN-independent biphasic activation of signal transducer and activator of transcription 1 (STAT1) during infection of monocytes, differential roles of mitochondrial and peroxisomal mitochondrial antiviral-signaling protein (MAVS), and the ability of human CMV (HCMV) immediate early protein 1 (IE1) protein to reroute IL-6 signaling and activation of STAT1 and its associated ISGs. This review examines the role of identified IFN-independent ISGs in the antiviral response to CMV and describes pathways of IFN-independent innate immune response induction by CMV.
Highlights
human CMV (HCMV) has a 236 kbp double stranded DNA genome, 165 genes [1] encoding up to 751 protein products [2], a 45–100% seroprevalence in the adult population [3,4,5,6,7], and remains a significant human pathogen in those with an underdeveloped or suppressed immune system
To interrogate the IFN-independent, IFN regulatory factor 3 (IRF3)-dependent response to HCMV human fibroblasts (HFs) have been engineered [92, 93] to lack either IRF3 through expression of the nPro protein of bovine viral diarrhea virus (BVDV) which binds and degrades IRF3 [94] or signal transducer and activator of transcription 1 (STAT1), by expression of the parainfluenza virus type 5 (PIV-5) V protein (V/HFs) which targets STAT1 for proteasomal degradation [95]. These nPro/HFs and V/HFs were recently utilized, alongside IRF3 KO CRISPR/Cas9 HFs, to demonstrate that expression of viperin, ISG15, IFIT1, IFIT2, IFIT3, Mx1, and Mx2 mRNA during infection with HCMV can be induced in an IRF3-dependent, STAT1-independent manner [96]
MRNA levels of IFIT1, IFIT2, and IFIT3 were as highly elevated in the absence of STAT1-mediated IFNAR signaling as in the parental HFs [96] underlining the capacity of such IFN-independent mechanisms to profoundly regulate interferon-stimulated gene (ISG) expression. Many of these IFN-independent, IRF3-dependent ISGs are among the most potently induced by CMV infection and examining the roles these genes play in the innate response to CMV is essential to understanding the ramifications of this non-canonical regulation
Summary
HCMV has a 236 kbp double stranded DNA (dsDNA) genome, 165 genes [1] encoding up to 751 protein products [2], a 45–100% seroprevalence in the adult population [3,4,5,6,7], and remains a significant human pathogen in those with an underdeveloped or suppressed immune system. These nPro/HFs and V/HFs were recently utilized, alongside IRF3 KO CRISPR/Cas9 HFs, to demonstrate that expression of viperin, ISG15, IFIT1, IFIT2, IFIT3, Mx1, and Mx2 mRNA during infection with HCMV can be induced in an IRF3-dependent, STAT1-independent manner [96].
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