Figure 1.

The innate antiviral type I IFN response and interactions with the AXL receptor

Infection with SARS-CoV-2, and other RNA viruses, results in viral RNA (vRNA) in the cytoplasm or endosomes that triggers the activation of RLRs and TLRs, respectively. Downstream of vRNA-RLR interactions, RLRs interact with MAVS at mitochondrial membranes to facilitate the assembly of a signalosome where TBK1 and IKKε are recruited. TLR signaling activates TNF receptor-associated factor (TRAF)3 for downstream activation of TBK1/IKKε. These kinases then phosphorylate IRFs 3 and 7, which translocate to the nuclear to induce the expression of IFN-I. IFN-I signals through the IFNAR1 to simulate the phosphorylation of STAT1 and STAT2, resulting in the formation of ISGF3, which translocates to the nucleus to bind ISRE-containing promoters and facilitate the expression of ISGs. Gas6 is AXL’s natural ligand and activates AXL signaling that negatively regulates the IFN-I pathway. AXL is able to interact with IFNAR1, and this interaction results in the preferential formation of STAT1 homodimers. STAT1 activation then leads to the induction of SOCS 1 and 3, which inhibit TRAF3 and JAK1, resulting in reduced activation of IFN-I induction and signaling pathways. Gilteritinib is a small molecule that inhibits AXL’s tyrosine kinase activity allowing for enhanced IFN-I induction following SARS-CoV-2 infection.