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Mrzdovnik N, Babič J, Lužnik D, Žigon D, Mrzdovnik M, Tavčar-Kalcher G, Tomič V, Prescott JF, Vengust M. The presence of acylated homoserine lactones and diffusible signal factor in bronchoalveolar lavage fluid from horses with clinical exacerbation of severe equine asthma. Res Vet Sci 2025; 192:105720. [PMID: 40441075 DOI: 10.1016/j.rvsc.2025.105720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 04/30/2025] [Accepted: 05/23/2025] [Indexed: 06/11/2025]
Abstract
Several bacteria associated with chronic lung pathology use quorum sensing (QS) signaling molecules to regulate their virulence in pure cultures and poly-microbial communities. Their excessive growth and biofilm formation in the respiratory tract increase the morbidity and mortality of inflammatory airway diseases in humans, such as chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (CF). In horses, severe equine asthma (SEA) has many parallels to these human diseases. We hypothesized that QS molecules associated with the most common biofilm-forming lung pathogens in humans (Pseudomonas aeruginosa, Stenotrophomonas maltophilia) may also be present in the lungs of horses with SEA. Samples of bronchoalveolar lavage fluid (BALf) were taken from twenty horses with exacerbated SEA. Microbiological cultures of the BALf samples were performed. Liquid chromatography coupled with tandem mass spectrometry was used to identify C4-HSL, C6-HSL, 3-oxo-C12-HSL and 11-methyl-2-dodecenoic acid, which are associated with the QS mechanisms of Pseudomonas aeruginosa and Stenotrophomonas maltophilia. Stenotrophomonas maltophilia was identified in three horses. Pseudomonas aeruginosa was not identified in any sample. The quorum sensing molecules C4-HSL, C6-HSL, 3-oxo-C12-HSL associated with biofilm formation by P. aeruginosa and 11-methyl-2-dodecenoic acid associated with biofilm formation by S. maltophila were not detected. It is unlikely that biofilm-forming bacterial strains associated with chronic lung disease in humans express similar virulence in SEA.
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Affiliation(s)
- Neza Mrzdovnik
- Veterinary Faculty, University of Ljubljana, Gerbičeva Ulica 60, 1000 Ljubljana, Slovenia
| | - Janja Babič
- Veterinary Faculty, University of Ljubljana, Gerbičeva Ulica 60, 1000 Ljubljana, Slovenia
| | - Dane Lužnik
- Laboratory for Respiratory Microbiology, University Clinic of Respiratory and Allergic Diseases Golnik, Golnik 36, 4204 Golnik, Slovenia
| | - Dušan Žigon
- Jozef Stefan Institute, Department of Environmental Sciences, Jamova cesta 39, 1000 Ljubljana, Slovenia
| | - Matic Mrzdovnik
- Veterinary Faculty, University of Ljubljana, Gerbičeva Ulica 60, 1000 Ljubljana, Slovenia
| | | | - Viktorija Tomič
- Laboratory for Respiratory Microbiology, University Clinic of Respiratory and Allergic Diseases Golnik, Golnik 36, 4204 Golnik, Slovenia
| | - John Francis Prescott
- Pathobiology, Ontario Veterinary College, University of Guelph, Gordon St & College Ave W, Guelph, ON N1G 2W1, Canada
| | - Modest Vengust
- Veterinary Faculty, University of Ljubljana, Gerbičeva Ulica 60, 1000 Ljubljana, Slovenia.
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Shin J, Ahn SH, Oh DJ. Pseudomonas aeruginosa N-3-Oxododecanoyl Homoserine Lactone Disrupts Endothelial Integrity by Activating the Angiopoietin-Tie System. Cell Biochem Biophys 2024; 82:1555-1566. [PMID: 38762714 DOI: 10.1007/s12013-024-01307-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2024] [Indexed: 05/20/2024]
Abstract
The activation of the angiopoietin (Angpt)-Tie system is linked to endothelial dysfunction during sepsis. Bacterial quorum-sensing molecules function as pathogen-associated molecular patterns. However, their impact on the endothelium and the Angpt-Tie system remains unclear. Therefore, this study investigated whether treatment with N-3-oxododecanoyl homoserine lactone (3OC12-HSL), a quorum-sensing molecule derived from Pseudomonas aeruginosa, impaired endothelial function in human umbilical vein endothelial cells. 3OC12-HSL treatment impaired tube formation even at sublethal concentrations, and immunocytochemistry analysis revealed that it seemed to reduce vascular endothelial-cadherin expression at the cell-cell interface. Upon assessing the mRNA expression patterns of genes associated with the Angpt-Tie axis, the expressions of Angpt2, Forkhead box protein O1, Tie1, and vascular endothelial growth factor 2 were found to be upregulated in the 3OC12-HSL-treated cells. Moreover, western blot analysis revealed that 3OC12-HSL treatment increased Angpt2 expression. A co-immunoprecipitation assay was conducted to assess the effect of 3OC12-HSL on the IQ motif containing GTPase activating protein 1 (IQGAP1) and Rac1 complex and the interaction between these proteins was consistently maintained regardless of 3OC12-HSL treatment. Next, recombinant human (rh)-Angpt1 was added to assess whether it modulated the effects of 3OC12-HSL treatment. rh-Angpt1 addition increased cellular viability, improved endothelial function, and reversed the overall patterns of mRNA and protein expression in endothelial cells treated with 3OC12-HSL. Additionally, it was related to the increased expression of phospho-Akt and the IQGAP1 and Rac1 complex. Collectively, our findings indicated that 3OC12-HSL from Pseudomonas aeruginosa can impair endothelial integrity via the activation of the Angpt-Tie axis, which appeared to be reversed by rh-Angpt1 treatment.
