SARS-CoV-1 activates/modulates innate immune responses

Stable Identifier
Homo sapiens
Related Species
Human SARS coronavirus
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Coronaviruses (CoVs) are positive-sense RNA viruses that replicate in the interior of double membrane vesicles (DMV) in the cytoplasm of infected cells (Stertz S et al. 2007; Knoops K et al. 2008). The viral replication and transcription are facilitated by virus-encoded non-structural proteins (SARS-CoV-1 nsp1–nsp16) that assemble to form a DMV-bound replication-transcription complex (RTC). The replication strategy of CoVs can generate both single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) species, that may act as pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptor (PRR) such as toll-like receptor 7 (TLR7) and TLR8, antiviral innate immune response receptor RIG-I (also known as DEAD box protein 58, DDX58) and interferon-induced helicase C domain-containing protein 1 (IFIH1, also known as MDA5) (Cervantes-Barragan L et al. 2007; Chen Y et al. 2009, 2011; Daffis S et al. 2010; Li Y et al. 2013). The activated PRRs trigger signaling pathways to produce type I and type III interferons IFNs and proinflammatory mediators that perform antiviral functions. This Reactome module describes the mechanisms underlying PRR-mediated sensing of the severe acute respiratory syndrome coronavirus type 1 (SARS-CoV-1) infection. First, endosomal recognition of viral ssRNA occurs by means of TLR7 and TLR8 which detect GU-rich ssRNA sequences. Specifically, GU-rich ssRNA oligonucleotides derived from SARS-CoV-1 stimulated mononuclear phagocytes to release considerable levels of pro‑inflammatory cytokines TNF‑a, IL‑6 and IL‑12 via TLR7 and TLR8 (Li Y et al. 2013). Second, SARS-CoV-1 dsRNA replication intermediates can be recognized by cytoplasmic receptors DDX58 and IFIH1 which bind to mitochondrial antiviral-signaling protein (MAVS, IPS-1) to induce the IFN-mediated antiviral response. In addition, the module shows an antiviral function of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) that directly binds and sequesters viral single-stranded uncapped 5′-ppp RNA and cap-0 RNA (Daffis S et al. 2010). This module also describes several strategies developed by SARS-CoV-1 to evade or alter host immunity, including escaping innate immune sensors, inhibiting IFN production and signaling, and evading antiviral function of IFN stimulated gene (ISG) products. For example, viral dsRNA replication intermediates derived from SARS‑CoV‑1 were shown to associate with RTC bound to double membrane vesicles, which protected viral RNA from sensing by DDX58 or IFIH1 (Stertz S et al. 2007; Knoops K et al. 2008). Further, SARS-CoV-1 encodes nsp14 and nsp16 which possess guanine-N7-methyltransferase activity and 2’-O-methyl-transferase activity respectively (Chen Y et al. 2009, 2011). SARS-CoV-1 nsp14 generates 5' cap-0 viral RNA (m7GpppN, guanine N7-methylated) and nsp16 further methylates cap-0 viral RNA. These viral RNA modifications mimic the 5'-cap structure of host mRNAs allowing the virus to efficiently evade recognition by cytosolic DDX58 and IFIH1 (Chen Y et al. 2009, 2011; Daffis S et al. 2010). The nsp16-mediated ribose 2′-O-methylation of viral RNA also blocks the antiviral function of IFIT1 complexes (Menachery VD et al. 2014). Further, the uridylate‐specific endoribonuclease (EndoU) activity of viral nsp15 degrades viral RNA to hide it from innate immune sensors (Bhardwaj K et al. 2006; Ricagno S et al. 2006). Moreover, SARS-CoV-1 encodes several proteins that directly bind to host