Molecular and Structural Basis of DNA Sensors in Antiviral Innate Immunity.

Ayesha Zahid,Tengchuan Jin,Hazrat Ismail,Bofeng Li

doi:10.3389/fimmu.2020.613039

Abstract

DNA viruses are a source of great morbidity and mortality throughout the world by causing many diseases; thus, we need substantial knowledge regarding viral pathogenesis and the host’s antiviral immune responses to devise better preventive and therapeutic strategies. The innate immune system utilizes numerous germ-line encoded receptors called pattern-recognition receptors (PRRs) to detect various pathogen-associated molecular patterns (PAMPs) such as viral nucleic acids, ultimately resulting in antiviral immune responses in the form of proinflammatory cytokines and type I interferons. The immune-stimulatory role of DNA is known for a long time; however, DNA sensing ability of the innate immune system was unraveled only recently. At present, multiple DNA sensors have been proposed, and most of them use STING as a key adaptor protein to exert antiviral immune responses. In this review, we aim to provide molecular and structural underpinnings on endosomal DNA sensor Toll-like receptor 9 (TLR9) and multiple cytosolic DNA sensors including cyclic GMP-AMP synthase (cGAS), interferon-gamma inducible 16 (IFI16), absent in melanoma 2 (AIM2), and DNA-dependent activator of IRFs (DAI) to provide new insights on their signaling mechanisms and physiological relevance. We have also addressed less well-understood DNA sensors such as DEAD-box helicase DDX41, RNA polymerase III (RNA pol III), DNA-dependent protein kinase (DNA-PK), and meiotic recombination 11 homolog A (MRE11). By comprehensive understanding of molecular and structural aspects of DNA-sensing antiviral innate immune signaling pathways, potential new targets for viral and autoimmune diseases can be identified.

Highlights

Viruses are a threat to humans since ancient times; many mechanisms exist in the human body to cope with viral infections
Numerous innate immune receptors named patternrecognition receptors (PRRs) are present at the cell surface or within the cells, which are employed by the innate immune defense to detect conserved structural features of the pathogens called pathogen-associated molecular patterns (PAMPs) [1]
Millions of years of evolution have evolved PRRs substantially in three ways: (i) they control the infection and induce cellular senescence [2]; (ii) they operate at cellular intrinsic levels and are associated with cellular machinery so that a danger signal can be relayed to the local microenvironment when necessary [3, 4]; and (iii) they have obtained the capability to detect the presence of non-compartmentalized host nucleic acids [5, 6]

Summary

Introduction

Viruses are a threat to humans since ancient times; many mechanisms exist in the human body to cope with viral infections. Pathogen-derived nucleic acids as single-stranded (ss) or double-stranded (ds) DNA and RNA serve as the most potent PAMPs that derive antiviral responses that are fundamental for the induction of resulting acquired immunity [8]. Signaling pathways that result in the synthesis of interferons, inflammatory cytokines, and chemokines are triggered by the activation of such receptors and lead to antiviral inflammatory and cell-mediated immune responses [9,10,11]. Two paradigmatic cytosolic nucleic acid sensing pathways in mammalian cells include the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway and RLRMAVS (RIG-I like receptor-mitochondrial antiviral signaling protein) pathway, which sense cytosolic DNA and RNA respectively [12].

Objectives

Conclusion