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Affiliation(s)
- Jungho Shin
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Sun Hee Ahn
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Dong-Jin Oh
- Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Goyang, South Korea.
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Quaye JA, Wood KE, Snelgrove C, Ouedraogo D, Gadda G. An active site mutation induces oxygen reactivity in D-arginine dehydrogenase: A case of superoxide diverting protons. J Biol Chem 2024; 300:107381. [PMID: 38762175 PMCID: PMC11193025 DOI: 10.1016/j.jbc.2024.107381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/09/2024] [Accepted: 05/13/2024] [Indexed: 05/20/2024] Open
Abstract
Enzymes are potent catalysts that increase biochemical reaction rates by several orders of magnitude. Flavoproteins are a class of enzymes whose classification relies on their ability to react with molecular oxygen (O2) during catalysis using ionizable active site residues. Pseudomonas aeruginosa D-arginine dehydrogenase (PaDADH) is a flavoprotein that oxidizes D-arginine for P. aeruginosa survival and biofilm formation. The crystal structure of PaDADH reveals the interaction of the glutamate 246 (E246) side chain with the substrate and at least three other active site residues, establishing a hydrogen bond network in the active site. Additionally, E246 likely ionizes to facilitate substrate binding during PaDADH catalysis. This study aimed to investigate how replacing the E246 residue with leucine affects PaDADH catalysis and its ability to react with O2 using steady-state kinetics coupled with pH profile studies. The data reveal a gain of O2 reactivity in the E246L variant, resulting in a reduced flavin semiquinone species and superoxide (O2•-) during substrate oxidation. The O2•- reacts with active site protons, resulting in an observed nonstoichiometric slope of 1.5 in the enzyme's log (kcat/Km) pH profile with D-arginine. Adding superoxide dismutase results in an observed correction of the slope to 1.0. This study demonstrates how O2•- can alter the slopes of limbs in the pH profiles of flavin-dependent enzymes and serves as a model for correcting nonstoichiometric slopes in elucidating reaction mechanisms of flavoproteins.
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Affiliation(s)
- Joanna A Quaye
- Department of Chemistry, Georgia State University, Atlanta, Georgia, USA
| | - Kendall E Wood
- Biology Department, Morehouse College, Atlanta, Georgia, USA
| | - Claire Snelgrove
- The Gwinnett School of Mathematics, Science, and Technology, Lawrenceville, Georgia, USA
| | - Daniel Ouedraogo
- Department of Chemistry, Georgia State University, Atlanta, Georgia, USA
| | - Giovanni Gadda
- Department of Chemistry, Georgia State University, Atlanta, Georgia, USA; Department of Biology, Georgia State University, Atlanta, Georgia, USA; Department of the Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA.
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Shvets Y, Khranovska N, Senchylo N, Ostapchenko D, Tymoshenko I, Onysenko S, Kobyliak N, Falalyeyeva T. Microbiota substances modulate dendritic cells activity: A critical view. Heliyon 2024; 10:e27125. [PMID: 38444507 PMCID: PMC10912702 DOI: 10.1016/j.heliyon.2024.e27125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/23/2024] [Accepted: 02/23/2024] [Indexed: 03/07/2024] Open
Abstract
Contemporary research in the field of microbiota shows that commensal bacteria influence physiological activity of different organs and systems of a human organism, such as brain, lungs, immune and metabolic systems. This influence is realized by various processes. One of them is trough modulation of immune mechanisms. Interactions between microbiota and the human immune system are known to be complex and ambiguous. Dendritic cells (DCs) are unique cells, which initiate the development and polarization of adaptive immune response. These cells also interconnect native and specific immune reactivity. A large set of biochemical signals from microbiota in the form of different microbiota associated molecular patterns (MAMPs) and bacterial metabolites that act locally and distantly in the human organism. As a result, commensal bacteria influence the maturity and activity of dendritic cells and affect the overall immune reactivity of the human organism. It then determines the response to pathogenic microorganisms, inflammation, associated with different pathological conditions and even affects the effectiveness of vaccination.
