The interplay between viruses and innate immune signaling: recent insights and therapeutic opportunities.
The immediate response to viral infection relies on pattern-recognition receptors (PRRs), most prominently the Toll-like receptors (TLRs) and the RNA helicases RIG-I and MDA5, as well as double stranded RNA-dependent protein kinase (PKR) and the DNA receptor, DAI. These PRRs recognize pathogen-associated molecular patterns (PAMPs) such as viral proteins and nucleic acids. The engagement of these receptors then initiates intracellular signaling cascades which ultimately cause the activation of transcription factors and the expression of type I interferons and pro-inflammatory cytokines. This innate response establishes an anti-viral state in the infected cell and its neighbours and alerts immune cells to the danger. In order to establish a productive infection, viruses need to overcome this initial anti-viral response. Evasion of innate immune defences is achieved by means of viral proteins that inhibit the signaling cascades emanating from the PRRs. The same innate signal transduction pathways have been implicated in conditions of sterile inflammation, such as rheumatoid arthritis and multiple sclerosis, and in autoimmunity. Because viral proteins target crucial host proteins involved in these pathways, they can point the way to key drug targets. Further, the viral proteins themselves or derivatives of them may be of use therapeutically to curtail inflammation and autoimmunity.
Unterholzner
Leonie
L
School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
Bowie
Andrew G
AG
D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors; D050839:Interferon Regulatory Factor-7 / Q000037:antagonists & inhibitors; D000072640:Interferon-Induced Helicase, IFIH1; D016328:NF-kappa B / Q000502:physiology; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology; D014777:Virus Diseases / Q000188:drug therapy / Q000276:immunology*; D019892:eIF-2 Kinase / Q000502:physiology
C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016328:NF-kappa B; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D019892:eIF-2 Kinase; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1