Involvement of the STING signaling in COVID-19

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has cast a notorious damage to the public health and global economy. The Stimulator of Interferon Genes (STING) is a crucial element of the host antiviral pathway and plays a pivotal but complex role in the infection and development of COVID-19. Herein, we discussed the antagonistic mechanism of viral proteins to the STING pathway as well as its activation induced by host cells. Specifically, we highlighted that the persistent activation of STING by SARS-CoV-2 led to abnormal inflammation, and STING inhibitors could reduce the excessive inflammation. In addition, we also emphasized that STING agonists possessed antiviral potency against diverse coronavirus and showed adjuvant efficacy in SARS-CoV-2 vaccines by inducing IFN responses.

cGAS‐STING pathway agonists are promising vaccine adjuvants

“…As adjuvants, the STING agonist CF501 was combined with human IgG Fc-conjugated receptor binding domain (RBD) from the original SARS-CoV-2 strain, inducing highly potent and durable protective immunity responses without apparent biological toxicity. 123,186 As mentioned earlier, Mn 2+ NPs can enhance retention and cellular uptake, leading to prolonged activation of the cGAS-STING pathway after injection. Zhang et al 187 found that NP manganese was the most potent adjuvant in stimulating immune responses to SARS-CoV-2 protein-based subunit vaccines, as evidenced by the concentration of RBD-specific IgG and specific neutralizing antibodies of SARS-CoV-2 and variants in mouse models.…”

“…121 Additionally, diABZI-4 has demonstrated efficacy in inhibiting virus replication in cells as a diABZI analogue. 122,123 Xie et al 117 explored enhancing the efficacy of the STING agonist by increasing diABZIs asymmetry. They incorporated a furan ring into benzimidazole to replace one benzimidazole moiety in diABZIs, creating a more asymmetric structure named HB3089.…”

“…The diABZI based adjuvant significantly increased IFN‐γ, IL‐2, and TNF marker‐positive CD4 + T cells 121 . Additionally, diABZI‐4 has demonstrated efficacy in inhibiting virus replication in cells as a diABZI analogue 122,123 . Xie et al 117 explored enhancing the efficacy of the STING agonist by increasing diABZIs asymmetry.…”

STING agonists as promising vaccine adjuvants to boost immunogenicity against SARS-related coronavirus derived infection: possible role of autophagy

“…In parallel with this, a recent study corroborated that the cGAS-STING pathway is a leading cause of aberrant IFN-I-induced immune responses in COVID-19, via mitochondrial DNA release in the endothelial cells, while pharmacological blocking of the STING pathway significantly reduced inflammatory status, particularly in the respiratory system [ 71 ]. Others advocate that designing STING inhibitors, such as H-151and VS-X4, could serve as novel therapeutic options in the late phase of SARS-CoV-2-like infections to alleviate the hyper-inflammation, as a result of the persistent STING activation, particularly in severe or critically ill patients [ 71 , 75 , 76 ].…”

Potential Therapeutic Value of the STING Inhibitors

“…The relationship between STING and SARS-CoV-2 is complex [ 213 ]. During the initial stages of COVID-19 infection, the virus effectively suppresses STING activation by directly binding viral accessory protein ORF3a to STING [ 214 ].…”