Mechanisms of Antiviral Immune Evasion of SARS-CoV-2

Abstract

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is characterized by a delayed interferon (IFN) response and high levels of proinflammatory cytokine expression. Type I and III IFNs serve as a first line of defense during acute viral infections and are readily antagonized by viruses to establish productive infection. A rapidly growing body of work has interrogated the mechanisms by which SARS-CoV-2 antagonizes both IFN induction and IFN signaling to establish productive infection. Here, we summarize these findings and discuss the molecular interactions that prevent viral RNA recognition, inhibit the induction of IFN gene expression, and block the response to IFN treatment. We also describe the mechanisms by which SARS-CoV-2 viral proteins promote host shutoff. A detailed understanding of the host-pathogen interactions that unbalance the IFN response is critical for the design and deployment of host-targeted therapeutics to manage COVID-19.

Keywords: COVID-19; ISGs; SARS-CoV-2; immune evasion; interferons.

Graphical abstract

Figure 1

Targeted host innate immune evasion by SARS-CoV-2. (A) Genome Structure of SARS-CoV-2 delineating the open reading frames that encode the non-structural (blue), structural (purple) and accessory (orange) proteins. (B) Interactions leading to the inhibition of early signaling cascades that lead to the induction of interferon (IFN) and virus-stress inducible genes (VSIGs) (right). Viral antagonism of the late antiviral response that follows type I and type III IFN sensing and downstream IFN-stimulated gene (ISG) induction (left). Created with BioRender.com.

Figure 2

Broad modulation of host cell responses that impair innate immune functions. SARS-CoV-2 mediates host shutoff through the inhibition of messenger RNA (mRNA) translation. Translation of viral RNA (vRNA) is favored in infected cells. Additional inhibition of antiviral responses is due to deficits in RNA maturation. SARS-CoV-2 gene products block the splicing of host RNA. Similarly, the nuclear trafficking of transcription factors involved in the induction and response to interferon (IFN) and IFN-stimulated genes (ISGs) is impaired. Sequestration of subunits of the nuclear pore complex, RAE1 and NUP68 prevent the nuclear import of transcription factors, IRF3 and STAT1. Blockade of nuclear export of IFN and ISG mRNA inhibits antiviral immunity. This can be partly achieved by inhibition of the nuclear RNA export factor 1 (NFX1). Lastly, SARS-CoV-2 blocks the trafficking of proteins through the secretory pathway by inhibiting structural components of the Signal Recognition Particle (SRP). Created with BioRender.com.