Innate immune detection of microbial nucleic acids

Abstract

Detection of pathogen-derived nucleic acids by pattern recognition receptors (PRRs) is essential for the host to mount an appropriate immune response, which for viruses involves the induction of type I interferons (IFNs). By contrast, inappropriate activation of PRRs by self nucleic acids can lead to autoimmunity. Recent developments in PRR research have uncovered important new molecular details as to how Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) distinguish pathogen from self RNA, while the discovery of cytosolic DNA sensing pathways for IFN induction has revealed completely new innate signaling mechanisms, and also questions how innate immunity discriminates between self and non-self DNA, if at all.

Keywords: RIG-I; STING; Toll-like receptors; antiviral immunity; cytosolic DNA sensing.

Figure 1. Nucleic acid sensing by PRRs in distinct cellular compartments

Immune cells detect pathogen-derived nucleic acids by various PRR family members present in distinct cellular compartments. The four TLR family members TLR3, TLR7/8 and TLR9 are located in the endosome, where they detect dsRNA, ssRNA or unmethylated CpG DNA, respectively, leading to activation of TRIF- or MyD88-dependent pathways and the upregulation of type I IFNs, inflammatory cytokines and chemokines via IRF and NF-κB transcription factors. Cytosolic RNA detection is mediated by RLRs, i.e. RIG-I and MDA5, that subsequently signal via the mitochondria-localized signaling adaptor MAVS. Uncapped 5′-triphosphate (ppp) RNA is a potent RIG-I ligand, also generated by Pol III following binding to AT-rich dsDNA. However, other dsDNA-induced responses require the ER protein STING to activate the TBK1–IRF3 axis. Upstream candidate DNA receptors include DDX41 and the ALR family member IFI16. cGAS, on the other hand, was identified to synthesize the cyclic dinucleotide (CDN) cGAMP upon DNA stimulation, which then acts as a direct ligand for STING, similarly to bacterial CDNs. The cell type-specific DNA sensor DAI might transduce downstream signaling independently of STING. Furthermore, the ALRs AIM2 and IFI16 trigger the formation of an inflammasome following detection of cytosolic or nuclear DNA, respectively, by recruiting ASC and caspase-1 to induce processing of the inflammatory cytokines IL-1β and IL-18.