Viral evasion of intracellular DNA and RNA sensing

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Key Points

Germline-encoded pattern recognition receptors (PRRs) mediate an early innate immune response against viral pathogens.
Retinoic acid-inducible gene I protein (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) are cytoplasmic sensors that detect viral RNA species and signal through the mitochondrial antiviral-signalling protein (MAVS) to induce the production of type I interferons (IFNs) and other cytokines.
Intracellular DNA sensors, such as cyclic GMP–AMP synthase (cGAS) and IFNγ-inducible protein 16 (IFI16), detect viral DNA in the cytoplasm and/or nucleus and signal through the stimulator of IFN genes (STING) to trigger an immune response.
Viruses antagonize PRRs through the sequestration or modification of their viral genomes and through the manipulation of post-translational modifications of PRRs or their adaptor proteins. Some viruses cleave or degrade PRRs or their adaptors, or sequester and relocalize PRRs to escape immunity.
A better understanding of the cellular immune-surveillance machinery and viral immune evasion strategies may guide the development of antiviral therapeutics and vaccines.

Supplementary information

The online version of this article (doi:10.1038/nrmicro.2016.45) contains supplementary material, which is available to authorized users.

Abstract

Pattern recognition receptors (PRRs) detect conserved molecular features of viral pathogens and initiate signalling that results in the expression of antiviral genes. In this Review, Chan and Gack highlight the major classes of intracellular viral RNA and DNA sensors and discuss the viral strategies that are used to escape immune surveillance by those sensors.

Supplementary information

The online version of this article (doi:10.1038/nrmicro.2016.45) contains supplementary material, which is available to authorized users.

Abstract

The co-evolution of viruses with their hosts has led to the emergence of viral pathogens that are adept at evading or actively suppressing host immunity. Pattern recognition receptors (PRRs) are key components of antiviral immunity that detect conserved molecular features of viral pathogens and initiate signalling that results in the expression of antiviral genes. In this Review, we discuss the strategies that viruses use to escape immune surveillance by key intracellular sensors of viral RNA or DNA, with a focus on RIG-I-like receptors (RLRs), cyclic GMP–AMP synthase (cGAS) and interferon-γ (IFNγ)-inducible protein 16 (IFI16). Such viral strategies include the sequestration or modification of viral nucleic acids, interference with specific post-translational modifications of PRRs or their adaptor proteins, the degradation or cleavage of PRRs or their adaptors, and the sequestration or relocalization of PRRs. An understanding of viral immune-evasion mechanisms at the molecular level may guide the development of vaccines and antivirals.

Supplementary information

The online version of this article (doi:10.1038/nrmicro.2016.45) contains supplementary material, which is available to authorized users.

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Double-stranded RNA (dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviral immunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.

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The ubiquitin ligase TRIM25 mediates Lysine 63-linked ubiquitination of the N-terminal CARD domains of the viral RNA sensor RIG-I to facilitate type I interferon (IFN) production and antiviral immunity. Here, we report that the influenza A virus nonstructural protein 1 (NS1) specifically inhibits TRIM25-mediated RIG-I CARD ubiquitination, thereby suppressing RIG-I signal transduction. A novel domain in NS1 comprising E96/E97 residues mediates its interaction with the coiled-coil domain of TRIM25, thus blocking TRIM25 multimerization and RIG-I CARD domain ubiquitination. Furthermore, a recombinant influenza A virus expressing an E96A/E97A NS1 mutant is defective in blocking TRIM25-mediated antiviral IFN response and loses virulence in mice. Our findings reveal a mechanism by which influenza virus inhibits host IFN response and also emphasize the vital role of TRIM25 in modulating antiviral defenses.

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Author and article information

Contributors

Ying Kai Chan:

Bio :

Ying Kai Chan is a research fellow in the laboratory of George Church at Harvard Medical School, Boston, Massachusetts, USA. He completed his B.A. in neuroscience at Washington University in St. Louis, Missouri, USA, his M.Sc. in biological sciences at Stanford University, California, USA and his Ph.D. in microbiology and immunobiology at Harvard Medical School. As a doctoral student in the laboratory of Michaela Gack, he uncovered a novel phosphomimetic-based mechanism that is used by dengue virus to subvert the host immune response, and engineered a mutant dengue virus that fails to antagonize the sensor retinoic acid-inducible gene I protein (RIG-I). His research interests include viral pathogenesis, antiviral immunity, vaccine development, gene therapy and synthetic biology.

Michaela U. Gack: mgack@uchicago.edu

Bio :

Michaela U. Gack is an associate professor in the Department of Microbiology at The University of Chicago, Illinois, USA. In 2008, she received her Ph.D. in virology from the collaborative graduate training programme between Harvard University, Cambridge, Massachusetts, USA, and the Friedrich-Alexander University Erlangen–Nuremberg, Germany. After a postdoctoral fellowship at the University of Southern California, Los Angeles, USA, she was appointed Assistant Professor and later Associate Professor at Harvard Medical School, Boston, Massachusetts, USA, and then joined The University of Chicago in 2015. Her laboratory studies the molecular mechanisms through which innate immune proteins control viral infections, as well as the strategies used by viral pathogens to block cell-intrinsic immune responses.

Journal

Journal ID (nlm-ta): Nat Rev Microbiol

Journal ID (iso-abbrev): Nat. Rev. Microbiol

Title: Nature Reviews. Microbiology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1740-1526

ISSN (Electronic): 1740-1534

Publication date (Electronic): 13 May 2016

Publication date (Print): 2016

Volume: 14

Issue: 6

Pages: 360-373

Affiliations

[1 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Microbiology and Immunobiology, , Harvard Medical School, ; Boston, 02115 Massachusetts USA

[2 ]GRID grid.170205.1, ISNI 0000 0004 1936 7822, Department of Microbiology, , The University of Chicago, ; Chicago, 60637 Illinois USA

Article

Publisher ID: BFnrmicro201645

DOI: 10.1038/nrmicro.2016.45

PMC ID: 5072394

PubMed ID: 27174148

SO-VID: 7a943bc8-eddd-435c-b7f6-e9793270e718

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.