Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Oct 1:11:568412.
doi: 10.3389/fimmu.2020.568412. eCollection 2020.

Vaccinia Virus Activation and Antagonism of Cytosolic DNA Sensing

Misbah El-Jesr  1 , Muad Teir  1 , Carlos Maluquer de Motes  1
Affiliations
Review

Vaccinia Virus Activation and Antagonism of Cytosolic DNA Sensing

Misbah El-Jesr et al. Front Immunol. .

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.

Keywords: CGAS; STING; antiviral signaling; interferons; vaccinia virus (VACV).

PubMed Disclaimer

Figures

Figure 1
Figure 1
Anti-viral DNA sensing and its antagonism by VACV. Upon infection the VACV genome is released into the cytosol and recognized primarily by cGAS, although other sensors such as DNA-PK play a role in a cell-specific manner. Activated cGAS catalizes the production of 2′ 3′ -cGAMP, which binds and activates STING. In addition, cGAMP is transferred to neighboring cells via gap junctions and imported from the extracellular environment via the transporter SLC19A1. cGAMP-bound STING oligomers mediate the recruitment of TBK1, which subsequently leads to the activation of IRF3 and NF-κB signal transduction and the induction of anti-viral responses. A number of VACV proteins have the capacity to block cytosolic DNA sensing and are shown here in orange or red depending on the level of conservation (see Table 1). These proteins counteract multiple stages of the signaling cascade (shown here with a blocked line). Evidence exists for additional inhibitors acting in the cell nucleus, although they remain yet unidentified. At present no VACV inhibitors of STING have been discovered, but this is a convergent signaling point known to be blocked by several viruses. These potential target sites are indicated with a question mark.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Esparza J, Schrick L, Damaso CR, Nitsche A. Equination (inoculation of horsepox): an early alternative to vaccination (inoculation of cowpox) and the potential role of horsepox virus in the origin of the smallpox vaccine. Vaccine. (2017) 35:7222–30. 10.1016/j.vaccine.2017.11.003 - DOI - PubMed
    1. Sanchez-Sampedro L, Perdiguero B, Mejias-Perez E, Garcia-Arriaza J, Di Pilato M, Esteban M. The evolution of poxvirus vaccines. Viruses. (2015) 7:1726–803. 10.3390/v7041726 - DOI - PMC - PubMed
    1. Goebel SJ, Johnson GP, Perkus ME, Davis SW, Winslow JP, Paoletti E. The complete DNA sequence of vaccinia virus. Virology. (1990) 179:247–66, 517–63. 10.1016/0042-6822(90)90294-2 - DOI - PubMed
    1. Volz A, Sutter G. Modified vaccinia virus ankara: history, value in basic research, and current perspectives for vaccine development. Adv Virus Res. (2017) 97:187–243. 10.1016/bs.aivir.2016.07.001 - DOI - PMC - PubMed
    1. Moss B. Poxviridae: the viruses and their replication. In: Knipe DM, editor. Fields Virology. Philadelphia, PA: Lippincott Williams and Wilkins; (2007).

Publication types