Staphylococcus aureus Induces IFN-β Production via a CARMA3-Independent Mechanism

Zhou, Yang; Zhao, Shasha; Gao, Xiao; Jiang, Songhong; Ma, Jialu; Wang, Rui; Li, Qing; Qin, Leiying; Tong, Zhizi; Wu, Junwei; Zhao, Jianjun

doi:10.3390/pathogens10030300

Cited by 10 publications

(7 citation statements)

References 41 publications

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“…Our data are in line with other studies showing a STING dependent IFN-β production in RAW 264.7 cells or mouse BMDMs upon infection with clinically relevant SA strains [23,31]. STING activation was only observed for living SA and disappeared when bacteria were heat-killed indicating that the stimulus had to be actively produced by the bacteria.…”

Section: Discussionsupporting

confidence: 92%

Staphylococcus aureusplanktonic but not biofilm environment induces an IFN-β macrophage immune response via the STING/IRF3 pathway

Seebach

Sonnenmoser

Kubatzky

2023

Preprint

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Chronic implant-related bone infections are a severe complication in orthopedic surgery. Biofilm formation on the implant surface impairs an effective immune response leading to bacterial persistence. In a previous study, we found thatStaphylococcus aureus(SA) induced IRF3 activation andIfnbgene expression only in its planktonic form but not in the biofilm. The aim of this study was to clarify the role of the stimulator of interferon genes (STING) in this process. We treated murine RAW 264.7 macrophages with conditioned media (CM) generated from planktonic or biofilm cultured SA in combination with agonists or inhibitors of the cGAS/STING pathway. We further evaluated bacterial gene expression of planktonic and biofilm SA to find potential mediators. STING inhibition resulted in a loss of IRF3 activation andIfnbinduction in SA planktonic CM, whereas STING activation induced an IRF3 dependent IFN-β response in SA biofilm CM. Expression levels of genes associated with virulence decreased with biofilm formation while those associated with cyclic dinucleotide (CDN) synthesis did not correlate withIfnbinduction. We further observed that cGAS contributed to theIfnbinduction by SA planktonic CM although cGAS activation was not sufficient to induceIfnbgene expression in SA biofilm CM. Our data indicate that the different degrees of virulence associated with planktonic and biofilm SA environnments result in an altered induction of an IRF3 mediated IFN-β response via the STING pathway. This finding suggests that the STING/IRF3/IFN-β axis is a potential candidate for further investigation as immunotherapeutic target in implant-related bone infections.

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Section: Discussionsupporting

confidence: 92%

Staphylococcus aureusplanktonic but not biofilm environment induces an IFN-β macrophage immune response via the STING/IRF3 pathway

Seebach

Sonnenmoser

Kubatzky

2023

Preprint

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“…However, STING deficiency did not worsen pulmonary inflammation during the early stage of infection [88]. Another study that implicated cGAS/STING signalling in S. aureus infection showed that S. aureus infection promoted IFN-β mRNA expression and TBK1/IRF3-dependent production of IFN-β in murine macrophages [40]. Production of IFN-β has been reported to be protective against S. aureus infection, as IFN-β is required to turn on downstream genes important for local inflammatory responses [89].…”

Section: Cgas-sting Pathwaymentioning

confidence: 99%

“…CDNs bind to the endoplasmic reticulum (ER)-localised STING, which promotes STING dimerization and translocation from the ER to golgi compartments [36,37] where STING recruits and activates TBK1 and nuclear translocation of the transcription factor IRF3) and to a lesser extent, NF-κB) [38], leading to the production of type 1 IFNs and many other inflammatory cytokines. Type I IFN induction is a critical component of innate immune response to several bacterial pathogens including S. aureus [40].…”

Section: Cgas-sting Pathwaymentioning

confidence: 99%

The Influence of Antibiotic Resistance on Innate Immune Responses to Staphylococcus aureus Infection

2022

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Staphylococcus aureus (S. aureus) causes a broad range of infections and is associated with significant morbidity and mortality. S. aureus produces a diverse range of cellular and extracellular factors responsible for its invasiveness and ability to resist immune attack. In recent years, increasing resistance to last-line anti-staphylococcal antibiotics daptomycin and vancomycin has been observed. Resistant strains of S. aureus are highly efficient in invading a variety of professional and nonprofessional phagocytes and are able to survive inside host cells. Eliciting immune protection against antibiotic-resistant S. aureus infection is a global challenge, requiring both innate and adaptive immune effector mechanisms. Dendritic cells (DC), which sit at the interface between innate and adaptive immune responses, are central to the induction of immune protection against S. aureus. However, it has been observed that S. aureus has the capacity to develop further antibiotic resistance and acquire increased resistance to immunological recognition by the innate immune system. In this article, we review the strategies utilised by S. aureus to circumvent antibiotic and innate immune responses, especially the interaction between S. aureus and DC, focusing on how this relationship is perturbed with the development of antibiotic resistance.

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“…During the early stage of S. aureus infection, the Toll-like receptor (TLR) and cGAS-STING pathways are both activated by live S. aureus but exhibit opposite roles in the host immune response to S. aureus. TLR signaling restricts infection, while the cGAS-STING pathway enhances bacterial growth ( 83 , 84 ). The transcription and expression of IFN-I are well-known to be induced by phosphorylation of IRF3.…”

Section: Intracellular Gram-positive 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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Staphylococcus aureus Induces IFN-β Production via a CARMA3-Independent Mechanism

Cited by 10 publications

References 41 publications

Staphylococcus aureusplanktonic but not biofilm environment induces an IFN-β macrophage immune response via the STING/IRF3 pathway

Staphylococcus aureusplanktonic but not biofilm environment induces an IFN-β macrophage immune response via the STING/IRF3 pathway

The Influence of Antibiotic Resistance on Innate Immune Responses to Staphylococcus aureus Infection

The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

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