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Affiliation(s)
- Yuliia Shvets
- Taras Shevchenko National University of Kyiv, 64/13 Volodymyrska Str., Kyiv, Ukraine
| | - Natalia Khranovska
- National Cancer Institute of Ukraine, 33/43 Yuliia Zdanovska Str., Kyiv, Ukraine
| | - Natalia Senchylo
- Taras Shevchenko National University of Kyiv, 64/13 Volodymyrska Str., Kyiv, Ukraine
| | - Danylo Ostapchenko
- Taras Shevchenko National University of Kyiv, 64/13 Volodymyrska Str., Kyiv, Ukraine
| | - Iryna Tymoshenko
- Bogomolets National Medical University, 13 Shevchenka Blvd., Kyiv, Ukraine
| | - Svitlana Onysenko
- Taras Shevchenko National University of Kyiv, 64/13 Volodymyrska Str., Kyiv, Ukraine
| | - Nazarii Kobyliak
- Bogomolets National Medical University, 13 Shevchenka Blvd., Kyiv, Ukraine
- Medical Laboratory CSD, 22b Zhmerynska Str., Kyiv, Ukraine
| | - Tetyana Falalyeyeva
- Taras Shevchenko National University of Kyiv, 64/13 Volodymyrska Str., Kyiv, Ukraine
- Medical Laboratory CSD, 22b Zhmerynska Str., Kyiv, Ukraine
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Kushwaha A, Agarwal V. Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)-L-homoserine lactone mediates Ca +2 dysregulation, mitochondrial dysfunction, and apoptosis in human peripheral blood lymphocytes. Heliyon 2023; 9:e21462. [PMID: 38027911 PMCID: PMC10660034 DOI: 10.1016/j.heliyon.2023.e21462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 09/01/2023] [Accepted: 10/21/2023] [Indexed: 12/01/2023] Open
Abstract
N-(3-oxododecanoyl)-l-homoserine lactone is a Pseudomonas aeruginosa secreted quorum-sensing molecule that mediates the secretion of virulence factors, biofilm formation and plays a pivotal role in proliferation and persistence in the host. Apart from regulating quorum-sensing, the autoinducer signal molecule N-(3-oxododecanoyl)-l-homoserine lactone (3O-C12-HSL or C12) of a LasI-LasR circuit exhibits immunomodulatory effects and induces apoptosis in various host cells. However, the precise pathophysiological impact of C12 on human peripheral blood lymphocytes and its involvement in mitochondrial dysfunction remained largely elusive. In this study, the results suggest that C12 (100 μM) induces upregulation of cytosolic and mitochondrial Ca+2 levels and triggers mitochondrial dysfunction through the generation of mitochondrial ROS (mROS), disruption of mitochondrial transmembrane potential (ΔΨm), and opening of the mitochondrial permeability transition pore (mPTP). Additionally, it was observed that C12 induces phosphatidylserine (PS) exposure and promotes apoptosis in human peripheral blood lymphocytes. However, apoptosis plays a critical role in the homeostasis and development of lymphocytes, whereas enhanced apoptosis can cause immunodeficiency through cell loss. These findings suggest that C12 exerts a detrimental effect on lymphocytes by mediating mitochondrial dysfunction and enhancing apoptosis, which might further impair the effective mounting of immune responses during Pseudomonas aeruginosa-associated infections.
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Affiliation(s)
- Ankit Kushwaha
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, Uttar Pradesh, 211004, India
| | - Vishnu Agarwal
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, Uttar Pradesh, 211004, India
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Gerner E, Giraldo-Osorno PM, Johansson Loo A, Firdaus R, Ben Amara H, Werthén M, Palmquist A, Thomsen P, Omar O, Almqvist S, Trobos M. Targeting Pseudomonas aeruginosa quorum sensing with sodium salicylate modulates immune responses in vitro and in vivo. Front Cell Infect Microbiol 2023; 13:1183959. [PMID: 37614559 PMCID: PMC10442818 DOI: 10.3389/fcimb.2023.1183959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 07/18/2023] [Indexed: 08/25/2023] Open
Abstract
Introduction Chronic infections are a major clinical challenge in hard-to-heal wounds and implanted devices. Pseudomonas aeruginosa is a common causative pathogen that produces numerous virulence factors. Due to the increasing problem of antibiotic resistance, new alternative treatment strategies are needed. Quorum sensing (QS) is a bacterial communication system that regulates virulence and dampens inflammation, promoting bacterial survival. QS inhibition is a potent strategy to reduce bacterial virulence and alleviate the negative impact on host immune response. Aim This study investigates how secreted factors from P. aeruginosa PAO1, cultured in the presence or absence of the QS inhibitor sodium salicylate (NaSa), influence host immune response. Material and methods In vitro, THP-1 macrophages and neutrophil-like HL-60 cells were used. In vivo, discs of titanium were implanted in a subcutaneous rat model with local administration of P. aeruginosa culture supernatants. The host immune response to virulence factors contained in culture supernatants (+/-NaSa) was characterized through cell viability, migration, phagocytosis, gene expression, cytokine secretion, and histology. Results In vitro, P. aeruginosa supernatants from NaSa-containing cultures significantly increased THP-1 phagocytosis and HL-60 cell migration compared with untreated supernatants (-NaSa). Stimulation with NaSa-treated supernatants in vivo resulted in: (i) significantly increased immune cell infiltration and cell attachment to titanium discs; (ii) increased gene expression of IL-8, IL-10, ARG1, and iNOS, and (iii) increased GRO-α protein secretion and decreased IL-1β, IL-6, and IL-1α secretion, as compared with untreated supernatants. Conclusion In conclusion, treating P. aeruginosa with NaSa reduces the production of virulence factors and modulates major immune events, such as promoting phagocytosis and cell migration, and decreasing the secretion of several pro-inflammatory cytokines.
