Fig. 2

Stepwise model of PRR-mediated activation of innate immune response in lung tissues during SARS-CoV-2 infection. In the first step, RIG-I senses (+)gRNA of SARS-CoV-2 that is released from a viral particle and directly inhibits viral replication without activation of the conventional RIG-I downstream signaling A. In the condition of reduced RIG-I expression or in the epithelial cells with low/no levels of RIG-I expression, viral (−)RNAs initiate to be transcribed from (+)gRNA by viral RdRp. Then, MDA5 in turn plays a role as an innate sensor to induce the expression of types I/III IFNs and proinflammatory cytokines. This signaling might result in cell damage, leading to activation of cGAS pathway via possibly the sensing of host nuclear or mitochondrial DNA B. In immune cells such as macrophages/monocytes, TLRs, CLRs, NLRP3, and AIM2 function as major innate sensors to recognize viral proteins, nucleic acids, and host DAMPs, resulting in innate cytokine responses C. These innate inflammatory responses induce the death of neighboring endothelial cells, leading to the activation of cGAS pathway via its mitochondrial DNA in the cells. The dead endothelial cells are engulfed by perivascular macrophages, and then the host damaged DNA activates cGAS pathway, which induces type I IFNs and proinflammatory cytokines D. This cGAS machinery may initiate a self-perpetuating loop of the sterile inflammation, causing the detrimental inflammation in late phase of infection