A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis

Dey, Bappaditya; Dey, Ruchi Jain; Cheung, Laurene S.; Pokkali, Supriya; Guo, Haidan; Lee, Jong Hee; Bishai, William R.

doi:10.1038/nm.3813

Cited by 223 publications

(261 citation statements)

References 43 publications

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“…Cyclic di-AMP released from intracellular pathogens is sensed by STING within the host cytosol and induces a type I IFN response (26)(27)(28)(29)(30)(31)(32)(33)(34). A previous report described IFN-␤ production following c-di-AMP treatment in vivo and in human and murine dendritic cells in vitro (46); how- ever, effects of extracellular c-di-AMP on macrophages have not yet been reported.…”

Section: Resultsmentioning

confidence: 99%

“…For example, c-di-AMP secretion into the macrophage cytosol induces a robust type I interferon (IFN [IFN-␤]) response during intracellular bacterial infections, including those caused by Listeria monocytogenes (26,27), Chlamydia trachomatis (28), and Mycobacterium spp. (29,30). Cytosolic c-di-AMP is sensed by both the endoplasmic reticulum resident protein stimulator of interferon genes (STING) (31-33) and the helicase DDX41 (34); however, the individual contributions of these proteins in sensing c-di-AMP remain unclear.…”

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confidence: 99%

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Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response

et al. 2016

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Staphylococcus aureus is a leading cause of community-and nosocomial-acquired infections, with a propensity for biofilm formation. S. aureus biofilms actively skew the host immune response toward an anti-inflammatory state; however, the biofilm effector molecules and the mechanism(s) of action responsible for this phenomenon remain to be fully defined. The essential bacterial second messenger cyclic diadenylate monophosphate (c-di-AMP) is an emerging pathogen-associated molecular pattern during intracellular bacterial infections, as c-di-AMP secretion into the infected host cytosol induces a robust type I interferon (IFN) response. Type I IFNs have the potential to exacerbate infectious outcomes by promoting anti-inflammatory effects; however, the type I IFN response to S. aureus biofilms is unknown. Additionally, while several intracellular proteins function as c-di-AMP receptors in S. aureus, it has yet to be determined if any extracellular role for c-di-AMP exists and its release during biofilm formation has not yet been demonstrated. This study examined the possibility that c-di-AMP released during S. aureus biofilm growth polarizes macrophages toward an anti-inflammatory phenotype via type I interferon signaling. DacA, the enzyme responsible for c-di-AMP synthesis in S. aureus, was highly expressed during biofilm growth, and 30 to 50% of total c-di-AMP produced from S. aureus biofilm was released extracellularly due to autolytic activity. S. aureus biofilm c-di-AMP release induced macrophage type I IFN expression via a STING-dependent pathway and promoted S. aureus intracellular survival in macrophages. These findings identify c-di-AMP as another mechanism for how S. aureus biofilms promote macrophage anti-inflammatory activity, which likely contributes to biofilm persistence. Staphylococcus aureus is a leading cause of prosthetic joint infections (1, 2), whereupon adherence to the implant surface facilitates biofilm formation. These infections are particularly challenging to treat and typically require a two-stage surgical process for insertion of a new device (1). Moreover, biofilms actively skew the host immune response toward an anti-inflammatory state, thereby contributing to the chronic nature of biofilm-mediated infections (3-5). This is evident by macrophage polarization toward an alternatively activated phenotype and the recruitment of myeloid-derived suppressor cells (MDSCs) (3,(6)(7)(8). While this immune deviation appears to be driven by S. aureus biofilm products, the effectors and their mechanism(s) of action remain to be fully identified.To further understand mechanisms of immune modification by S. aureus biofilms, we investigated the role of the essential bacterial second messenger cyclic diadenylate monophosphate (c-di-AMP), since it has been identified as an emerging pathogen-associated molecular pattern (PAMP) that influences immune responsiveness (9, 10). While c-di-AMP has been found to regulate many important functions in bacteria, including cell wall stress and peptidoglycan homeostas...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response

et al. 2016

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“…In M. tuberculosis, secretion of Mt-EsxA by the ESX-1 pathway into host cells activates cyclic GMP-AMP synthase (cGAS) and cyclic GMP-AMP (cGAMP) signaling via STING, the mammalian sensor for cytoplasmic DNA and bacterial cyclic dinucleotides (38), thereby stimulating type I interferon (IFN) responses (39)(40)(41). IFN activation is associated with disease progression in tuberculosis (TB) and other infectious diseases.…”