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Affiliation(s)
- Erik Gerner
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Centre for Antibiotic Resistance Research in Gothenburg (CARe), Gothenburg, Sweden
- Mölnlycke Health Care AB, Gothenburg, Sweden
| | - Paula Milena Giraldo-Osorno
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Centre for Antibiotic Resistance Research in Gothenburg (CARe), Gothenburg, Sweden
| | - Anna Johansson Loo
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Rininta Firdaus
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Centre for Antibiotic Resistance Research in Gothenburg (CARe), Gothenburg, Sweden
| | - Heithem Ben Amara
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria Werthén
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Centre for Antibiotic Resistance Research in Gothenburg (CARe), Gothenburg, Sweden
| | - Anders Palmquist
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Peter Thomsen
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Omar Omar
- Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | | | - Margarita Trobos
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Centre for Antibiotic Resistance Research in Gothenburg (CARe), Gothenburg, Sweden
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Souche A, Vandenesch F, Doléans-Jordheim A, Moreau K. How Staphylococcus aureus and Pseudomonas aeruginosa Hijack the Host Immune Response in the Context of Cystic Fibrosis. Int J Mol Sci 2023; 24:ijms24076609. [PMID: 37047579 PMCID: PMC10094765 DOI: 10.3390/ijms24076609] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Cystic fibrosis (CF) is a serious genetic disease that leads to premature death, mainly due to impaired lung function. CF lungs are characterized by ongoing inflammation, impaired immune response, and chronic bacterial colonization. Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) are the two most predominant bacterial agents of these chronic infections. Both can colonize the lungs for years by developing host adaptation strategies. In this review, we examined the mechanisms by which SA and PA adapt to the host immune response. They are able to bypass the physical integrity of airway epithelia, evade recognition, and then modulate host immune cell proliferation. They also modulate the immune response by regulating cytokine production and by counteracting the activity of neutrophils and other immune cells. Inhibition of the immune response benefits not only the species that implements them but also other species present, and we therefore discuss how these mechanisms can promote the establishment of coinfections in CF lungs.
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Affiliation(s)
- Aubin Souche
- Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
- Institut des Agents Infectieux, Hospices Civils de Lyon, 69002 Lyon, France
| | - François Vandenesch
- Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
- Institut des Agents Infectieux, Hospices Civils de Lyon, 69002 Lyon, France
| | - Anne Doléans-Jordheim
- Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
- Institut des Agents Infectieux, Hospices Civils de Lyon, 69002 Lyon, France
| | - Karen Moreau
- Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
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Marzhoseyni Z, Mousavi MJ, Saffari M, Ghotloo S. Immune escape strategies of Pseudomonas aeruginosa to establish chronic infection. Cytokine 2023; 163:156135. [PMID: 36724716 DOI: 10.1016/j.cyto.2023.156135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 01/08/2023] [Accepted: 01/12/2023] [Indexed: 02/02/2023]
Abstract
The infection caused by P. aeruginosa still is dangerous throughout the world. This is partly due to its immune escape mechanisms considerably increasing the bacterial survival in the host. By escape from recognition by TLRs, interference with complement system activation, phagocytosis inhibition, production of ROS, inhibition of NET production, interference with the generation of cytokines, inflammasome inhibition, reduced antigen presentation, interference with cellular and humoral immunity, and induction of apoptotic cell death and MDSc, P. aeruginosa breaks down the barriers of the immune system and causes lethal infections in the host. Recognition of other immune escape mechanisms of P. aeruginosa may provide a basis for the future treatment of the infection. This manuscript may provide new insights and information for the development of new strategies to combat P. aeruginosa infection. In the present manuscript, the escape mechanisms of P. aeruginosa against immune response would be reviewed.
