Type I interferon pathway genetic variants in severe COVID-19

Abstract

Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2. According to the World Health Organization (WHO), there have been over 760 million reported cases and over 6 million deaths caused by this disease worldwide. The severity of COVID-19 is based on symptoms presented by the patient and is divided as asymptomatic, mild, moderate, severe, and critical. The manifestations are interconnected with genetic variations. The innate immunity is the quickest response mechanism of an organism against viruses. Type I interferon pathway plays a key role in antiviral responses due to viral replication inhibition in infected cells and adaptive immunity stimulation induced by interferon molecules. Thus, variants in type I interferon pathway's genes are being studied in different COVID-19 manifestations. This review summarizes the role of variants in type I interferon pathway's genes on prognosis and severity progression of COVID-19.

Keywords: COVID-19; Single nucleotide polymorphisms; Type I interferon.

Fig. 1

Type I interferon pathway activation by SARS-CoV-2 infection. SARS-CoV-2 enters the host epithelial alveolar cells through the ACE2 protein located at the cell surface, with the assistance of TMPRSS2 protein. The cell membrane fuses with the viral envelope and the single-stranded virus RNA enters the cell in an endosome. TLR3, TLR7, and TLR8 are endomosomaly expressed and can detect viral RNA. RIG-I and MDA5 are located at the cytoplasm but can also detect viral RNA if it reaches this location without detection. The expression of interferon regulatory factors (IRF3 and IRF7) is stimulated after detection by PRRs. IRF3 and IRF7 are phosphorylated and homodimerized to serve as transcription factors to produce IFN-α and IFN-β. These type I interferon (IFN-I) molecules are then detected by type I interferon receptor subunits (IFNAR1 and IFNAR2), which have JAK and STAT proteins that bind to their intracellular domain (ICD). The JAK (TYK2 and JAK1) and STAT proteins are responsible for signal transduction. TYK2 binds to IFNAR1 ICD and JAK1 and STAT1 bind to IFNAR2 ICD. When the IFNAR subunits are bind to IFN-I, these proteins cross-phosphorylate and internalize the receptor through endosome formation. STAT proteins form homo- and heterodimers such as the IRF9/STAT1/STAT2 complex. The resulting complexes serve as transcription factors for interferon stimulated genes (ISGs), which have several antiviral functions (Figure created with Biorender, adapted from Schreiber 2020; Carter-Timofte et al., 2020).