Editorial: Sensing DNA in Antiviral Innate Immunity.

Abstract

Editorial on the Research TopicSensing DNA in Antiviral Innate Immunity The editorial team welcomes you to the specific Research Topic on “Sensing DNA in Antiviral Innate Immunity”. We appreciate the hard work and outstanding contributions from all authors. Effective defense mechanisms against virus infection and pathogenesis rely on a prompt and robust induction of antiviral innate immunity. Central to antiviral innate immune responses is the detection of evolutionarily conserved structures, termed pathogen-associated molecular patterns (PAMPs), by a set of germline-encoded pattern-recognition receptors (PRRs) (1). In the case of DNA virus or retrovirus infection, cytosolic viral DNA or reverse transcription intermediates (RTI) is detected by DNA sensors cyclic GMP-AMP synthase (cGAS) as well as other cytosolic DNA binding proteins such as interferon-gamma inducible protein 16 (IFI16) (2, 3). Conversely, endosome-associated viral nucleic acids are recognized by toll-like receptor 7 (TLR7) and TLR9 (1). Furthermore, a recent report identified heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a nuclear DNA sensor for viral double-stranded DNA, but not cellular DNA, in the nucleus (4). Additionally, cGAS is recently reported to sense nuclear DNA (5–11). Following the detection of specific viral PAMPs, PRRs trigger the activation of intracellular signaling cascades, ultimately leading to the activation of NF-κB, interferon regulatory factor (IRF) 3 and 7, and the production of type I interferons (IFN-I) and various inflammatory cytokines such as CXCL10, TNFα and IL-6 (12). The antiviral program is subsequently amplified by paracrine and autocrine signaling of IFN through IFN receptors and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling, resulting in the induction of antiviral IFN-stimulated genes (ISGs) (13). This Research Topic will feature different contributions providing the molecular and structural basis of endosomal, nuclear, and cytosolic DNA sensors in antiviral response, the dynamic regulations of DNA sensors and their adaptor protein activation, trafficking, and post-translational modifications, and virus evasion of the host DNA-sensing antiviral innate immune responses. These approaches could contribute to the development of novel antiviral therapies and oncolytic viruses in the future. Zahid et al. introduced the PAMPs, PRRs, and the sources of cytotoxic DNA. The authors showed the structures of endosomal and cytosolic DNA sensors alone or complexed with DNA to provide insights on how binding the DNA to these sensors triggers the signaling pathways to activate the antiviral immune responses. They focused on the endosomal DNA sensor TLR9 and multiple cytosolic DNA sensors, including cGAS, IFI16, absent in melanoma 2 (AIM2), and DNA-dependent activator IRFs (DAI). The authors also covered other cytosolic DNA sensors, including DEAD-box helicase DDX41, RNA polymerase III, DNA-dependent protein kinase (DNA-PK), and meiotic recombination 11 homolog A (MRE11), as well as adaptor protein stimulator of interferon genes (STING). To ensure successful antiviral defenses and avoid aberrant or dysregulation of host immune signaling, antiviral pathways need to be tightly regulated. PRRs and their adaptor proteins are regulated at multiple levels. Two papers have discussed the recent advances in DNA sensors’ dynamic regulations and their adaptor protein STING. Zheng described the role of TLR9 dimerization, trafficking, and a multiprotein signaling complex formation in regulating endosomal DNA-sensing signaling. He also provided an update on the role of STING trafficking and polymerization in cGAS-STING signaling, how cellular proteins involve in cGAS-STING activation, and the evasion of cGAS-STING signaling by DNA viruses. Li et al. focused on trafficking and post-translational modifications in STING activation. They also summarized the proteins encoded by different DNA and RNA viruses to inhibit the intracellular trafficking and STING signaling activation. Recent studies have identified nucleus-localized DNA and RNA sensors to detect pathogenic nucleic acids for triggering antiviral innate immune responses. IFI16, hnRNPA2B1, and nuclear cGAS are all defined as possible sensors for nuclear DNA that is unwinded from histone complexes. Zhang et al. summarized the recent advances in identifying nuclear DNA sensors IFI16, hnRNPA2B1, and nuclear cGAS and their roles in regulating antiviral innate immune responses and tumorigenesis. The authors also discussed the transcriptional, post-transcriptional, and post-translational regulations of these nuclear DNA sensors. Viruses have evolved various strategies to inhibit and subvert the host’s antiviral immune responses. Three papers have been contributed to discuss recent advances in DNA viruses-induced and antagonize innate immune responses via DNA sensors. Zhao et al. reviewed how herpes simplex viruses (HSVs) are detected by the cytosolic DNA sensor cGAS-STING, IFI16, AIM2, and DAI, and how HSV-encoded proteins antagonize the signaling pathways triggered by DNA sensors. The authors also provided an overview of RIG-I-like receptors (RLRs) and protein kinase R (PKR) in the antiviral immune responses against HSVs. A paper from El-Jesr et al. and another paper from Lu and Zhang reviewed the latest studies on how the cytosolic DNA sensors recognize vaccinia virus (VACV) and trigger the activation of innate immune responses, and the strategies evolved by VACV to antagonize innate immune responses induced via cytosolic DNA sensing pathways. In a large genome-wide association study (GWAS) of the immune responses to primary smallpox vaccination, Kennedy et al. reported a cluster of SNPs on chromosome 5 (5q31.2) that were significantly associated with IFNα response to in vitro poxvirus stimulation. The authors identified rs1131769, a non-synonymous SNP in TMEM173...