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Affiliation(s)
- Zeynab Marzhoseyni
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Javad Mousavi
- Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mahmood Saffari
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Somayeh Ghotloo
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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9
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Laganenka L, Sourjik V. Bacterial Quorum Sensing Signals at the Interdomain Interface. Isr J Chem 2022. [DOI: 10.1002/ijch.202200080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
| | - Victor Sourjik
- Max Planck Institute for Terrestrial Microbiology and Center for Synthetic Microbiology (SYNMIKRO) Marburg Germany
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10
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Ogbechi J, Huang YS, Clanchy FIL, Pantazi E, Topping LM, Darlington LG, Williams RO, Stone TW. Modulation of immune cell function, IDO expression and kynurenine production by the quorum sensor 2-heptyl-3-hydroxy-4-quinolone (PQS). Front Immunol 2022; 13:1001956. [PMID: 36389710 PMCID: PMC9650388 DOI: 10.3389/fimmu.2022.1001956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 10/05/2022] [Indexed: 12/29/2023] Open
Abstract
Many invasive micro-organisms produce 'quorum sensor' molecules which regulate colony expansion and may modulate host immune responses. We have examined the ability of Pseudomonas Quorum Sensor (PQS) to influence cytokine expression under conditions of inflammatory stress. The administration of PQS in vivo to mice with collagen-induced arthritis (CIA) increased the severity of disease. Blood and inflamed paws from treated mice had fewer regulatory T cells (Tregs) but normal numbers of Th17 cells. However, PQS (1μM) treatment of antigen-stimulated lymph node cells from collagen-immunised mice in vitro inhibited the differentiation of CD4+IFNγ+ cells, with less effect on CD4+IL-17+ cells and no change in CD4+FoxP3+Tregs. PQS also inhibited T cell activation by anti-CD3/anti-CD28 antibodies. PQS reduced murine macrophage polarisation and inhibited expression of IL1B and IL6 genes in murine macrophages and human THP-1 cells. In human monocyte-derived macrophages, IDO1 gene, protein and enzyme activity were all inhibited by exposure to PQS. TNF gene expression was inhibited in THP-1 cells but not murine macrophages, while LPS-induced TNF protein release was increased by high PQS concentrations. PQS is known to have iron scavenging activity and its suppression of cytokine release was abrogated by iron supplementation. Unexpectedly, PQS decreased the expression of indoleamine-2, 3-dioxygenase genes (IDO1 and IDO2), IDO1 protein expression and enzyme activity in mouse and human macrophages. This is consistent with evidence that IDO1 inhibition or deletion exacerbates arthritis, while kynurenine reduces its severity. It is suggested that the inhibition of IDO1 and cytokine expression may contribute to the quorum sensor and invasive actions of PQS.
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Affiliation(s)
- Joy Ogbechi
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Yi-Shu Huang
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Felix I. L. Clanchy
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Eirini Pantazi
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Louise M. Topping
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | | | - Richard O. Williams
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Trevor W. Stone
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
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11
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Zhang Y, Ma N, Tan P, Ma X. Quorum sensing mediates gut bacterial communication and host-microbiota interaction. Crit Rev Food Sci Nutr 2022; 64:3751-3763. [PMID: 36239296 DOI: 10.1080/10408398.2022.2134981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Gut bacteria employ quorum sensing (QS) to coordinate their activities and communicate with one another, this process relies on the production, detection, and response to autoinducers, which are extracellular signaling molecules. In addition to synchronizing behavioral activities within the species, QS plays a crucial role in the gut host-microbiota interaction. In this review, an overview of classical QS systems is presented as well as the interspecies communication mediated by QS, and recent advances in the host-microbiota interaction mediated by QS. A greater knowledge of the communication network of gut microbiota is not only an opportunity and a challenge for developing nutritional and therapeutic strategies against bacterial illnesses, but also a means for improving gut health.
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Affiliation(s)
- Yucheng Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Ning Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Peng Tan
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
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12
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Kushwaha A, Verma RS, Agarwal V. Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl) homoserine lactone induces calcium signaling-dependent crosstalk between autophagy and apoptosis in human macrophages. Cell Signal 2022; 99:110441. [PMID: 35995303 DOI: 10.1016/j.cellsig.2022.110441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/09/2022] [Accepted: 08/15/2022] [Indexed: 01/18/2023]
Abstract
N-(3-oxododecanoyl) homoserine lactone (3oc) is a Pseudomonas aeruginosa secreted quorum-sensing signal molecule playing a crucial role in regulating quorum-sensing (QS) dependent biofilm formation and secretion of virulence factors. In addition to regulating quorum sensing, 3oc also plays an immunomodulatory role in the host by triggering regulated cell death in immune cells. The molecular mechanisms of 3oc in modulating macrophage pathologies are still unclear. In this study, we hypothesized the novel 3oc mediated crosstalk between autophagy and apoptosis at the interphase of calcium signaling in human macrophages. The study showed that 3oc induces mitochondrial dysfunction and apoptosis in macrophages through elevating cytosolic Ca+2 ([Ca+2]cyt) levels. Pre-treatment with the calcium-specific chelator BAPTA-AM effectively abrogated 3oc-induced apoptotic events, like mitochondrial ROS generation (mROS), mitochondrial membrane potential (MMP) drop, and phosphatidylserine (PS) exposure. The study also showed that 3oc induces autophagy, as assessed by the accumulation of autophagic vacuoles, induction of lysosomal biogenesis, upregulation of autophagy genes (LC3, BECLIN 1, STX17, PINK1, and TFEB), autophagosomes formation, and LC3 lipidation. Mechanistically, our study proved that 3oc-induced autophagy was [Ca+2]cyt dependent as BAPTA-AM pre-treatment reduced autophagosome formation. Furthermore, inhibiting autophagy with chloroquine attenuated 3oc-induced apoptosis, while autophagy induction with rapamycin aggravated cell death, suggesting autophagy plays a role in cell death in 3oc-treated macrophages. In conclusion, our findings indicate that 3oc activates a multifaceted death signaling by activating autophagy and apoptosis through Ca+2 signaling, and we propose pharmacological modulation of Ca+2 signaling may act as a combinatorial therapeutic intervention in patients with Pseudomonas aeruginosa-associated infections.
