A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation

• Published in: Trends in microbiology (Regular ed.) Vol. 27; no. 1; pp. 75 - 85
• Main Authors: Dias Junior, Antonio Gregorio, Sampaio, Natalia G., Rehwinkel, Jan
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2019; Elsevier Science Ltd; The Authors. Published by Elsevier Ltd
• Subjects: Animals; antiviral defence; Antiviral drugs; autoinflammation; Cancer; genes; Hereditary Autoinflammatory Diseases - genetics; Humans; IFIH1; Immunity; Immunity, Innate; Inflammation; Interferon; Interferon-Induced Helicase, IFIH1 - genetics; Interferon-Induced Helicase, IFIH1 - metabolism; interferons; MDA5; Mutation; neoplasm cells; Nucleic acids; Picornaviridae; Protein structure; Proteins; Receptors, Immunologic - metabolism; Ribonucleic acid; RNA; RNA, Viral - metabolism; Secondary structure; type I interferon; Viral infections; Virus Diseases - immunology; Viruses; IFIH1; type I interferon; autoinflammation; RNA; antiviral defence; MDA5
• ISSN: 0966-842X; 1878-4380; 1878-4380
• DOI: 10.1016/j.tim.2018.08.007

Induction of interferons during viral infection is mediated by cellular proteins that recognise viral nucleic acids. MDA5 is one such sensor of virus presence and is activated by RNA. MDA5 is required for immunity against several classes of viruses, including picornaviruses. Recent work showed that mutations in the IFIH1 gene, encoding MDA5, lead to interferon-driven autoinflammatory diseases. Together with observations made in cancer cells, this suggests that MDA5 detects cellular RNAs in addition to viral RNAs. It is therefore important to understand the properties of the RNAs which activate MDA5. New data indicate that RNA length and secondary structure are features sensed by MDA5. We review these developments and discuss how MDA5 strikes a balance between antiviral immunity and autoinflammation. MDA5 is a pattern-recognition receptor for RNA and induces a type I interferon response. MDA5 is activated in a variety of clinically relevant settings. This includes infection with ssRNA, dsRNA, and dsDNA viruses; several autoimmune and autoinflammatory diseases, such as type 1 diabetes and Aicardi–Goutières syndrome; and some forms of cancer treatment. Synthetic, viral, and cellular RNAs can all activate MDA5. The latter may include transcripts from endogenous retroelements such as Alu repeats. Length and secondary structure are important features that determine whether an RNA molecule is detected by MDA5. Indeed, long, base-paired RNA molecules potently activate MDA5 in the test tube.