Fig. 4.

Virus‐induced type I IFN and TLR3 responses and their dysregulation in severe COVID‐19 pneumonia. Nonhematopoietic cells sense viral invasion through a panel of PPRs (such as TLR3, RIG‐I, MDA‐5) and produce type I IFNs by activating IRF3/7. Moreover, plasmacytoid dendritic cells (pDCs) have an extraordinary ability to detect virus and to secrete type I IFNs, particularly IFN‐α. These type I IFNs act via autocrine or paracrine modes to induce antiviral immunity in pDCs and surrounding cells through IFNARs (IFNAR1 and INFAR2 heterodimer). Recently, IEI in the genes encoding TLR3, Unc93B1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2 (marked with *) have been shown to impair induction of type I/III IFN responses to viral infection, and this scenario has been linked to severe COVID‐19 disease [9]. Moreover, the presence of neutralizing autoantibodies against IFN‐α and IFN‐ω, which can block the function of these crucial antiviral cytokines, can also cause severe COVID‐19‐related pneumonia [8].