Title: Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?
Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology. more »« less
Aryal, Uma K.; Hedrick, Victoria; Onyedibe, Kenneth Ikenna; Sobreira, Tiago Jose Paschoal; Sooreshjani, Moloud Aflaki; Wang, Modi; Gürsoy, Ulvi Kahraman; Sintim, Herman O.(
, PROTEOMICS – Clinical Applications)
Purpose
Cyclic guanosine monophosphate‐adenosine monophosphate and other bacterial‐derived cyclic di‐guanosine monophosphate or cyclic di‐adenosine monophosphate trigger innate immune responses through binding to stimulator of interferon genes (STING). Thus in chronic infection, such as in periodontitis, immune cells can be exposed to bacterial DNA and/or cyclic dinucleotides, potentially activating STING to cause inflammation. Thus far the cyclic GMP‐AMP synthase‐STING‐ TANK‐binding kinase 1 pathway has been well characterized but a global perspective of how the presence or lack of STING affect the proteome is lacking. The aim of this study is to identify macrophage proteins that are affected by STING.
Experimental Design
Proteins are extracted from a macrophage cell line harboring STING (RAW‐Blue ISG) as well as a STING knockout (STING KO) cell line (RAW‐Lucia ISG‐KO‐STING) and global proteomics analyses are performed.
Results
Proteins related to kinase and phosphatase signaling, spliceosome, terpenoid backbone biosynthesis, glycosylation, ubiquitination, and phagocytosis are affected by STING knock out.
Conclusions and Clinical Relevance
STING pathway in macrophages is related to the regulation of several proteins that are known as potent biomarkers of various cancers and autoimmune diseases. Moreover, the relation between STING and phagocytosis is demonstrated for the first time. Further validation studies will help identify molecules and pathways that may function as diagnostic or therapeutic targets.
BACKGROUND Diverse organisms, from archaea and bacteria to plants and humans, use receptor systems to recognize both pathogens and dangerous self-derived or environmentally derived stimuli. These intricate, well-coordinated immune systems, composed of innate and adaptive components, ensure host survival. In the late 20th century, researchers identified the Toll/interleukin-1/resistance gene (TIR) domain as an evolutionarily conserved component of animal and plant innate immune systems. Today, TIR-domain proteins are known to be broadly distributed across the tree of life. The TIR domain was first recognized as an adaptor for the assembly of macromolecular signaling complexes in mammalian innate immune pathways. Work on axon degeneration in animals—as well as on plant, archaeal, and bacterial immune systems—has uncovered additional enzymatic activities for TIR domains. ADVANCES Mammalian axons initiate a self-destruct program upon injury and during disease that is mediated by the sterile alpha and TIR motif containing 1 (SARM1) protein. The SARM1 TIR domain enzymatically consumes the essential metabolic cofactor nicotinamide adenine dinucleotide (NAD + ) to promote axonal death. Identification of the SARM1 NAD + -consuming enzyme (NADase) revealed that TIR domains can function as enzymes. Given the evolutionary conservation of TIR domains, studies investigated whether the SARM1 TIR NADase was also conserved. Indeed, bacteria, archaea, and plant TIR domains possess NADase activity. In prokaryotes, TIR NADase activity is found in an ancient antiphage immune system. In plants, identification of TIR NADase activity and linkage of TIR enzymatic products to downstream signaling components addressed the question of how nucleotide-binding, leucine-rich repeat (NLR) receptors trigger hypersensitive cell death during an immune response. Studies in plants show that their TIR domains can cleave nucleic acids and possess 2′,3′ cyclic adenosine monophosphate (2′,3′-cAMP) and 2′,3′ cyclic guanosine monophosphate (2′,3′-cGMP) synthetase activity that aids cell death programs in plant innate immunity. Thus, TIR domains constitute an ancient family of enzymes that are activated in immune and cell death pathways. OUTLOOK The discovery of TIR-domain enzyme activities carries implications for innate immunity and neurodegeneration. The identification of the SARM1 NADase defined a drug target for a wide number of neurodegenerative diseases that is being exploited in both preclinical and clinical studies. Hyperactive mutations in the SARM1 NADase have been discovered in amyotrophic lateral sclerosis (ALS) patients. Future work will seek to clarify the contribution of the SARM1 axon degeneration pathway to ALS pathogenesis. NAD + biology influences cellular processes from metabolism to DNA repair to aging. How TIR enzymes influence the NAD + metabolome and its associated pathways in bacteria, archaea, plants, and animals will be an exciting area for upcoming investigation. The discovery of the diversity of TIR enzymatic products is revealing signaling pathways across kingdoms. Discovery of TIR enzymatic function in plants and animals may yet inspire studies of enzymatic functions for Toll-like receptors in animals. We anticipate that cross-kingdom studies of TIR-domain function will guide interventions that will span the tree of life, from treating human neurodegenerative disorders and bacterial infections to preventing plant diseases. Conserved TIR-domain enzymatic activity. TIR-domain proteins from prokaryotes and eukaryotes cleave NAD + into nicotinamide (Nam), ADP-ribose (ADPR), cyclic ADP-ribose (cADPR), isomers of cyclic ADP-ribose (2′ or 3′cADPR), and related molecules [e.g., phosphoribosyl adenosine monophosphate (pRib-AMP)]. Plant TIR domains also possess a nuclease activity, can degrade DNA and RNA, and can function as a 2′,3′-cAMP or 2′,3′-cGMP synthetase. TIR enzymatic activity drives cell death and immune pathways across kingdoms. TIR activity can kill cells directly through NAD + depletion or indirectly using enzymatic products as signal molecules. The representative TIR domain structure shown here is Protein Data Bank ID 6O0Q. EDS1, enhanced disease susceptibility 1; ThsA, Thoeris A.
