Key Points
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Immune sensing of foreign nucleic acids among abundant self nucleic acids is a hallmark of virus detection and antiviral defence.
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Efficient antiviral defence requires a balanced process of sensing foreign nucleic acids and ignoring self nucleic acids. This balance is accomplished by a multilevel, fail-safe system which combines immune sensing of pathogen-specific nucleic acid structures with specific labelling of self nucleic acids and nuclease-mediated degradation.
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Cellular localization of nucleic acids, nucleic acid secondary structure, nucleic acid sequence and chemical modification all contribute to selective recognition of foreign nucleic acids.
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Nucleic acid sensing occurs in immune cells and non-immune cells and results in antiviral responses that include the induction of antiviral effector proteins, the secretion of cytokines alarming neighbouring cells, the secretion of chemokines, which attract immune cells, and the induction of cell death.
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Vertebrate cells cannot completely avoid the occurrence of endogenous self nucleic acid structures with immunostimulatory properties. Therefore, additional mechanisms involving self-nucleic acid modification and nuclease-mediated degradation are necessary to diminish uncontrolled immune activation.
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Viruses have established sophisticated mechanisms to exploit and adopt endogenous tolerance mechanisms or to avoid the presentation of characteristic molecular features recognized by nucleic acid sensing receptors.
Abstract
Innate immunity against pathogens relies on an array of immune receptors to detect molecular patterns that are characteristic of the pathogens, including receptors that are specialized in the detection of foreign nucleic acids. In vertebrates, nucleic acid sensing is the dominant antiviral defence pathway. Stimulation of nucleic acid receptors results in antiviral immune responses with the production of type I interferon (IFN), as well as the expression of IFN-stimulated genes, which encode molecules such as cell-autonomous antiviral effector proteins. This Review summarizes the tremendous progress that has been made in understanding how this sophisticated immune sensory system discriminates self from non-self nucleic acids in order to reliably detect pathogenic viruses.
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The authors would like to thank E. Bartok for critically reading the manuscript.
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M.S. and G.H. are supported by the Deutsche Forschungsgemeinschaft (www.dfg.de); SFB670 to M.S. and G.H.; DFG SCHL1930/1–1 to M.S.; SFB704 to G.H.; SFB832 and KFO177 to G.H. G.H. and M.S. are supported by the DFG Excellence Cluster ImmunoSensation. G.H. is supported by the German Center of Infectious Disease (DZIF). G.H. is a co-founder and shareholder of Rigontec GmbH; M.S. and G.H. are inventors on a patent covering structures described in a manuscript that is cited in this Review.
Glossary
- RNA interference
-
(RNAi). The use of double-stranded RNA molecules containing sequences that match a given gene to 'knockdown' the expression of that gene by inhibiting translation of the targeted mRNA or by directing RNA-degrading enzymes to destroy the encoded mRNA transcript.
- Cyclic GMP–AMP synthetase
-
(cGAS). A cellular protein that binds to cytosolic DNA species and generates stimulator of interferon genes (STING)-activating cyclic dinucleotides.
- Inflammasome
-
A molecular complex that upon assembly activates inflammatory caspases, which in turn promote the maturation of pro-inflammatory cytokines and induce pyroptosis.
- Cap-dependent translation
-
A mechanism for initiation of translation. It involves the binding of the eIF4F complex — which is composed of the mRNA helicase eIF4A (eukaryotic translation initiation factor 4A), eIF4E and the scaffolding protein eIF4G — to mRNA transcripts that have a 5′ 7-methylguanosine cap, resulting in recruitment of the 43S ribosome. The ribosome then scans the mRNA until it reaches the first AUG codon, and it initiates translation following the GTP-dependent release of eIF2B.
- Ribonuclease L
-
(RNaseL). A constitutively expressed, latent, nonspecific endoribonuclease that is activated by 2′-5′-oligoadenylate. Type I interferons induce RNaseL expression as part of the host antiviral response.