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Affiliation(s)
- Ankit Kushwaha
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, Uttar Pradesh 211004, India
| | - Rama Shanker Verma
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, Uttar Pradesh 211004, India
| | - Vishnu Agarwal
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, Uttar Pradesh 211004, India.
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13
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Coquant G, Aguanno D, Brot L, Belloir C, Delugeard J, Roger N, Pham HP, Briand L, Moreau M, de Sordi L, Carrière V, Grill JP, Thenet S, Seksik P. 3-oxo-C12:2-HSL, quorum sensing molecule from human intestinal microbiota, inhibits pro-inflammatory pathways in immune cells via bitter taste receptors. Sci Rep 2022; 12:9440. [PMID: 35676403 PMCID: PMC9177545 DOI: 10.1038/s41598-022-13451-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 05/13/2022] [Indexed: 12/26/2022] Open
Abstract
In the gut ecosystem, microorganisms regulate group behaviour and interplay with the host via a molecular system called quorum sensing (QS). The QS molecule 3-oxo-C12:2-HSL, first identified in human gut microbiota, exerts anti-inflammatory effects and could play a role in inflammatory bowel diseases where dysbiosis has been described. Our aim was to identify which signalling pathways are involved in this effect. We observed that 3-oxo-C12:2-HSL decreases expression of pro-inflammatory cytokines such as Interleukine-1β (- 35%) and Tumor Necrosis Factor-α (TNFα) (- 40%) by stimulated immune RAW264.7 cells and decreased TNF secretion by stimulated PBMC in a dose-dependent manner, between 25 to 100 µM. Transcriptomic analysis of RAW264.7 cells exposed to 3-oxo-C12:2-HSL, in a pro-inflammatory context, highlighted JAK-STAT, NF-κB and TFN signalling pathways and we confirmed that 3-oxo-C12:2-HSL inhibited JAK1 and STAT1 phosphorylation. We also showed through a screening assay that 3-oxo-C12:2-HSL interacted with several human bitter taste receptors. Its anti-inflammatory effect involved TAS2R38 as shown by pharmacologic inhibition and led to an increase in intracellular calcium levels. We thus unravelled the involvement of several cellular pathways in the anti-inflammatory effects exerted by the QS molecule 3-oxo-C12:2-HSL.
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Affiliation(s)
- Garance Coquant
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France
| | - Doriane Aguanno
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France
- EPHE, PSL University, 75014, Paris, France
| | - Loïc Brot
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France
| | - Christine Belloir
- Centre des Sciences du Goût et de l'Alimentation, UMR 1324 INRAE, UMR 6265 CNRS, University of Bourgogne Franche-Comté, 21000, Dijon, France
| | - Julie Delugeard
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France
| | - Nathalie Roger
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France
| | | | - Loïc Briand
- Centre des Sciences du Goût et de l'Alimentation, UMR 1324 INRAE, UMR 6265 CNRS, University of Bourgogne Franche-Comté, 21000, Dijon, France
| | - Marielle Moreau
- LVMH Recherche, Life Science Department, 45800, Saint Jean de Braye, France
| | - Luisa de Sordi
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France
| | - Véronique Carrière
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France
| | - Jean-Pierre Grill
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France
| | - Sophie Thenet
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France
- EPHE, PSL University, 75014, Paris, France
| | - Philippe Seksik
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, 75012, Paris, France.
- Paris Center for Microbiome Medicine (PaCeMM) FHU, APHP, Paris, Ile-de-France, France.
- Département de Gastroentérologie et Nutrition, APHP, Hôpital Saint-Antoine, Sorbonne Université, 75012, Paris, France.
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14
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Li K, Ly K, Mehta S, Braithwaite A. Importance of crosstalk between the microbiota and the neuroimmune system for tissue homeostasis. Clin Transl Immunology 2022; 11:e1394. [PMID: 35620584 PMCID: PMC9125509 DOI: 10.1002/cti2.1394] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 04/30/2022] [Accepted: 05/01/2022] [Indexed: 11/23/2022] Open
Abstract
The principal function of inflammation is cellular defence against ‘danger signals’ such as tissue injury and pathogen infection to maintain the homeostasis of the organism. The initiation and progression of inflammation are not autonomous as there is substantial evidence that inflammation is known to be strongly influenced by ‘neuroimmune crosstalk’, involving the production and expression of soluble signalling molecules that interact with cell surface receptors. In addition, microbiota have been found to be involved in the development and function of the nervous and immune systems and play an important role in health and disease. Herein, we provide an outline of the mechanisms of neuroimmune communication in the regulation of inflammation and immune response and then provide evidence for the involvement of microbiota in the development and functions of the host nervous and immune systems. It appears that the nervous and immune systems in multicellular organisms have co‐evolved with the microbiota, such that all components are in communication to maximise the ability of the organism to adapt to a wide range of environmental stresses to maintain or restore tissue homeostasis.
