The Dual Role of cGAS-STING Signaling in COVID-19: Implications for Therapy

Abstract

The progression of COVID-19 involves a sophisticated and intricate interplay between the SARS-CoV-2 virus and the host's immune response. The immune system employs both innate and adaptive mechanisms to combat infection. Innate immunity initiates the release of interferons (IFNs) and pro-inflammatory cytokines, while the adaptive immune response involves CD4+ Th lymphocytes, B lymphocytes, and CD8+ Tc cells. Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs), activating the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, a crucial component of the innate immune response to SARS-CoV-2. This pathway fulfills a dual function during infection. In the early phase of infection, the virus can suppress cGAS-STING signaling to avoid immune detection. However, in the late stages, the activation of this pathway may trigger excessive inflammation and tissue damage, exacerbating disease severity. Modulating the cGAS-STING pathway, whether through agonists like dimeric amidobenzimidazole (diABZI) or inhibitors targeting viral proteins, such as 3CLpro, for example, offers a promising approach for personalized therapy to control the immune response and mitigate severe inflammation, ultimately improving clinical outcomes in patients with severe COVID-19.

Keywords: COVID-19; SARS-CoV-2 infection; cGAS–STING pathway; innate immunity.

Figure 1

Innate immune response activation by RNA and DNA sensors. MAVS and STING are activated by viral RNA or cytosolic DNA, activating kinases IKK and TBK1. These, in turn, phosphorylate the adaptor proteins (MAVS or STING), which recruit IRF3, allowing its phosphorylation by TBK1. Phosphorylated IRF3 suffers dimerization and induces IFN in the nucleus. Non-continuous arrows indicate recruitment and activation. Modified from Liu et al. [12]. Reproduced with permission.

Figure 2

The dual role of cGAS-STING signaling in COVID-19 and potential therapeutic targeting. In the early phase of infection, the virus can suppress cGAS-STING signaling to evade immune detection. Thus, cGAS-STING agonists are beneficial at this stage in order to reduce viral replication and control infection. However, in the late stages, activation of this pathway can lead to excessive inflammation and tissue damage, exacerbating disease severity. In this case, therapy might antagonize cGAS-STING. Modified from Elahi et al. Downward arrow indicates reduction [55].