- A-form dsRNA
-
Double-stranded RNA (dsRNA) molecules usually assemble into A-form helices within the cell. A-form helices are right-handed with 11 base pairs per helical turn, and the bases are not completely perpendicular to the helical axis. In A-form dsRNA, the major groove is deep and narrow.
- Z-form dsRNA
-
Certain conditions (high ionic strength and/or CG-rich sequences) force the transition of A-form dsRNA helices into Z-form helices. Z-form helices are left-handed with 12.4 base pairs per helical turn. In Z-form dsRNA, the minor groove is deep and narrow.
- Panhandle structures
-
Double-stranded stem structures with bulges that are formed by the partially complementary 5′- and 3′-ends of some (-)ssRNA viruses (for example, influenza virus) and are used as a replication control platform.
- Defective interfering RNA genomes
-
Virus genome mutants that are spontaneously generated owing to erroneous replication, most probably because of suboptimal replication conditions. They have lost a crucial portion of the genome. 'Snap back' defective interfering genomes occur when the replicase transcribes one strand and (without clearing the replication complex) immediately uses this new strand as a template.
- m7G cap
-
(7-methylguanosine cap). A type of cap that is linked by a triphosphate bridge to the first transcribed nucleotide at the 5′ end of eukaryotic mRNA. Recognition of the m7G cap by the cap-binding protein eIF4E is the initiation step of cap-dependent translation.
- Cap 1
-
In addition to 7-methylguanosine, the mRNA of higher eukaryotes has a 2′-O-methylation at the penultimate nucleotide (N1). This structure is called cap 1.
- Cap-snatching mechanism
-
The process by which some viruses (for example, influenza virus) cleave a 10–14 nt fragment from the capped 5′ end of cellular mRNAs and use it as a primer (leader) for their own mRNA transcription of a cap 1 structure.
- Endogenous retroviruses
-
(ERVs). 8% of the human genomic DNA contains sequences of retroviral origin that were acquired from ancestral retroviral infections and inherited into the germline.
- Unfolded protein response
-
(UPR). A response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins and causes the arrest of the cell cycle and apoptosis.
- SKIV2L RNA exosome
-
A multiprotein cellular complex in eukaryotes that degrades various types of RNA. In this way, the cytosolic 3′-to-5′ RNA exosome complex, defined by the SKIV2L RNA helicase subunit, is a crucial negative regulator that prevents the stimulation of RIG-I-like receptors by endogenous RNA.
- DNA-PK complex
-
The nuclear DNA-dependent serine/threonine protein kinase (DNA-PK) complex is composed of the proteins DNA-PKcs, Ku70 and Ku80. It is involved in DNA non-homologous end-joining during DNA double-strand break repair.
- Interferon stimulatory DNA pathway
-
(ISD pathway). A cytosolic dsDNA recognition pathway that involves the second messenger receptor STING, but not RIG-I, and leads to type I IFN production. The ISD pathway is triggered by any random dsDNA sequence of a certain minimum length (40–60 bp).
- Y-form DNA
-
DNA that contains a region of base-paired DNA at one end and a region of unpaired DNA strands at the opposite end.
- Elite controllers of HIV1 infection
-
HIV1-infected individuals with an immune system that can limit HIV1 infection without antiviral treatment.
- Autophagy
-
An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation through fusion to secondary lysosomes.
- Aicardi–Goutières syndrome
-
(AGS). A neurodegenerative disorder that can be caused by stimulator of IFN genes (STING)-dependent cytokine hyperproduction owing to mutations in genes such as TREX1.
- Necroptosis
-
A type of necrosis and a form of non-apoptotic cell death driven by receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 under conditions in which caspase 8 is inhibited.
- Pyroptosis
-
An inflammatory and lytic form of programmed cell death mediated by inflammatory caspases.
- MicroRNAs
-
Small, RNA molecules that regulate the expression of genes by binding to the 3′-untranslated regions (3′-UTR) of specific mRNAs.
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Schlee, M., Hartmann, G. Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol 16, 566–580 (2016). https://doi.org/10.1038/nri.2016.78
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DOI: https://doi.org/10.1038/nri.2016.78
