The research team of the School of Pharmacy of Shanghai Jiaotong University published a review of the research progress of STING signaling pathway mediating the multiple mechanisms of the new crown

Since the end of 2019, COVID-19 caused by SARS-CoV-2 infection has spread rapidly around the world, with a cumulative total of more than 600 million confirmed cases and more than 6 million deaths, seriously threatening human health and public health safety
.

At present, a number of drugs have been approved for the treatment of the new crown, including Pfizer oral drug Paxlovid for mild disease, Merck oral drug Molnupiravir, Remdesivir for mild and severe disease, glucocorticoids for severe and critical disease, IL-6 receptor blocker and Baricitinib, and azvudine developed by Real Bio in China for the treatment of adult patients with COVID-19
.
The rapid development of a variety of vaccines has also made a great contribution
to the fight against the new crown.
However, existing drugs and vaccines are insufficient to combat persistent virus variants, so there is an urgent need to develop new prevention and treatment measures to prevent the continued mutation and spread
of the new crown.

As the body's first line of defense, the natural immune system senses the virus through pattern recognition receptors and activates the inflammatory response to promote viral clearance
.
Among them, the Stimulator of interferon genes (STING) signaling pathway is an important member of the natural immune system, which activates the downstream interferon response by sensing the DNA from pathogens and exerts antiviral effects
.
As a typical RNA virus, SARS-CoV-2 is mainly recognized by the RNA receptor RLR in the host cell, rather than by the DNA receptor STING
.
However, there is growing evidence that the STING signaling pathway also has an inhibitory effect on SARS-CoV-2 infection, and the SARS-CoV-2-encoding protein can also antagonize the STING signaling pathway
.
There is a complex relationship
between the STING signaling pathway and SARS-CoV-2 infection and replication.

On December 8, 2022, Professor Zhang Ao's research group from the School of Pharmacy of Shanghai Jiao Tong University published a review article entitled "Involvement of the STING signaling in COVID-19" in Frontiers in immunology, summarizing the links between SARS-CoV-2 and STING signaling pathways that have been reported so far.
The antagonistic mechanism of viral proteins on STING pathway and the activation effect of host cells on STING pathway were discussed, the inflammatory abnormalities caused by continuous activation of STING during SARS-CoV-2 infection were emphasized, the antiviral effect of STING agonists on SARS-CoV-2 was summarized, and the potential application value
of STING agonists as adjuvants in the development of new crown vaccines was summarized.

The relationship between SARS-CoV-2 virus and STING signaling pathway is close and complex, and in the early stage of new crown infection, the virus inhibits the activation of STING pathway through the direct binding of its own protein to STING, weakens the host's natural immune response, and provides time
for the virus to replicate 。 With the development of the infection process, the number of viruses in the host gradually increases, the virus fuses with the host cells to form syncytia, and the micronucleus in it activates the STING pathway to mediate the inflammatory response due to genomic instability, while killing the virus to a certain extent, excessive immune response will also lead to serious lung inflammation and complications
。 Therefore, STING agonists or inhibitors are promising for the prevention and treatment of SARS-CoV-2 virus, such as the use of STING agonists early in infection to activate the body's natural immune response killer virus to inhibit its replication, and the use of STING inhibitors in the middle and late stages of infection to reduce the body's excessive immune response and reduce lung inflammation (Figure 1).

However, the specific application of STING modulators in the prevention and treatment of the new crown still needs further research, including specific medication timing and medication standards, etc.
, and the article proposes that STING agonists or inhibitors
should be used according to the level of interferon response in patients.
At present, Zhang Ao's team is carrying out corresponding agonists targeting the STING pathway (J.
Med.
Chem.
2021, 64,1649-1669.
) and antagonist studies (J.
Med.
Chem.
2021, 64, 7667-7690.
）
。

Fig.
1 Interaction between SARS-CoV-2 and STING signaling pathway

(Source: Xiao RX.
et al.
, Front Immunol, 2022）

Link to paper: _msthash="101746" _msttexthash="17440995">Xiao Ruoxuan, a postdoctoral fellow at the School of Pharmacy of Shanghai Jiao Tong University, is the first author of the article, and Professor Zhang Ao is the corresponding author
.