Vaccinia Virus Activation and Antagonism of Cytosolic DNA Sensing

Abstract

Cells express multiple molecules aimed at detecting incoming virus and infection. Recognition of virus infection leads to the production of cytokines, chemokines and restriction factors that limit virus replication and activate an adaptive immune response offering long-term protection. Recognition of cytosolic DNA has become a central immune sensing mechanism involved in infection, autoinflammation, and cancer immunotherapy. Vaccinia virus (VACV) is the prototypic member of the family Poxviridae and the vaccine used to eradicate smallpox. VACV harbors enormous potential as a vaccine vector and several attenuated strains are currently being developed against infectious diseases. In addition, VACV has emerged as a popular oncolytic agent due to its cytotoxic capacity even in hypoxic environments. As a poxvirus, VACV is an unusual virus that replicates its large DNA genome exclusively in the cytoplasm of infected cells. Despite producing large amounts of cytosolic DNA, VACV efficiently suppresses the subsequent innate immune response by deploying an arsenal of proteins with capacity to disable host antiviral signaling, some of which specifically target cytosolic DNA sensing pathways. Some of these strategies are conserved amongst orthopoxviruses, whereas others are seemingly unique to VACV. In this review we provide an overview of the VACV replicative cycle and discuss the recent advances on our understanding of how VACV induces and antagonizes innate immune activation via cytosolic DNA sensing pathways. The implications of these findings in the rational design of vaccines and oncolytics based on VACV are also discussed.

African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB Activation

“…Our results indicate that UBCv1 (I215L) is a new NF-ĸB modulator that cooperates with A238L. The presence of multiple viral proteins targeting the same innate immune pathway providing functional redundancy is not uncommon, and has been extensively reported for another large DNA virus such as VACV [ 39 , 41 , 42 , 43 ]. For instance, VACV protein A49 (used here as a control for NF-κB activation assays) acts at the level of IκBα degradation, blocking this by virtue of an N-terminal extension that mimics the IκBα phosphodegron recognised by the E3 ubiquitin ligase β-TrCP [ 30 , 34 , 44 , 45 ].…”

“…For instance, VACV protein A49 (used here as a control for NF-κB activation assays) acts at the level of IκBα degradation, blocking this by virtue of an N-terminal extension that mimics the IκBα phosphodegron recognised by the E3 ubiquitin ligase β-TrCP [ 30 , 34 , 44 , 45 ]. Upstream of A49, several other viral proteins have the capacity to suppress NF-κB activation, acting at the level of TLR adaptors, TRAFs and IKK (reviewed in [ 41 , 42 ]). The value of encoding for these viral upstream inhibitory molecules is thought to confer a stronger immunomodulatory potential not only due to the cumulative action of these proteins on one pathway, but also on other crosstalking pathways.…”

Innate Immune Sensing of Viruses and Its Consequences for the Central Nervous System

“…Knockdown of cGAS, STING or TBK1 in cells results in reduction of activated IRF3, IRF3 responsive genes, STAT1 and STAT2 following exposure AdVs [ 228 ]. VV can replicate its DNA genome in the cytoplasm of infected cells and can suppress the innate immune response through the expression of multiple inhibitors acting upstream and downstream of the immune pathway, and thus block cytosolic DNA sensing, which was recently reviewed by El-Jesr et.al 2020 [ 229 ]. The host’s DNA sensing of VV is complex and hence an attenuated VV strain, such as MVA or genetically engineered mice is widely used to gain insights into VV immunity.…”

“…Several studies indicated that type I IFN production by MVA is dependent of cGAS and its downstream adaptor STING [ 227 , 232 ]. Mice or human cells deficient in cGAS or STING show impaired production of type I IFNs in response to MVA [ 229 , 233 ]. Moreover, cGAS-deficient mice showed higher viral titer and greater susceptibility to VV (western reserve strain) [ 234 ].…”

Poxvirus cGAMP nucleases: Clues and mysteries from a stolen gene

“…Unlike most DNA viruses that replicate inside the cell nucleus avoiding the hostile cytosolic environment, poxviruses, a large family of linear dsDNA viruses, complete their life cycle exclusively in the cytoplasm. Such a strategy requires poxviruses to encode effective immune evasion mechanisms that dampen cellular cytosolic DNA surveillance, and a number of these have been described [ 4 , 5 ]. Recently, the immunomodulatory capacity of poxviruses gained a new perspective with the discovery of a viral cGAMP nuclease termed poxin (poxvirus immune nuclease) [ 6 ].…”