Human gingival fibroblasts (HGFs) recognize microbe-associated molecular patterns (MAMPs) and respond with inflammatory proteins. Simultaneous impacts of bacterial cyclic di-guanosine monophosphate (c-di-GMP), cyclic di-adenosine monophosphate (c-di-AMP), and lipopolysaccharide (LPS) on gingival keratinocytes have been previously demonstrated, but the effects of these MAMPs on other periodontal cell types, such as gingival fibroblasts, remain to be clarified. The present aim was to examine the independent and combined effects of these cyclic dinucleotides and LPS on interleukin (IL) and matrix metalloproteinase (MMP) response of HGFs. The cells were incubated with c-di-GMP and c-di-AMP, either in the presence or absence of Porphyromonas gingivalis LPS, for 2 h and 24 h. The levels of IL-8, -10, and -34, and MMP-1, -2, and -3 secreted were measured by the Luminex technique. LPS alone or together with cyclic dinucleotides elevated IL-8 levels. IL-10 levels were significantly increased in the presence of c-di-GMP and LPS after 2 h but disappeared after 24 h of incubation. Concurrent treatment of c-di-AMP and LPS elevated MMP-1 levels, whereas c-di-GMP with LPS suppressed MMP-2 levels but increased MMP-3 levels. To conclude, we produce evidence that cyclic dinucleotides interact with LPS-mediated early response of gingival fibroblasts, while late cellular response is mainly regulated by LPS.
Suboptimal maternal oral health during pregnancy is potentially associated with adverse birth outcomes and increased dental caries risks in children. This study aimed to assess the oral microbiome and immune response following an innovative clinical regimen, Prenatal Total Oral Rehabilitation (PTOR), that fully restores women’s oral health to a “disease-free status” before delivery.
Methods
This prospective cohort study assessed 15 pregnant women at baseline and 3 follow-up visits (1 week, 2 weeks, and 2 months) after receiving PTOR. The salivary and supragingival plaque microbiomes were analyzed using metagenomic sequencing. Multiplexed Luminex cytokine assays were performed to examine immune response following PTOR. The association between salivary immune markers and oral microbiome was further examined.
Results
PTOR was associated with a reduction of periodontal pathogens in plaque, for instance, a lower relative abundance ofTannerella forsythiaandTreponema denticolaat 2 weeks compared to the baseline (p < 0.05). The alpha diversity of plaque microbial community was significantly reduced at the 1-week follow-up (p < 0.05). Furthermore, we observed significant changes in theActinomyces defective-associated carbohydrate degradation pathway andStreptococcus Gordonii-associated fatty acid biosynthesis pathway. Two immune markers related to adverse birth outcomes significantly differed between baseline and follow-up. ITAC, negatively correlated with preeclampsia severity, significantly increased at 1-week follow-up; MCP-1, positively correlated with gestational age, was elevated at 1-week follow-up. Association modeling between immune markers and microbiome further revealed specific oral microorganisms that are potentially correlated with the host immune response.
Conclusions
PTOR is associated with alteration of the oral microbiome and immune response among a cohort of underserved US pregnant women. Future randomized clinical trials are warranted to comprehensively assess the impact of PTOR on maternal oral flora, birth outcomes, and their offspring’s oral health.
Elmanfi, Samira, Yilmaz, Mustafa, Ong, Wilson W., Yeboah, Kofi S., Sintim, Herman O., Gürsoy, Mervi, Könönen, Eija, and Gürsoy, Ulvi K. Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?. Retrieved from https://par.nsf.gov/biblio/10280665. Pathogens 10.6 Web. doi:10.3390/pathogens10060675.
Elmanfi, Samira, Yilmaz, Mustafa, Ong, Wilson W., Yeboah, Kofi S., Sintim, Herman O., Gürsoy, Mervi, Könönen, Eija, & Gürsoy, Ulvi K. Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?. Pathogens, 10 (6). Retrieved from https://par.nsf.gov/biblio/10280665. https://doi.org/10.3390/pathogens10060675
Elmanfi, Samira, Yilmaz, Mustafa, Ong, Wilson W., Yeboah, Kofi S., Sintim, Herman O., Gürsoy, Mervi, Könönen, Eija, and Gürsoy, Ulvi K.
"Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?". Pathogens 10 (6). Country unknown/Code not available. https://doi.org/10.3390/pathogens10060675.https://par.nsf.gov/biblio/10280665.
@article{osti_10280665,
place = {Country unknown/Code not available},
title = {Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?},
url = {https://par.nsf.gov/biblio/10280665},
DOI = {10.3390/pathogens10060675},
abstractNote = {Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.},
journal = {Pathogens},
volume = {10},
number = {6},
author = {Elmanfi, Samira and Yilmaz, Mustafa and Ong, Wilson W. and Yeboah, Kofi S. and Sintim, Herman O. and Gürsoy, Mervi and Könönen, Eija and Gürsoy, Ulvi K.},
editor = {null}
}
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