The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

Abstract

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), along with the adaptor stimulator of interferon genes (STING), are crucial components of the innate immune system, and their study has become a research hotspot in recent years. Many biochemical and structural studies that have collectively elucidated the mechanism of activation of the cGAS-STING pathway with atomic resolution have provided insights into the roles of the cGAS-STING pathway in innate immunity and clues to the origin and evolution of the modern cGAS-STING signaling pathway. The cGAS-STING pathway has been identified to protect the host against viral infection. After detecting viral dsDNA, cGAS synthesizes a second messenger to activate STING, eliciting antiviral immune responses by promoting the expression of interferons (IFNs) and hundreds of IFN-stimulated genes (ISGs). Recently, the cGAS-STING pathway has also been found to be involved in response to bacterial infections, including bacterial pneumonia, melioidosis, tuberculosis, and sepsis. However, compared with its functions in viral infection, the cGAS-STING signaling pathway in bacterial infection is more complex and diverse since the protective and detrimental effects of type I IFN (IFN-I) on the host depend on the bacterial species and infection mode. Besides, STING activation can also affect infection prognosis through other mechanisms in different bacterial infections, independent of the IFN-I response. Interestingly, the core protein components of the mammalian cGAS-STING signaling pathway have been found in the bacterial defense system, suggesting that this widespread signaling pathway may have originated in bacteria. Here, we review recent findings related to the structures of major molecules involved in the cGAS-STING pathway and the effects of the cGAS-STING pathway in various bacterial infections and bacterial immunity, which may pave the way for the development of new antibacterial drugs that specifically kill bacteria without harmful effects on the host.

Elevated c-di-GMP Levels and Expression of the Type III Secretion System Promote Corneal Infection by Pseudomonas aeruginosa

“…We corroborate that P. aeruginosa bacteria in keratitis likely possess a high content of c-di-GMP that promotes persistent biofilm pathogenesis and reduced production of cytokines. The efficiency of bacterial clearance by the host could also be affected by activation of the cyclic GMP-AMP synthase stimulator of interferon gene (cGAS-STING) pathway, which has been reported to be involved in protecting the host by activating the innate immune response during bacterial infection ( 48 – 50 ). Apart from bacterial DNA, cyclic dinucleotides like c-di-GMP and c-di-AMP can also activate cGAS, which in turn triggers STING to initiate the host immune response ( 51 – 53 ).…”

Borrelia burgdorferiengages mammalian type I interferon responses via the cGAS-STING pathway

“…The cGAS-STING pathway is a major inducer of IFN-I in response to both exogenous, pathogen-derived DNA, as well as host mitochondrial and nuclear DNA (45,51,52,(93)(94)(95)(96). cGAS non-discriminately binds double stranded DNA and produces cGAMP that binds and activates STING on the ER.…”

“…This results in the recruitment and activation of Tank-binding Kinase 1 (TBK1), leading to the phosphorylation of Interferon Regulatory Factor 3 (IRF3) for the induction of type I interferons (IFNα, β) and ISGs (42–44). Although initially identified as an antiviral host defense pathway, it is now well known that the cGAS-STING pathway is critical for induction of robust IFN-I responses to intracellular bacteria such as Mycobacterium tuberculosis and Listeria monocytogenes (45, 50, 51). A recent study revealed that the cGAS-STING pathway is also essential for IFN-I production in response to multiple extracellular pathogens, including Pseudomonas aeruginosa, Klebsiella pneumoniae , and Staphylococcus aureus (52, 53).…”

Research Progress on the Mechanism of Itaconate Regulating Macrophage Immunometabolism

“…STING is a key receptor protein in the natural immune response pathway ( 31 ). After PRRs recognize cytoplasmic viral nucleic acids, the conformation changes after STING binds to these receptors.…”