Pattern recognition receptors (PRRs) are germline-encoded sensors that detect conserved molecular features of pathogens. For viruses, the most important features are the nucleic acids themselves, but the problem is that viral RNA and DNA are chemically similar to host nucleic acids. Discrimination relies on three principles: location, structure, and modification. Host RNA is normally confined to the nucleus and cytoplasm in specific forms, while viral RNA often appears in the cytosol as long double-stranded RNA (dsRNA) or as RNA with a 5' triphosphate end, neither of which is typical of mature host mRNA. Cytosolic sensors such as RIG-I and MDA5 recognize these features. RIG-I binds short dsRNA with a 5' triphosphate, while MDA5 binds long dsRNA. Endosomal sensors such as TLR3, TLR7, and TLR8 detect dsRNA and single-stranded RNA within the endosomal compartment, where host RNA should not normally be present. Cytosolic DNA sensors such as cGAS detect double-stranded DNA in the cytosol, which is abnormal for a healthy cell.
Once a sensor binds its ligand, it undergoes a conformational change that exposes signaling domains. RIG-I and MDA5 signal through the mitochondrial antiviral signaling protein (MAVS) on mitochondria; cGAS produces the second messenger cGAMP, which activates STING on the endoplasmic reticulum; endosomal TLRs signal through TRIF or MyD88. These adaptors converge on kinases TBK1 and IKK, which activate the transcription factors IRF3 and IRF7, and NF-kB. IRF3 and IRF7 drive transcription of type I interferon genes, primarily interferon-beta and multiple interferon-alpha subtypes. The newly made interferon is secreted and acts on the same cell and neighboring cells.
The overall logic is a positive feedback loop: a small amount of interferon produced by the first infected cell induces IRF7 in neighboring cells, so that subsequent sensing produces a much larger interferon response. This amplification is why the interferon system can contain a spreading infection within hours.