targets associated with SARS‑CoV‑1 infection and cytokine production (Frieman M et al. 2009; Hu Y et al. 2017; Kopecky-Bromberg SA et al. 2007; Lindner H et al. 2005; Siu KL et al. 2009). This Reactome module describes several such binding events and their consequences. For example, as a de-ubiquitinating enzyme, viral nsp3 binds to and removes polyubiquitin chains of signaling proteins such as TRAF3, TRAF6, STING, IkBA, and IRF3 thereby modulating the formation of signaling complexes and the activation of IRF3/7 and NFkappaB (Sun L et al. 2012; Chen X et al. 2014; Li SW et al. 2016). This inhibits IFN production downstream of TLR7/8, DDX58, IFIH1, MAVS and STING signaling pathways. Binding of SARS-CoV-1 nucleocapsid (N) protein to E3 ubiquitin ligase TRIM25 inhibits TRIM25-mediated DDX58 ubiquitination and DDX58-mediated signaling pathway (Hu Y et al. 2017). Next, SARS‑CoV‑1 membrane (M) protein targets IBK1/IKBKE and TRAF3 to prevent the formation of the TRAF3:TANK:TBK1/IKBKE complex and thereby inhibits TBK1/IKBKE‑dependent activation of IRF3/IRF7 transcription factors downstream of DDX58, IFIH1 and adaptor MAVS (Siu KL et al. 2009; 2014). The ion channel activities of open reading frame 3a (orf3a or 3a) and E contribute to activation of the NLRP3 inflammasome leading to highly inflammatory pyroptotic cell death (Nieto‑Torres JL et al. 2015; Chen IY et al. 2019; Yue Y et al. 2018). Viral 3a promoted the NLRP3-mediated formation of PYCARD (ASC) speck by interaction with both TRAF3 and PYCARD (ASC) (Siu KL et al. 2019). Binding of 3a to caspase-1 (CASP1) enhanced CASP1-mediated cleavage of interleukin 1 beta (IL‑1β) downstream of the NLRP3 inflammasome pathway (Yue Y et al. 2018). Like 3a, SARS-CoV-1 8b was found to bind to NLRP3 activating the NLRP3 inflammasome and triggering IL‑1β release (Shi CS et al. 2019). 8b was also shown to bind IRF3, inhibiting subsequent IRF3 dimerization (Wong et al. 2018). At the plasma membrane, binding of SARS-CoV-1 7a to host BST2 disrupts the antiviral tethering function of BST2 which restricts the release of diverse mammalian enveloped viruses (Taylor JK et al. 2015). SARS-CoV-1 9b (orf9b) inhibits the MAVS-mediated production of type I IFNs by targeting TOMM70 on the mitochondria (Jiang HW et al. 2020). SARS-CoV-1 6 (orf6) inhibits the IFN signaling pathway by tethering karyopherins KPNA2 and KPNB1 to the endoplasmic reticulum (ER)/Golgi intermediate compartment (ERGIC) and thus blocking the KPNA1:KPNB1-dependent nuclear import of STAT1 (Frieman M et al. 2007). Binding of SARS-CoV-1 nsp1 to peptidyl-prolyl isomerases (PPIases) and calcipressin-3 (RCAN3) significantly activates the cyclophilin A/NFAT pathway, ultimately enhancing the induction of the IL-2 promoter (Pfefferle et al, 2011; Law et al, 2007). At last, SARS‑CoV‑1 3b, after translocating to the nucleus, binds to transcription factor RUNX1 and increases its promoting activity (Varshney et al, 2012).
Literature References
PubMed ID Title Journal Year
28466096 Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

Perlman, S, Channappanavar, R

Semin Immunopathol 2017
22572391 SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon

Totura, AL, Baric, RS

Curr Opin Virol 2012
27712625 Interaction of SARS and MERS Coronaviruses with the Antiviral Interferon Response

Thiel, V, Weber, F, Kindler, E

Adv Virus Res 2016
31226023 Human Coronavirus: Host-Pathogen Interaction

Fung, TS, Liu, DX

Annu. Rev. Microbiol. 2019
Name Identifier Synonyms
severe acute respiratory syndrome DOID:2945 SARS-CoV infection, SARS
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