Dataset Information

Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins.

ABSTRACT: The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.

SUBMITTER: Rui Y

PROVIDER: S-EPMC7958565 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins.

Rui Yajuan Y Su Jiaming J Shen Si S Hu Ying Y Huang Dingbo D Zheng Wenwen W Lou Meng M Shi Yifei Y Wang Meng M Chen Shiqi S Zhao Na N Dong Qi Q Cai Yong Y Xu Rongzhen R Zheng Shu S Yu Xiao-Fang XF

Signal transduction and targeted therapy 20210315 1

The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immun ...[more]

PMID: 33723219

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Project description:Background and aimsCyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) are key components of the innate immune system. This study aims to evaluate the research of cGAS-STING pathway and predict the hotspots and developing trends in this field using bibliometric analysis.MethodsWe retrieved publications from Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC) in 1975-2021 on 16 March 2022. We examined the retrieved data by bibliometrix package in R software, VOSviewer and CiteSpace were used for visualizing the trends and hotspots of research on the cGAS-STING pathway.ResultsWe identified 1047 original articles and reviews on the cGAS-STING pathway published between 1975 and 2021. Before 2016, the publication trend was increasing steadily, but there was a significant increase after 2016. The United States of America (USA) produced the highest number of papers (Np) and took the highest number of citations (Nc), followed by China and Germany. The University of Texas System and Frontiers in Immunology were the most prolific affiliation and journal respectively. In addition, collaboration network analysis showed that there were tight collaborations among the USA, China and some European countries, so the top 10 affiliations were all from these countries and regions. The paper published by Sun LJ in 2013 reached the highest local citation score (LCS). Keywords co-occurrence and co-citation cluster analysis revealed that inflammation, senescence, and tumor were popular terms related to the cGAS-STING pathway recently. Keywords burst detection suggested that STING-dependent innate immunity and NF-κB-dependent broad antiviral response were newly-emerged hotspots in this area.ConclusionsThis bibliometric analysis shows that publications related to the cGAS-STING pathway tend to increase continuously. The research focus has shifted from the mechanism how cGAS senses dsDNA and cGAMP binds to STING to the roles of the cGAS-STING pathway in different pathological state.

Project description:Cyclic GMP-AMP synthase (cGAS), a key DNA sensor, detects cytosolic viral DNA and activates the adaptor protein stimulator of interferon genes (STING) to initiate interferon (IFN) production and host innate antiviral responses. Duck enteritis virus (DEV) is a duck alphaherpesvirus that causes an acute and contagious disease with high mortality in waterfowl. In the present study, we found that DEV inhibits host innate immune responses during the late phase of viral infection. Furthermore, we screened DEV proteins for their ability to inhibit the cGAS-STING DNA-sensing pathway and identified multiple viral proteins, including UL41, US3, UL28, UL53, and UL24, which block IFN-β activation through this pathway. The DEV tegument protein UL41, which exhibited the strongest inhibitory effect, selectively downregulated the expression of interferon regulatory factor 7 (IRF7) by reducing its mRNA accumulation, thereby inhibiting the DNA-sensing pathway. Ectopic expression of UL41 markedly reduced viral DNA-triggered IFN-β production and promoted viral replication, whereas deficiency of UL41 in the context of DEV infection increased the IFN-β response to DEV and suppressed viral replication. In addition, ectopic expression of IRF7 inhibited the replication of the UL41-deficient virus, whereas IRF7 knockdown facilitated its replication. This study is the first report identifying multiple viral proteins encoded by a duck DNA virus, which inhibit the cGAS-STING DNA-sensing pathway. These findings expand our knowledge of DNA sensing in ducks and reveal a mechanism through which DEV antagonizes the host innate immune response. IMPORTANCE Duck enteritis virus (DEV) is a duck alphaherpesvirus that causes an acute and contagious disease with high mortality, resulting in substantial economic losses in the commercial waterfowl industry. The evasion of DNA-sensing pathway-mediated antiviral innate immunity is essential for the persistent infection and replication of many DNA viruses. However, the mechanisms used by DEV to modulate the DNA-sensing pathway remain poorly understood. In the present study, we found that DEV encodes multiple viral proteins to inhibit the cGAS-STING DNA-sensing pathway. The DEV tegument protein UL41 selectively diminished the accumulation of interferon regulatory factor 7 (IRF7) mRNA, thereby inhibiting the DNA-sensing pathway. Loss of UL41 potently enhanced the IFN-β response to DEV and impaired viral replication in ducks. These findings provide insights into the host-virus interaction during DEV infection and help develop new live attenuated vaccines against DEV.

Dataset Information

Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins.

Publications

Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins.

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