Fig. 1

Pattern recognition receptor signaling and potential innate immune-mediated pathogenesis during SARS-CoV-2 infection. A Toll-like receptor (TLR) signaling: Different TLRs recognize diverse SARS-CoV-2 components. TLR2 and TLR4 recognize E protein and S protein, respectively; TLR3, TLR7, and TLR8 sense viral RNA. TLR7 and TLR8 also recognize antiphospholipid antibodies (aPL). Sensing of SARS-CoV-2 components leads to activation of innate immune signaling and production of pro-inflammatory cytokines, which can eliminate virus but also drive COVID-19 severity. B Retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) and stimulator of IFN genes (STING) signaling: Melanoma differentiation-associated protein 5 (MDA5) senses viral RNA. STING can be activated by STING agonists or mitochondrial DNA (mtDNA) released by damaged cells. Signaling through MDA5 and STING engages interferon (IFN) regulatory factor 3 (IRF3) activation for the production of IFNs. Early on, IFNs are important to clear viruses. Delayed production of IFNs is pathogenic. C Inflammasome signaling: The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is assembled following sensing of spike (S) and nucleocapsid (N) proteins, viral RNA, and open reading frame 3a (ORF3a). This assembly leads to the production of interleukin (IL)-1β, which has been reported to drive COVID-19 pathology. D Caspase-4 (CASP4)/caspase-11 (CASP11) signaling: CASP4 and the murine homolog CASP11 sense oxidized phospholipids released from damaged cells and produce pro-inflammatory cytokines, which can drive COVID-19 pathology. E C-type lectin receptor (CLR) signaling: S protein from SARS-CoV-2 is sensed by CLRs such as dendritic cell specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), liver/lymph node-specific intercellular adhesion molecule-3-grabbing non-integrin (L-SIGN), and liver sinusoidal endothelial cell lectin (LSECtin) to induce innate immune signaling and the production of pro-inflammatory cytokines, which can be pathogenic in COVID-19