Fig. 1: Inborn errors of type I IFN immunity and auto-antibodies neutralizing type I IFNs underlie life-threatening COVID-19 pneumonia by interfering with type I IFN immunity in tissue-resident RECs and blood plasmacytoid dendritic cells.
From: Human genetic and immunological determinants of critical COVID-19 pneumonia
There are 17 human type I IFNs (red), each encoded by a specific, intronless gene: 13 subtypes of IFNα, IFNβ, IFNε, IFNκ and IFNω, and three human type III IFNs (IFNλ1–3). Auto-antibodies to IFNα, IFNβ and/or IFNω have been identified in about 15% of patients with critical COVID-19 pneumonia. Monogenic inborn errors of TLR3- and/or TLR7-dependent type I IFN immunity have been identified in about 1–5% of patients with critical COVID-19 pneumonia (genes shown in red). SARS-CoV-2 infection can induce type I IFN production in a TLR3-dependent manner in tissue-resident RECs (which express TLR3 but not TLR7) and in a TLR7-dependent manner in circulating plasmacytoid dendritic cells (pDCs, which express TLR7 but not TLR3)200. IRF7 is constitutively expressed in pDCs, at higher levels than in other cell types, whereas it is mostly induced by viral infection in RECs200. IRF7 activation is required to produce type I IFNs other than IFNβ33.
