Interferon-Independent Innate Responses to Cytomegalovirus

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.

Cell type- and replication stage-specific influenza virus responses in vivo

“…Moreover, mCherry high and low cells display distinct antiviral gene signatures ( Fig 1D ). While the genes analyzed in this study are designated as interferon-simulated genes (ISGs), IFN-independent upregulation by virus replication of some of these genes has been described [ 22 – 24 ] and we do not distinguish between virus induced and interferon induced. The putative protective ISGs found in the mCherry low cells at 12 hpi overlap with the genes identified using both ΔHA-mCherry and ΔHA-destabilized GFP at 24 hpi identified previously [ 14 ] ( Fig 1E , top, S1 Table ).…”

“…IFN-independent, IRF-dependent upregulation of some ISGs has been described [ 22 – 24 ]. In these studies, detection of viral RNA products is still required for virus-induced gene expression.…”

Asymptomatic Infection of Marburg Virus Reservoir Bats Is Explained by a Strategy of Immunoprotective Disease Tolerance

“…For instance, recent work by the Mü hlberger lab showed that MARV VP35 inhibits PKR in human but not ERB cells, and there is precedent for IFN-independent response induction by IRF3 or STAT1 of subsets of canonical antiviral genes during in vitro human cytomegalovirus (HCMV) infection. [40][41][42] This does not preclude, however, the alternative possibilities that induction of IFN gene transcription simply occurs at levels too low for nCounter to detect, certain IFN proteins are activated on a post-transcriptional level, and/or the ability of MARV proteins to fully suppress IFN is cell type-dependent, any of which would suggest that IFNs still act as master antiviral response regulators in MARV-infected ERBs, perhaps in a paracrine fashion, without a need for noncanonical explanations. Of most relevance to pathogenesis among the cytokine/chemokine non-DEGs in ERBs is that they appear to be largely pro-or ambi-inflammatory; several are highly induced in primate filoviral infections, including IFNg, IL2, IL4, MIP-1b (CCL4), and CSF2.…”

Tuning the Orchestra: HCMV vs. Innate Immunity

“…Unlike other classical components of innate immunity, they are constitutively expressed within the host cells and are generally IFN inducible, thus allowing an immediate response against viral infection through specific targeting of viral/cellular components (Bieniasz, 2003;Hotter and Kirchhoff, 2018). Interestingly, during HCMV infection a subset of classical IFN-stimulated genes (ISGs) may be also induced or upregulated independently of IFN (Ashley et al, 2019).…”