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Affiliation(s)
- Kunyu Li
- Department of Pathology Dunedin School of Medicine University of Otago Dunedin New Zealand
| | - Kevin Ly
- Department of Pathology Dunedin School of Medicine University of Otago Dunedin New Zealand
| | - Sunali Mehta
- Department of Pathology Dunedin School of Medicine University of Otago Dunedin New Zealand
| | - Antony Braithwaite
- Department of Pathology Dunedin School of Medicine University of Otago Dunedin New Zealand
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15
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Xiao Y, Zou H, Li J, Song T, Lv W, Wang W, Wang Z, Tao S. Impact of quorum sensing signaling molecules in gram-negative bacteria on host cells: current understanding and future perspectives. Gut Microbes 2022; 14:2039048. [PMID: 35188058 PMCID: PMC8865250 DOI: 10.1080/19490976.2022.2039048] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Quorum sensing is a molecular signaling-based communication mechanism in prokaryotes. In the basic mode, signaling molecules released by certain bacteria are sensed by intracellular receptors or membrane-bound receptors of other members in the community, leading to the collective isogenic signaling molecule synthesis and synchronized activities. This regulation is important for the symbiosis of the bacterium with the host, as well as virulence and biofilm formation. Notably, quorum sensing signaling molecules are not only able to control microbial community behavior but can likewise regulate the physiological status of host cells. Here, we provide a comprehensive review of the importance of quorum sensing signaling molecules in gram-negative bacteria in regulating host cell function and gut health, and suggest possible opportunities for application in combating human and animal diseases by blocking the pathways through which quorum sensing signaling molecules exert their functions.
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Affiliation(s)
- Yingping Xiao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products and Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Huicong Zou
- College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, China
| | - Jingjing Li
- College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, China
| | - Tongxing Song
- College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, China
| | - Wentao Lv
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products and Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Wen Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products and Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Zhenyu Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shiyu Tao
- College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, China,CONTACT Shiyu TaoCollege of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, 430070China
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16
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Choe H, Tatro JM, Hausman BS, Hujer KM, Marshall SH, Akkus O, Rather PN, Lee Z, Bonomo RA, Greenfield EM. Staphylococcus aureus and Acinetobacter baumannii Inhibit Osseointegration of Orthopedic Implants. Infect Immun 2022; 90:e0066921. [PMID: 35099267 PMCID: PMC8929340 DOI: 10.1128/iai.00669-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/06/2022] [Indexed: 11/20/2022] Open
Abstract
Bacterial infections routinely cause inflammation and thereby impair osseointegration of orthopedic implants. Acinetobacter spp., which cause osteomyelitis following trauma, on or off the battlefield, were, however, reported to cause neither osteomyelitis nor osteolysis in rodents. We therefore compared the effects of Acinetobacter strain M2 to those of Staphylococcus aureus in a murine implant infection model. Sterile implants and implants with adherent bacteria were inserted in the femur of mice. Bacterial burden, levels of proinflammatory cytokines, and osseointegration were measured. All infections were localized to the implant site. Infection with either S. aureus or Acinetobacter strain M2 increased the levels of proinflammatory cytokines and the chemokine CCL2 in the surrounding femurs, inhibited bone formation around the implant, and caused loss of the surrounding cortical bone, leading to decreases in both histomorphometric and biomechanical measures of osseointegration. Genetic deletion of TLR2 and TLR4 from the mice partially reduced the effects of Acinetobacter strain M2 on osseointegration but did not alter the effects of S. aureus. This is the first report that Acinetobacter spp. impair osseointegration of orthopedic implants in mice, and the murine model developed for this study will be useful for future efforts to clarify the mechanism of implant failure due to Acinetobacter spp. and to assess novel diagnostic tools or therapeutic agents.
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Affiliation(s)
- Hyonmin Choe
- Department of Orthopaedics, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Orthopaedics, Yokohama City University, Yokohama, Kanagawa, Japan
| | - Joscelyn M. Tatro
- Department of Orthopaedics, Case Western Reserve University, Cleveland, Ohio, USA
| | - Bryan S. Hausman
- Department of Orthopaedics, Case Western Reserve University, Cleveland, Ohio, USA
| | - Kristine M. Hujer
- CWRU–Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA
| | - Steve H. Marshall
- CWRU–Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA
| | - Ozan Akkus
- Department of Mechanical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Phillip N. Rather
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
- Research Service, Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA
| | - Zhenghong Lee
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Robert A. Bonomo
- CWRU–Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA
- Medical Service and GRECC, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Edward M. Greenfield
- Department of Orthopaedics, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
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17
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Coquant G, Aguanno D, Pham S, Grellier N, Thenet S, Carrière V, Grill JP, Seksik P. Gossip in the gut: Quorum sensing, a new player in the host-microbiota interactions. World J Gastroenterol 2021; 27:7247-7270. [PMID: 34876787 PMCID: PMC8611211 DOI: 10.3748/wjg.v27.i42.7247] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 08/17/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Bacteria are known to communicate with each other and regulate their activities in social networks by secreting and sensing signaling molecules called autoinducers, a process known as quorum sensing (QS). This is a growing area of research in which we are expanding our understanding of how bacteria collectively modify their behavior but are also involved in the crosstalk between the host and gut microbiome. This is particularly relevant in the case of pathologies associated with dysbiosis or disorders of the intestinal ecosystem. This review will examine the different QS systems and the evidence for their presence in the intestinal ecosystem. We will also provide clues on the role of QS molecules that may exert, directly or indirectly through their bacterial gossip, an influence on intestinal epithelial barrier function, intestinal inflammation, and intestinal carcinogenesis. This review aims to provide evidence on the role of QS molecules in gut physiology and the potential shared by this new player. Better understanding the impact of intestinal bacterial social networks and ultimately developing new therapeutic strategies to control intestinal disorders remains a challenge that needs to be addressed in the future.