Section: Discussionmentioning

confidence: 99%

EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection

et al. 2017

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Staphylococcus aureus, an invasive pathogen of humans and animals, requires a specialized ESS pathway to secrete proteins (EsxA, EsxB, EsxC, and EsxD) during infection. Expression of ess genes is required for S. aureus establishment of persistent abscess lesions following bloodstream infection; however, the mechanisms whereby effectors of the ESS pathway implement their virulence strategies were heretofore not known. Here, we show that EssE forms a complex with other members of the ESS secretion pathway and its substrates, promoting the secretion of EsxA, EsxB, EsxC, EsxD, and EssD. During bloodstream infection of mice, the S. aureus essE mutant displays defects in host cytokine responses, specifically in the production of interleukin-12 (IL-12) (p40/p70) and the suppression of RANTES (CCL5), activators of T H 1 T cell responses and immune cell chemotaxis, respectively. Thus, essE-mediated secretion of protein effectors via the ESS pathway may enable S. aureus to manipulate host immune responses by modifying the production of cytokines.IMPORTANCE Staphylococcus aureus and other firmicutes evolved a specialized ESS (EsxA/ESAT-6-like secretion system) pathway for the secretion of small subsets of proteins lacking canonical signal peptides. The molecular mechanisms for ESSdependent secretion and their functional purpose are still unknown. We demonstrate here that S. aureus EssE functions as a membrane assembly platform for elements of the secretion machinery and their substrates. Furthermore, S. aureus EssEmediated secretion contributes to the production or the suppression of specific cytokines during host infection, thereby modifying immune responses toward this pathogen.

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“…STING is pivotal in the innate response to a variety of pathogens (15,50,53,54). This is largely through its ability to recognize cytosolic dsDNA and subsequently interact with TBK, facilitating phosphorylation of IRF-3 and induction of IFNdependent antiviral responses.…”

Section: Discussionmentioning

confidence: 99%

Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1

Parker

Murphy

Leib

2015

J Virol

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STING is a protein in the cytosolic DNA and cyclic dinucleotide sensor pathway that is critical for the initiation of innate responses to infection by various pathogens. Consistent with this, herpes simplex virus 1 (HSV-1) causes invariable and rapid lethality in STING-deficient (STING ؊/؊ ) mice following intravenous (i.v.) infection. In this study, using real-time bioluminescence imaging and virological assays, as expected, we demonstrated that STING ؊/؊ mice support greater replication and spread in ocular tissues and the nervous system. In contrast, they did not succumb to challenge via the corneal route even with high titers of a virus that was routinely lethal to STING ؊/؊ mice by the i.v. route. Corneally infected STING ؊/؊ mice also showed increased periocular disease and increased corneal and trigeminal ganglia titers, although there was no difference in brain titers. They also showed elevated expression of tumor necrosis factor alpha (TNF-␣) and CXCL9 relative to control mice but surprisingly modest changes in type I interferon expression. Finally, we also showed that HSV strains lacking the ability to counter autophagy and the PKR-driven antiviral state had near-wild-type virulence following intracerebral infection of STING ؊/؊ mice. Together, these data show that while STING is an important component of host resistance to HSV in the cornea, its previously shown immutable role in mediating host survival by the i.v. route was not recapitulated following a mucosal infection route. Furthermore, our data are consistent with the idea that HSV counters STING-mediated induction of the antiviral state and autophagy response, both of which are critical factors for survival following direct infection of the nervous system. Herpes simplex virus 1 (HSV-1) is a member of the Alphaherpesvirus subfamily with high seroprevalence in the human population (1). Infection at mucosal surfaces such as the mouth, eyes, and genitalia leads initially to lytic replication in mucosal epithelial cells, followed by infection of the innervating sensory neurons. HSV-1 then travels in a retrograde direction to the neuronal cell body, where it establishes latency. It is this ability to establish latency that renders HSV-1 refractory to clearance by the immune system, allowing persistence for the lifetime of the host. During periods of reactivation from latency, HSV-1 can travel in the anterograde direction to mucosal tissues, causing diseases ranging in severity from the common cold sore to herpetic stromal keratitis (HSK), the most common cause of infectious blindness in the developed world (2). HSV-1 can also gain entry into the central nervous system (CNS) to cause herpes simplex encephalitis (HSE) (3). HSE is a leading cause of viral encephalitis, further underscoring the significant morbidity and mortality associated with HSV-1.In order to effectively respond to infection, host cells have evolved a broad spectrum of sensors of evolutionarily conserved pathogen-associated molecular patterns (PAMPS) (for reviews, see refer...

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A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis

Cited by 223 publications

References 43 publications

Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response

Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response

EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection

Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1

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