3-2- IFNs
The effective innate immune response against viral infection heavily relies on the IFN type I response and its downstream cascade that culminates in controlling viral replication and induction of the effective adaptive immune response (P. Zhou et al., 2020). To counter innate antiviral cytokine responses, SARS-CoV and MERS-CoV encode several structural and non-structural proteins (NSPs) that antagonize antiviral immune responses. SARS-CoV encodes nsp1, nsp3-macrodomain, nsp3 deubiquitinase (DUB), and ORF3b, ORF6, and ORF9b subvert antiviral response by antagonizing IFN and ISG (Interferon-stimulated gene) responses (M. Frieman et al., 2007; Totura & Baric, 2012). Additionally, structural proteins such as the membrane (M) and nucleocapsid (N) proteins dampen IFN signaling through inhibiting TBK1/IKKe and unknown mechanisms, respectively (M. Frieman, Ratia, Johnston, Mesecar, & Baric, 2009; Kopecky-Bromberg, Martínez-Sobrido, Frieman, Baric, & Palese, 2007; Lu, Pan, Tao, & Guo, 2011; Siu, Chan, Kok, Chiu-Yat Woo, & Jin, 2014). Similarly, MERS-CoV structural proteins M and N and accessory proteins ORF3, ORF4a, and ORF4b antagonize IFN responses (Kindler, Thiel, & Weber, 2016; Lui et al., 2016; Y. Yang et al., 2013). Structural and non-structural protein antagonism of IFN responses further amplifies inflammatory responses by promoting unrestrained virus replication, resulting in an increased viral pathogen-associated molecular pattern (PAMPs) that further dampens IFN signaling and stimulates pattern recognition receptors (PRRs) to induce an aberrant inflammatory response. The lack of IFN signaling also leads to an excessive accumulation of Ly6C low monocytes and neutrophils (Channappanavar & Perlman, 2017).
Previous evidence demonstrated that SARS-CoV-2 is sensitive to the IFN-I/III pretreatment in vitro, perhaps to a greater degree than SARS-CoV-1 (Blanco-Melo et al., 2020; Lokugamage et al., 2020; Mantlo, Bukreyeva, Maruyama, Paessler, & Huang, 2020; Stanifer et al., 2020). Moreover, IFN induced transmembrane family (IFITM) proteins inhibit SARS-CoV-2 entry, as demonstrated for SARS-CoV (Huang et al., 2011), although their action in promoting infection has also been described for other CoVs (X. Zhao et al., 2018).
According to several studies on antiviral treatments against SARS-CoV replication, administration of IFN type I inhibits SARS-CoV growth in cell culture as well as viral replication in cynomolgus macaques and mouse models (Barnard et al., 2006; Dahl, Linde, & Strannegård, 2004; Haagmans et al., 2004; Kumaki et al., 2011; Sainz, Mossel, Peters, & Garry, 2004; Smits et al., 2010; Ströher et al., 2004). Despite the potential importance of IFNs in controlling SARS-CoV replication, infection of mice deficient in IFN type I, II, or III receptors was associated with a minimal phenotypic difference in weight loss, viral titer, lung pathology, and mortality from wild-type mice in the MA15-SARS-CoV model (M. B. Frieman et al., 2010). In response to viral infections, mononuclear phagocytes (MNPs) induce IFN-I and IFN-III production, resulting in inflammasome activation, induction of pathogenic Th1 and Th17 cell responses, recruitment of effector immune cells, and cytokine release syndrome (CRS) pathology (Prokunina-Olsson et al., 2020; Tanaka, Narazaki, & Kishimoto, 2016). A study conducted by Chu et al. demonstrated that monocyte-derived dendritic cells (Mo-DCs) infected with MERS-CoV exhibit no expression of IFN-β, despite the marginally early expression of IFN-α (H. Chu et al., 2014). However, another recent in vitro study failed to stimulate the pro-inflammatory innate response and produce IFNs type I in the cultured infected cells, primary human airway epithelial cells, and Mo-DCs infected with MERS-CoV (Chan et al., 2013; Zielecki et al., 2013). The mechanisms behind this response may be initially related to interference with the NF-κB signaling pathway, which is usually responsible for the induction of the pro-inflammatory response (Canton et al., 2018). The effect of applying IFN-α in MERS-CoV-infected cells was 50- to 100-fold greater than that in SARS-CoV-infected cells (de Wilde et al., 2013).
Upregulation of IFNs type I and ISGs is not observed until two days after infection. According to the published reports, IFN deficiency does not exacerbate SARS-CoV disease in animals, while treatment with IFNs type I could help controlling the SARS-CoV replication (Totura & Baric, 2012).