Innate Immune Responses

Abstract

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 rig-I -1- 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 mda-5 -1- 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.