Impaired Interferon Response
Based on previous molecular and clinical studies on SARS-CoV and the recent data on SARS-CoV-2, it is becoming evident that the delay in primary IFN response may be due to multiple factors such as (1) poor overall immune function of a patient with a compromised adaptive response as in older people, (2) patients with comorbidity, (3) genetic factors or epigenetic changes associated with crucial genes and transcriptional factors involved in IFN signaling, and (4) age and sex of the patient, probably making the older individuals and males more susceptible to COVID-19 (Bastard et al., 2020; Li M.Y. et al., 2020; Nguyen et al., 2020; Verdecchia et al., 2020; Zhou F. et al., 2020). Thus, overall these factors may compromise the host cell immune system and delay the early antiviral response. Especially in the case of RNA viruses, evasion of host immune response is managed by interfering with PRRs, PLRs, TLRs, and IFN signaling (Kikkert, 2020). Additionally, inhibition is also conferred by hijacking host cell biosynthetic machinery and eventually inducing host cell apoptosis as discussed above.
Previous studies have unequivocally demonstrated poor IFN response to SARS-CoV during severe infection, which is also apparently the case with SARS-CoV-2, reviewed recently by Park and Iwasaki (2020). In vitro culture of the primary lung, epithelial cells infected with the SARS-CoV-2 generated inadequate IFN response (Blanco-Melo et al., 2020). By looking at the clinical samples, a large body of data suggests impaired IFN signaling in severe and critically ill COVID-19 patients. Blood analysis from across the studies reveals low or undetectable levels of IFN-β and IFN-λ levels in patients exhibiting severe disease symptoms or patients admitted to the ICU with in a critical condition (Hadjadj et al., 2020). Of note, an elegant study was conducted to explore the functional role of IFN signaling during various stages of COVID-19 disease severity. The study found robust impairment of IFN signaling in critically ill and severe patients in comparison to mild/moderate and healthy individuals. IFN-β mRNA and protein were undetectable in all patients, whereas IFN-α2 protein was highly reduced in the plasma of severe and critically ill patients, corroborated with reduced IFN activity. In line with the impaired IFN signaling, robust downregulation of some of the ISGs (MX1, IFITM1, IFIT2) observed in severe and critically ill patients suggest an overall reduced IFN response (Hadjadj et al., 2020).
Consistent with the low circulating levels of IFNs, transcriptional analysis of post-mortem lung samples further confirmed these observations and revealed no detectable type I or Type III IFNs. Among the SARS-CoV-2 proteins which directly interfere with IFN response, ORF6, ORF8, and N protein inhibit IFN-β and NF-κB signaling (Li J.Y. et al., 2020). Further, Konno et al. (2020) have identified a more extended variant of ORF3b with presumably more vigorous anti-IFN activity. Thus, these early observations may point towards an impaired early IFN response by the host cells against SARS-CoV-2
Adding to the essential role of IFN in early antiviral response, two recent studies have shown that genetic changes are associated with inadequate IFN response. In the first study, the presence of IFN neutralizing auto-antibodies found in patients who exhibited more severe disease condition (Bastard et al., 2020). These auto-antibodies were more prevalent in men than women, that partly explains the susceptibility of men to COVID-19. None of the asymptomatic or mild cases had detectable auto-antibodies. In the other study, mutations in 13 key genes implicated in TLR3- and IRF7-dependent exhibit loss-of-function (Zhang Q. et al., 2020). Patients or the cells derived from these patients with loss-of-function in these genes had inadequate IFN response and vulnerable to SARS-CoV-2 infection. In a similar study on four patients with severe disease symptoms, the whole exome-sequencing revealed loss-of-function of TLR7, which is essentially involved in IFN signaling. These patients exhibited decreased expression of IRF7, IFNB1, and ISG15, along with reduced production of IFN-γ (Van Der Made et al., 2020). Thus, impaired IFN signaling, mediated either directly by the virus by interfering at various steps in the IFN signaling, or genetic predisposition of some individuals to inadequate IFN response and presence of IFN neutralizing auto-antibodies are some of the significant factors which determine the COVID-19 disease severity. The dysfunctional IFN response in conjunction with other innate and adaptive immune responses may thus decide the path to recovery or progression to more severe form of the disease (Hadjadj et al., 2020). Impaired type I interferon activity and exacerbated inflammatory responses in severe COVID-19 patients (Hadjadj et al., 2020; Park and Iwasaki, 2020). A comprehensive understanding of the molecular mechanisms by which SARS-CoV-2 causes impaired IFN response is still lacking, and future studies may help us to understand this.
Nevertheless, these initial reports, along with the previous findings on SARS-CoV, are the basis behind exploring the therapeutic efficacy of IFN treatment for COVID-19 patients. Currently, there are ongoing clinical trials with IFN-β1a (NCT04350671), which is in phase II, and IFN-l (NCT04388709) for the treatment of COVID-19. The preliminary results with these drugs have been encouraging as of now (Davoudi-Monfared et al., 2020).