Chapter 18 : Innate Immune Responses

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When viruses enter the host, they are first detected by the innate immune system, which comprises cytokines, sentinel cells (dendritic cells [DCs] and macrophages), complement, and natural killer (NK) cells. A second family of pattern recognition receptors comprises the cytoplasmic sensors of viral nucleic acids, MDA-5 (melanoma differentiation associated gene-5), RIG-I (retinoic acid-inducible gene I), and LGP2. Interferon (IFN) production after infection of cultured cells with paramyxoviruses, VSV, influenza virus, and the flavivirus Japanese encephalitis virus is impaired in fibroblasts from mice. RIG- I- like receptors (RLRs) play central roles in viral recognition and induction of antiviral innate responses in cDCs, macrophages, and fibroblasts. Infection of mice revealed that this protein is critical for detection of infection with picornaviruses, but not flaviviruses, influenza viruses, or paramyxoviruses. Mice lacking the nitric oxide synthase gene have reduced macrophage activation and β-cell apoptosis and consequently reduced virus-induced diabetes. Understanding viral countermeasures not only improves one's understanding of innate sensing pathways but may also suggest avenues for therapeutic intervention. Infection of cells with several picornaviruses leads to cleavage or degradation of MDA-5 and RIG-I. We survive only because we possess powerful intrinsic, innate, and adaptive immune defense systems. The study of how picornaviruses interact with the innate immune system is in its infancy. Understanding innate signaling pathways and how viruses counteract them should be a productive area of research for many years.

Citation: Racaniello V. 2010. Innate Immune Responses, p 287-302. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch18
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Image of Figure 1.
Figure 1.

Recognition of viral RNA by TLRs and RLRs in mammalian cells. TLR3 and TLR7/8 recognize dsRNA and ssRNA in the endosome, while RIG-I and MDA-5 recognize viral RNAs in the cytoplasm. The ligands for RIG-I are believed to be short dsRNAs or ssRNAs with a 5′-triphosphate. Different adaptor proteins transduce the signal from activated TLRs or RLRs through a pathway leading to activation of transcription proteins needed for synthesis of type I IFN and inflammatory cytokines. TRIF- and IPS-1-dependent pathways lead to activation of IRF3 and NF-κB, while MyD88-dependent pathways lead to activation of IRF7 and NF-κB.

Citation: Racaniello V. 2010. Innate Immune Responses, p 287-302. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch18
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Image of Figure 2.
Figure 2.

Structure and activation of RLRs by RNA. RIG-I and MDA-5 reside in the cytoplasm in an inactive form in the absence of RNA. In this state, the sensor molecules are folded in a way that the CTD blocks the CARD (top). Viral RNAs (either dsRNA or ssRNA with 5′-phosphates) bind the CTD, leading to an ATP-dependent structural change that exposes the CARD. The CARD is available to interact with IPS-1, ultimately leading to transcription of IFN genes.

Citation: Racaniello V. 2010. Innate Immune Responses, p 287-302. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch18
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