ABSTRACT: Viruses are obligatory intracellular parasites and hijack the host cell machinery to make more identical copies of it and continue self-propagation. They attach and replicate in the susceptible and permissive hosts and host derived cell lines. They enter the cells either through direct attachment, receptor-mediated endocytosis, or phagocytosis. Hence, to thwart the invasion by viruses, hosts have developed immunity in ascending stages—intrinsic, innate and adaptive immunity. A robust intrinsic and innate immune response governs an effective adaptive immune response, should that be needed. Both enveloped as well as non-enveloped viruses are subject to distinct types of DNA sensors, subject to their site of replication. DNA sensors of viral PAMPs can be classified into three types, based on the location of their PAMPs in the host cellular compartment viz. cell surface, cytoplasmic and nuclear. The host cell membrane both, surface as well as intra cellular, is continuously monitored for the non-host, pathogenic components or PAMPs. Among the intracellular sensors of the viral genome, there are two types—essentially due to the two types of major viral genomes i.e. RNA and DNA sensors. The cytosolic DNA sensors include AIM2, IFI16, cGAS, RNA Pol III, DNA-PK, DDX9, DHX36, DDX41, DDX60, DAI, LRRFIP1, HMGB, ABCF1 and MRE11. PYHIN family of sensors include AIM2, IFI16, IFIX and MNDA. Another recently discovered family of sensor called stimulator of interferon (IFN) genes (STING), specifically houses on the endoplasmic reticulum (ER) and functions in association with its upstream sensor, cGAS. Some DNA sensors shuttle between the cytosol and nucleus pre- and post-extraneous DNA binding. These include IFI16, IFIX, RNA Pol III, etc. There is no exclusive nuclear DNA sensor. Many enzymes known to be present in the cells for their obvious primary functions also additionally function as DNA sensors. The DNAse family of sensors include DNAse II and TREX1, which are ubiquitously present in the cell for their housekeeping functions. The RNAse family of sensor includes one member—RNA Pol III. Additionally, DNA-PK also functions to cater to viral DNA sensing. The endosomal DNA sensors include TLR7 and TLR9, which belong to the Toll-like receptor (TLR) family. The DExD/H-box helicase family include the putative DNA sensors recently discovered including DDX9, DHX36, DDX41 and DDX60. Several other sensors remain to be characterised or are less classified viz. DAI, LRRFIP1, HMGB, ABCF1, MRE11. In general, response to a viral RNA or DNA produces three types of responses, namely, production of antiviral cytokines including Types I and III IFNs, release of pro-inflammatory and inflammatory cytokines and chemotactic factors. This chapter discusses the structure, function and mechanism of action of the viral DNA sensors explored till date.
