Identification of cGAS as an innate immune sensor of extracellular bacterium Pseudomonas aeruginosa

Zhou, Chunkui; Wang, Biao; Wu, Qun; Lin, Ping; Qin, Shugang; Pu, Qinqin; Yu, Xue‐Jie; Wu, Min

doi:10.1016/j.isci.2020.101928

Cited by 23 publications

(26 citation statements)

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“…Indeed, the activation of cGAS—a recognition receptor for double-stranded DNA (dsDNA)—generates cyclic GMP–AMP (cGAMP)—a secondary messenger of STING (the stimulator of interferon genes)—which promotes inflammatory responses through interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling [ 14 ]. Although cGAS is naturally prepared for the recognition of intracellular organisms (bacteria and viruses), it can also recognize host DNA and DNA from extracellular bacteria [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Then, cfDNA, from either bacteria or host cells, might affect sepsis severity, so that the manipulation of cfDNA in sepsis could have beneficial effects. Due to sepsis increasing serum cfDNAs and mtDNAs [ 40 ], which promote inflammation through cGAS activation [ 14 , 15 , 41 ], and with injection of bacterial DNA with LPS worsening sepsis severity [ 28 ], the fact that blockage of cGAS downstream-signaling, STING and Interferon regulatory factor 3 (IRF3) attenuates sepsis [ 23 ] suggests that the exploration of sepsis in cGAS -/- mice and macrophages would be worthwhile, especially considering the limitedness of research into sepsis in cGAS deficient (cGAS -/- ) mice. Hence, we produced sepsis models, using cecal ligation and puncture (CLP) and LPS injection, and examined in vitro cGAS -/- macrophages.…”

Section: Introductionmentioning

confidence: 99%

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Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

Visitchanakun

Kaewduangduen

Chareonsappakit

et al. 2021

IJMS

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Although the enhanced responses against serum cell-free DNA (cfDNA) in cases of sepsis—a life-threatening organ dysfunction due to systemic infection—are understood, the influence of the cytosolic DNA receptor cGAS (cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase) on sepsis is still unclear. Here, experiments on cGAS deficient (cGAS-/-) mice were conducted using cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection sepsis models and macrophages. Severity of CLP in cGAS-/- mice was less severe than in wildtype (WT) mice, as indicated by mortality, serum LPS, cfDNA, leukopenia, cytokines (TNF-α, IL-6 and IL-10), organ histology (lung, liver and kidney) and spleen apoptosis. With the LPS injection model, serum cytokines in cGAS-/- mice were lower than in WT mice, despite the similar serum cfDNA level. Likewise, in LPS-activated WT macrophages, the expression of several mitochondria-associated genes (as revealed by RNA sequencing analysis) and a profound reduction in mitochondrial parameters, including maximal respiration (determined by extracellular flux analysis), DNA (mtDNA) and mitochondrial abundance (revealed by fluorescent staining), were demonstrated. These data implied the impact of cfDNA resulting from LPS-induced cell injury. In parallel, an additive effect of bacterial DNA on LPS, seen in comparison with LPS alone, was demonstrated in WT macrophages, but not in cGAS-/- cells, as indicated by supernatant cytokines (TNF-α and IL-6), M1 proinflammatory polarization (iNOS and IL-1β), cGAS, IFN-γ and supernatant cyclic GMP–AMP (cGAMP). In conclusion, cGAS activation by cfDNA from hosts (especially mtDNA) and bacteria was found to induce an additive proinflammatory effect on LPS-activated macrophages which was perhaps responsible for the more pronounced sepsis hyperinflammation observed in WT mice compared with the cGAS-/- group.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

Visitchanakun

Kaewduangduen

Chareonsappakit

et al. 2021

IJMS

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“…Pseudomonas aeruginosa is an opportunistic bacterium that can easily cause infection in immunocompromised people ( 119 ). The cGAS-STING pathway has been reported to have a protective effect in P. aeruginosa infection by promoting host resistance against P. aeruginosa infection and negatively modulating host inflammatory responses ( 120 , 121 ). After penetrating P. aeruginosa into host cells, its genomic DNA can be sensed by cGAS, which mediates the IFN-I response by activating STING.…”

Section: Extracellular Gram-negative Bacteriamentioning

confidence: 99%

The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

et al. 2022

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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.

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“…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.…”

Section: B Burgdorferi Elicits Robust Innate and Adaptive Immune Resp...mentioning

confidence: 99%

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

Farris

Torres-Odio

Adams

et al. 2022

Preprint

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Borrelia burgdorferi, the etiologic agent of Lyme disease, is a spirochete that modulates numerous host pathways to cause a chronic, multi-system inflammatory disease in humans. B. burgdorferi infection can lead to Lyme carditis, neurologic complications, and arthritis, dependent upon the ability of specific borrelial strains to disseminate, invade, and drive inflammation. B. burgdorferi elicits type I interferon (IFN-I) responses in mammalian cells and tissues that are associated with the development of severe arthritis or other Lyme-related complications. However, the innate immune sensors and signaling pathways controlling IFN-I induction remain unclear. In this study, we examined whether intracellular nucleic acid sensing is required for the induction of IFN-I to B. burgdorferi. Using confocal microscopy, we show that B. burgdorferi is taken up by mouse and human cells in culture, indicating a route for intracellular detection. In addition, we report that IFN-I responses in primary mouse macrophages and murine embryonic fibroblasts are significantly attenuated in the absence of the pattern recognition receptor cyclic GMP-AMP synthase (cGAS) or its adaptor Stimulator of Interferon Genes (STING), which function together to sense and respond to intracellular DNA. In vivo tracking of bioluminescent B. burgdorferi during infection of C57BL/6 wild-type, cGAS knockout, or STING deficient mice revealed similar dissemination kinetics and borrelial load. However, tibiotarsal joint pathology and inflammation were reduced in cGAS knockout compared to wild-type mice. Collectively, these results indicate that the cGAS-STING pathway is an innate immune sentinel of B. burgdorferi that plays a key role in the induction of mammalian IFN-I responses.

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Identification of cGAS as an innate immune sensor of extracellular bacterium Pseudomonas aeruginosa

Cited by 23 publications

References 50 publications

Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

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

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