Nucleic Acid-Sensing Pathways During SARS-CoV-2 Infection: Expectations versus Reality

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people and crippled economies worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for this pandemic has triggered avid research on its pathobiology to better understand the pathophysiology of COVID-19. In the absence of approved antiviral therapeutic strategies or vaccine platforms capable of effectively targeting this global threat, the hunt for effective therapeutics has led to many candidates being actively evaluated for their efficacy in controlling or preventing COVID-19. In this review, we gathered current evidence on the innate nucleic acid-sensing pathways expected to be elicited by SARS-CoV-2 and the immune evasion mechanisms they have developed to promote viral replication and infection. Within the nucleic acid-sensing pathways, SARS-CoV-2 infection and evasion mechanisms trigger the activation of NOD-signaling and NLRP3 pathways leading to the production of inflammatory cytokines, IL-1β and IL-6, while muting or blocking cGAS-STING and interferon type I and III pathways, resulting in decreased production of antiviral interferons and delayed innate response. Therefore, blocking the inflammatory arm and boosting the interferon production arm of nucleic acid-sensing pathways could facilitate early control of viral replication and dissemination, prevent disease progression, and cytokine storm development. We also discuss the rationale behind therapeutic modalities targeting these sensing pathways and their implications in the treatment of COVID-19.

Keywords: COVID-19; NLRP3; SARS-CoV-2; cGAS-STING; coronavirus; immune evasion; innate immune system; nucleic acid sensing.

Figure 1

Nucleic acid-sensing pathways and their evasion by SARS-CoV-2 during COVID-19 infection. The nucleic acid-sensing pathways within the innate immune system recognizes the pathogen-associated molecular patterns (PAMPs) comprising of viral nucleic acids and other viral intermediates including single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA), via distinct pattern recognition receptors (PRRs). The RNA-sensing arm is activated by RNA viruses such as SARS-CoV-2, while DNA-sensing is triggered by host genome released as byproducts of viral reproduction and tissue injury. These receptors include toll‐like receptor (TLR), RIG‐I‐like receptor (RLR), C‐type lectin‐like receptors (CLmin) as well as certain cytoplasmic free‐molecule receptors, such as stimulator of interferon genes (STING), cyclic GMP-AMP synthase (cGAS), and NOD‐like receptor (NLR). Coronaviruses (CoVs) which are typically ssRNA viruses, form dsRNA during their replicative stage. While ssRNA can be detected by TLR7 or TLR8 and potentially RIG-I and PKR, dsRNA engages TLR3 in the endosome and RIG-I, MDA5, and PKR in the cytosol. The cGAS-STING pathway is incapable of directly sensing RNA of CoVs; however, they are likely to get activated by danger-associated molecular patterns (DAMP) signals, such as mitochondrial DNA (mtDNA), released as a result of CoV infection. These PRRs initiate a signaling cascade culminating in primarily type I interferon (IFN-α/β) and inflammatory cytokine production (IL-6 and IL-1β). The presence of low innate antiviral defenses to SARS-CoV-2 suggests the presence of effective evasion mechanisms by SARS-CoV-2 to escape immune surveillance. SARS-CoV-2 is suggested to suppress IFN-I response by means of similar mechanisms as used by SARS-CoV-1, namely Nsp1, Nsp3d/PLpro, Nsp7, Nsp15/EndoU, Nsp16, ORF3, ORF6, ORF8, ORF9b, M, and N.