Natural immunity is the first line of physiological defense that to protect the body against the invasion of pathogenic microorganisms. For virus invasion, our body has evolved a complete set of defense systems, in which signal pathways that RIG-I-MAVS and cGAS-STING mediated play an important role in the natural immune response of the body against RNA and DNA viruses respectively.

In the RIG-I-MAVS pathway, RIG-I like receptors (such as RIG-I, MDA5 and DHX58) are a series of cytoplasmic RNA helicases that detect viral RNA. RIG-I and MDA5 show different ligand specificity and react to different viruses, while DHX58 promotes or antagonizes the recognition of viral RNA by MDA5 and RIG-I. When RIG-I or MDA5 recognized viral RNA, it quickly combined with MAVS to form a dimer, and MAVS then recruited TRAF2, TRAF3, TRAF5, TRAF6, CARD9 and TRADD to form a mitochondrial outer membrane assembly signal complex platform. The platform continues to recruit more functional proteins, such as CIAP1/2, TANK-NAP1-Tbkbp1, TAB2/3-TAB1-TAK1, TBK1-IKKε, IKKα-IKKβ-IKKγ.

RIP1-FADD-Casp8-Casp10, final IRF3, IRF7, NF- κ B and AP-1 are activated by phosphorylation to induce the expression of interferon and pro-inflammatory cytokines. Therefore, it is a common and practical clinical method to determine whether antiviral immunity occurs by measuring the level of interferon or pro-inflammatory cytokines. In addition to RIG-I and MDA5, there are some common RNA receptors such as OAS1 and RnaseL.

CGAS is a cytoplasmic DNA receptor that can recognize viral DNA. When cGAS is activated by viral DNA, its conformation changes and forms cGAMP. cGAMP binds and activates endoplasmic reticulum junction protein STING. The activated STING starts to recruit TBK1 and migrate to Golgi apparatus, leading to IRF3 and NF- κ Phosphorylation and nuclear translocation of B and STAT6 lead to increased expression of interferon and other inflammatory genes. This period also involves the modification of many proteins, such as the kinase ULK1/ATG1 and phosphatase PPM1A involved in phosphorylation regulation, and the E3 ligases RNF5, TRIM21 and TRIM30 involved in ubiquitination regulation α, TRIM32, TRIM56, AMFR and INSIG1, palmitoyl transferases DHHC3, DHHC7 and DHHC15 involved in palmitoylation regulation.

Antiviral innate immunity is an extremely complex process. The RIG-I-MAVS signal pathway will also cross talk with multiple signal pathways such as cGAS-STING, inflammatory bodies, and autophagy. Similarly, cGAS-STING signal pathway will also cross talk with inflammatory bodies, TLR, JAK-STAT and autophagy, which further increases the complexity of anti-viral natural immune regulation and function.