*2.1. Cell Autonomous Immunity: The Antiviral Response*

The cell autonomous immune response provides the first line of defense against cellular pathogens, including viruses [1]. To deal with a wide variety of pathogens, activation of cell autonomous immunity occurs in an antigen-independent fashion. Instead, it relies on the ability of the cell to recognize molecular patterns which are abundant in pathogens (pathogen-associated-molecular patterns, PAMPs), yet relatively absent in healthy cells. These molecular patterns are recognized by pattern recognition receptors (PRRs), which survey distinct cellular compartments for the presence of PAMPs. In addition, aberrant intracellular localization of nucleic acids (e.g., intra-endosomal localization of RNA or DNA, or cytoplasmic localization of DNA) also serves to discern between nucleic acids of cellular vs. pathogen origin, and when detected, stimulates cell autonomous immune responses (reviewed in [2–4]). A prototypic PAMP is double stranded RNA (dsRNA), an obligatory molecular pattern of viral infection, which may be recognized by toll-like receptor 3 (TLR3) upon exposure to the endosomal lumen, or by RNA helicases—the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene 5 (MDA5) upon exposure in the cytoplasm [1,5]. DNA too can serve as a PAMP, depending on its composition or intracellular localization. In these contexts, TLR9 recognizes DNA molecules rich in unmethylated CpG sequences, as commonly occurs in genomes of viruses and bacteria [6]; while cytoplasm-localized DNA is recognized by cyclic GMP-AMP Synthase (cGAS) [7]. In a typical case, exemplified here by the cellular response to RNA virus infections, PAMP-induced PRR signals are transduced through mitochondrial antiviral-signaling protein (MAVS), Tank-binding kinase 1 (TBK1) and IKKs; resulting in the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and interferon (IFN)-regulatory factors (IRFs) 3 and 7. These in turn translocate to the nucleus and mediate the transcriptional activation of type I or type III IFNs (e.g., IFN-β). Following synthesis and secretion, IFNs activate Janus kinase (JAK)- signal transducer and activator of transcription (STAT) signaling, resulting in STAT-mediated massive amplification of the cell autonomous immune response via the induction of IFN-stimulated-genes (ISGs) [1,5,8].
