Fig 1.
SARS-CoV-2 genomic organization and encoded proteins.
ORF1a/1b encode a polyprotein, which is proteolytically processed into Nsp1–16, represented in blue. Structural proteins, including S, E, M, and N proteins are in green. Accessory proteins encoded at the 3′ end of the viral genome comprise ORF3a, 3b, 6, 7a, 7b, 8, 9b, 9c, and 10 and are colored in orange. Untranslated extremities of the genome (5′-UTR and 3′-UTR) are also represented. In red are depicted SARS-CoV-2 proteins that interfere with IFN induction pathway as well as their known or hypothetic target [5, 37, 147]. E, envelope; IFN, interferon; M, membrane; MAVS, mitochondrial antiviral-signaling protein; N, nucleocapsid; Nrdp1, neuregulin receptor degradation protein-1; Nsp, nonstructural protein; ORF, open reading frame; RNF41, ring finger protein 41; S, spike; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; TANK, TRAF family member-associated NF-κB activator; TBK1, TANK-binding kinase 1; Tom70, translocase of outer mitochondrial membrane 70; UTR, untranslated region.
Fig 2.
SARS-CoV interfering with IFN induction and signaling.
On this cartoon are schematically represented the signaling pathways triggered by SARS-CoV RNA recognition by the cytoplasmic RNA sensors RIG-I and MDA5, which leads to IFN induction (A) and subsequent IFN signaling in surrounding cells, resulting in the expression of ISGs (B). SARS-CoV proteins that have been reported to interfere with these pathways are indicated. IFN, interferon; IFNAR, interferon alpha and beta receptor; IκB, inhibitor of nuclear factor κB; IKKε, IκB kinase-ε; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; JAK, Janus kinase; M, membrane; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated gene 5; N, nucleocapsid; Nsp, nonstructural protein; ORF, open reading frame; P, phosphate; PLP, papain-like protease; RIG-I, retinoic acid-inducible gene 1; SARS-CoV, severe acute respiratory syndrome coronavirus; STAT, signal transducer and activator of transcription; TANK, TRAF family member associated NF-κB activator; TBK1, TANK-binding kinase 1; TRAF3, tumor necrosis factor receptor-associated factor 3; TYK2, tyrosine kinase 2.
Table 1.
SARS-CoV proteins interfering with IFN-I induction and signaling.
Fig 3.
Working model of the failure of IFN-I to control of SARS-CoV-2 infection, leading to COVID-19.
While IFN-I can control viral infection (upper panel), IFN-I deficiency is believed to play a key role in SARS-CoV-2 pathogenesis (lower panel). As shown for related coronaviruses, a delayed IFN-I signaling is associated with robust virus replication and severe complications, i.e., inflammation and “cytokine storm,” notably via the accumulation of monocytes resulting in lung immunopathology, vascular leakage, and suboptimal T cell response. ACE2, angiotensin I converting enzyme 2; IFNAR, interferon alpha and beta receptor; IFN-I, type I interferon; ISG, IFN-stimulated gene; pDC, plasmacytoid dendritic cell; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.
Table 2.
ISGs and IFN signature of SARS-CoV-2–infected samples.