Phase separation in cGAS-STING signaling / 医学前沿

Biomolecular condensates formed by phase separation are widespread and play critical roles in many physiological and pathological processes. cGAS-STING signaling functions to detect aberrant DNA signals to initiate anti-infection defense and antitumor immunity. At the same time, cGAS-STING signaling must be carefully regulated to maintain immune homeostasis. Interestingly, exciting recent studies have reported that biomolecular phase separation exists and plays important roles in different steps of cGAS-STING signaling, including cGAS condensates, STING condensates, and IRF3 condensates. In addition, several intracellular and extracellular factors have been proposed to modulate the condensates in cGAS-STING signaling. These studies reveal novel activation and regulation mechanisms of cGAS-STING signaling and provide new opportunities for drug discovery. Here, we summarize recent advances in the phase separation of cGAS-STING signaling and the development of potential drugs targeting these innate immune condensates.

Role of cGAS-cGAMP-STING pathway in antivirus / 药学实践杂志

Innate immunity is the host's first line defense against pathogens invading to the body. Detection of abnormal nucleic acids in the cytoplasm showed that some conserved pathogen associated molecular patterns (PAMPS) triggered type I interferon (IFN) -mediated innate immune responses. The DNA sensor— cGAS (cGAMP Synthase) recognizes and binds to host or pathogen cytoplasmic DNA, promotes the formation of the second messenger cGAMP (cyclic GMP-AMP), and triggers STING (stimulator of interferon genes) dependent downstream signaling. Here we briefly describe the latest progress of the cGAS-cGAMP-STING pathway and its important role in antivirus, and provide new ideas for virus prevention research and new direction for the development of antiviral drugs.

Cyclic guanosine monophosphate-adenosine monophosphate ( cGAMP) enhances the immune respon-ses against Helicobacter pylori in BALB/c mice / 中华微生物学和免疫学杂志

Objective To evaluate the adjuvant activities of cyclic guanosine monophosphate-adenosine monophosphate ( cGAMP) in enhancing humoral and cellular responses against Helicobacter pylori ( H. pylori) . Methods BALB/c mice were immunized with the protein antigens including UreA, UreB and NapA of H. pylori in combination with cGAMP as the adjuvant on 0 d and 14 d by subcutaneous administra-tion. Then, the serum-specific antibody responses were evaluated by ELISA. Flow cytometry ( FCM) and enzyme-linked immunospot assay ( ELISpot) were used to detect the cellular immune responses occurred in spleen and mesenteric lymph nodes (MLN). Results Subcutaneous administration of protein antigens of H. pylori together with cGAMP induced strong humoral and cellular immune responses in BALB/c mice. The levels of serum-specific IgG antibodies induced by adding cGAMP as the adjuvant were significantly higher than those by immunizing with antigens alone. The levels of splenic IFN-γ-producing lymphocytes in re-sponse to H. pylori antigens and cGAMP immunization were significantly higher than those in the correspond-ing groups without using cGAMP. Conclusion By using cGAMP as an adjuvant, H. pylori antigens could elicit significantly stronger humoral and cellular immune responses in mice than those induced by the anti-gens only. As a stable small molecular compound with strong adjuvant activity, cGAMP has the potential to be used for the development of H. pylori vaccine.

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP): a novel vaccine adjuvant / 中华微生物学和免疫学杂志

Aluminum salts are the most popular adjuvants applied in human vaccines currently. However,they can′t achieve satisfying results in the development of novel vaccines because of the cellular immune responses induced by them are weak and their adjuvant activities for some novel vaccines are poor, especially in vaccination against peptide antigens with small molecular weight. cGAMP (cyclic guanosine monophosphate-adenosine monophosphate) has recently been known as a mammalian second messenger, which plays an important role in the innate immune signaling pathway and is capable of boosting the immuno-genicity of vaccines,activating antigen-presenting cells and enhancing specific T cell responses. cGAMP is expected to become a new generation of vaccine adjuvants against infectious diseases and cancer. In this re-view,we summarize the application and current situation of vaccine adjuvants, describe the discovery of cGAMP and its mechanism as a vaccine adjuvant,and focus on the advances in using cGAMP in the fields of vaccination against infectious diseases, intradermal immunization and tumor immunotherapy. Finally, it is also pointed out that cGAMP,as a novel vaccine adjuvant,will have a broad prospect of application in areas such as anti-tumor,anti-virus,anti-inflammatory and vaccines.

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) enhances humoral immune responses against norovirus(GⅡ.4) virus-like particles / 中华微生物学和免疫学杂志

Objective To evaluate the immunopotentiating effect of cyclic guanosine monophos-phate-adenosine monophosphate (cGAMP) as an adjuvant on norovirus (GⅡ. 4) virus like particles (VLPs) in the development of norovirus vaccine. Methods BALB/c mice were intramuscularly immunized with norovirus (GⅡ.4) VLPs composed of capsid protein VP1 in combination with cGAMP or Al(OH)3. Norovirus VLPs-specific antibodies in serum were detected by ELISA. A synthetic histo-blood group antigen (HBGA)-VLPs blocking assay was used to analyze neutralizing antibodies against norovirus VLPs in serum samples. Results Immunization with norovirus VLPs in the presence of cGAMP induced a strong humoral immune response in BALB/c mice. Levels of specific IgG antibodies in serum induced by using cGAMP as the adjuvant were significantly higher than those induced by using Al(OH)3adjuvant when immunization of BALB/c mice with the same dosage of VLPs. The antibody level induced by 1 μg of VLPs in combination with cGAMP was equivalent to that elicited by 10 μg of VLPs combined with Al(OH)3adjuvant. Results of the synthetic HBGA-VLPs blocking assay showed that the blocking rate in cGAMP+VLPs immunization group were significantly higher than that in Al(OH)3+VLPs immunization group when using the same dosage of VLPs. No significant difference in blocking rate was observed between cGAMP+VLPs(1 μg) and Al(OH)3+VLPs (10 μg) immunization groups. Conclusion cGAMP significantly enhanced the specific humoral immune response induced by norovirus (GⅡ.4) VLPs in mice as compared with Al(OH)3adjuvant. It might be used as a novel adjuvant to replace the traditional aluminum adjuvant in the development of norovir-us vaccine.

DNA sensor cGAS-mediated immune recognition

The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.

cGAS-cGAMP Signaling and Antiviral Defense

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that plays an important role in innate immunity. Transfection of DNA or DNA virus infection results in the induction of type I interferon production in fibroblasts, macrophages, and dendritic cells which is dependent on cGAS. Recently, cGas (-/-) mice have been reported to be more vulnerable to fatal infection with herpes simplex virus 1 (HSV1) as compared to wild-type mice.

Role of Cyclic GMP-AMP Synthase in Sensing Human Immunodeficiency Virus

Cyclic guanosine monophosphate adenosine monophosphate (cGAMP) synthase (cGAS) detects human immunodeficiency virus (HIV) and produces cGAMP to induce cytokines. Reverse transcribed DNA of HIV is critical for triggering innate immune responses as inhibitor of HIV reverse transcriptase blocked the induction of interferon-beta by the virus. Furthermore, knockout of cGAS in human or mouse cell lines abrogated the production of cytokines by HIV infection highlighting the essential role of cGAS in detection of HIV and other retroviruses.