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).