Poxviral Targeting of Interferon Regulatory Factor Activation

Abstract

As viruses have a capacity to rapidly evolve and continually alter the coding of their protein repertoires, host cells have evolved pathways to sense viruses through the one invariable feature common to all these pathogens—their nucleic acids. These genomic and transcriptional pathogen-associated molecular patterns (PAMPs) trigger the activation of germline-encoded anti-viral pattern recognition receptors (PRRs) that can distinguish viral nucleic acids from host forms by their localization and subtle differences in their chemistry. A wide range of transmembrane and cytosolic PRRs continually probe the intracellular environment for these viral PAMPs, activating pathways leading to the activation of anti-viral gene expression. The activation of Nuclear Factor Kappa B (NFκB) and Interferon (IFN) Regulatory Factor (IRF) family transcription factors are of central importance in driving pro-inflammatory and type-I interferon (TI-IFN) gene expression required to effectively restrict spread and trigger adaptive responses leading to clearance. Poxviruses evolve complex arrays of inhibitors which target these pathways at a variety of levels. This review will focus on how poxviruses target and inhibit PRR pathways leading to the activation of IRF family transcription factors.

Poxviral Strategies to Overcome Host Cell Apoptosis

“…In addition to the numerous described poxviral encoded proteins used to disarm the plethora of apoptosis-associated host responses to viral infection, a number of poxviral modulators of another critical host defense system exist that counter interferon (IFN)-based responses. These have been critically reviewed recently [ 9 , 10 ], and consequently, we did not include IFN regulatory mechanisms in this review.…”

“…The importance of regulating host cell death and immune responses has triggered the assimilation of many apoptotic regulatory genes by viruses. Poxviruses, in particular, have captured numerous genes for manipulating apoptosis such as viral Bcl-2 (vBcl-2) homologs, serpin protease inhibitors, dsRNA inhibitors, NF-κB inhibitors [ 6 , 7 ], or Interferon (IFN) inhibitors [ 8 , 9 , 10 ].…”

Role of cytokines in poxvirus host tropism and adaptation

“…In most cases, whether these virus-encoded proteins targeting different cytokines and their network subsequently determine the tropism of poxviruses is yet to be studied in greater detail [24] . Several reviews have focused on this topic of how viruses counteract different cytokines, and it is beyond the scope of this mini-review 23 , 26 , 27 , 28 , 29• , 30 , 31 . Interferons: IFNs are the key cytokines that are rapidly produced and released from the cells in response to virus infection or by sensing virus-induced ligands such as pathogen-associated molecular patterns or damage-associated molecular patterns.…”

Special Issue: “Innate Immune Sensing of Viruses and Viral Evasion”

“…These publications exemplify the fact that viruses have evolved multiple ways to dampen the host IFN response by interfering, disrupting, or evading specific host regulators, both up-and downstream of IFN induction. The diverse viral escape pathways are described in the following reviews [7,8,[10][11][12][13] and one original article on herpes-viruses [14]. A recent discovery stems from the observation that DNA sensing by the cGAS/STING pathway can be triggered by certain RNA viruses.…”

“…The recognition of DNA viruses was enigmatic until the recent discovery of several DNA sensors. Poxviruses are an example of DNA viruses that express a plethora of viral antagonists that block sensing by DNA sensors, such as cGAS or DNA-PK and, interestingly, also by RNA sensors [ 8 ]. In contrast, Hepatitis B virus may evade recognition by shielding the DNA within the viral capsid, although naked HBV DNA elicits a strong immune response in primary myeloid cells mediated by cGAS/STING [ 9 ].…”