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Affiliation(s)
- Garance Coquant
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
| | - Doriane Aguanno
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
- EPHE, PSL University, Paris 75014, France
| | - Sandrine Pham
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
- EPHE, PSL University, Paris 75014, France
| | - Nathan Grellier
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
| | - Sophie Thenet
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
- EPHE, PSL University, Paris 75014, France
| | - Véronique Carrière
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
| | - Jean-Pierre Grill
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
| | - Philippe Seksik
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
- Department of Gastroenterology and Nutrition, Saint-Antoine Hospital, APHP, Paris 75012, France
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18
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Pallikkuth S, Mendez R, Russell K, Sirupangi T, Kvistad D, Pahwa R, Villinger F, Banerjee S, Pahwa S. Age Associated Microbiome and Microbial Metabolites Modulation and Its Association With Systemic Inflammation in a Rhesus Macaque Model. Front Immunol 2021; 12:748397. [PMID: 34737748 PMCID: PMC8560971 DOI: 10.3389/fimmu.2021.748397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/28/2021] [Indexed: 01/19/2023] Open
Abstract
Aging is associated with declining immunity and inflammation as well as alterations in the gut microbiome with a decrease of beneficial microbes and increase in pathogenic ones. The aim of this study was to investigate the age associated gut microbiome in relation to immunologic and metabolic profile in a non-human primate (NHP) model. 12 geriatric (age 19-24 years) and 4 young adult (age 3-4 years) Rhesus macaques were included in this study. Immune cell subsets were characterized in peripheral blood mononuclear cells (PBMC) by flow cytometry and plasma cytokines levels were determined by bead based multiplex cytokine analysis. Stool samples were collected by ileal loop and investigated for microbiome analysis by shotgun metagenomics. Serum, gut microbial lysate, and microbe-free fecal extract were subjected to metabolomic analysis by mass-spectrometry. Our results showed that the gut microbiome in geriatric animals had higher abundance of Archaeal and Proteobacterial species and lower Firmicutes than the young adults. Highly abundant microbes in the geriatric animals showed a direct association with plasma biomarkers of inflammation and immune activation such as neopterin, CRP, TNF, IL-2, IL-6, IL-8 and IFN-γ. Significant enrichment of metabolites that contribute to inflammatory and cytotoxic pathways was observed in serum and feces of geriatric animals compared to the young adults. We conclude that aging NHP undergo immunosenescence and age associated alterations in the gut microbiome that has a distinct metabolic profile. Aging NHP can serve as a model for investigating the relationship of the gut microbiome to particular age-associated comorbidities and for strategies aimed at modulating the microbiome.
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Affiliation(s)
- Suresh Pallikkuth
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Roberto Mendez
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Kyle Russell
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Tirupataiah Sirupangi
- New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, United States
| | - Daniel Kvistad
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Rajendra Pahwa
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Francois Villinger
- New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, United States
| | - Santanu Banerjee
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States.,Miami Integrative Metabolomics Research Center (MIMRC), University of Miami Miller School of Medicine, Miami, FL, United States.,Center for Scientific Review, National Institute of Health, Bethesda, MD, United States
| | - Savita Pahwa
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
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19
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Shin J, Ahn SH, Kim SH, Oh DJ. N-3-oxododecanoyl homoserine lactone exacerbates endothelial cell death by inducing receptor-interacting protein kinase 1-dependent apoptosis. Am J Physiol Cell Physiol 2021; 321:C644-C653. [PMID: 34432536 DOI: 10.1152/ajpcell.00094.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Endothelial dysfunction is associated with the initiation of sepsis-associated organ failure. Bacterial quorum-sensing molecules act as pathogen-associated molecular patterns; however, the effects of quorum-sensing molecules on endothelial cells remain less understood. This study investigated the molecular mechanisms of quorum-sensing molecule-induced cell death and their interaction with lipopolysaccharide (LPS) in human umbilical vein endothelial cells. Endothelial cells were treated with N-3-oxododecanoyl homoserine lactone (3OC12-HSL) and LPS derived from Pseudomonas aeruginosa. Treatment with 3OC12-HSL reduced cell viability in a dose-dependent manner, and cotreatment with 3OC12-HSL and LPS enhanced cell death. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay revealed an increase in apoptotic cell death following 3OC12-HSL treatment; furthermore, cotreatment with 3OC12-HSL and LPS enhanced apoptosis. Western blotting revealed that treatment with 3OC12-HSL activated the receptor-interacting protein kinase 1 (RIPK1) pathway, leading to an increase in the levels of cleaved caspase 8 and 3. In addition, we found that treatment with necrostatin-1, an RIPK1 inhibitor, reduced cell death and ameliorated the activation of the RIPK1-dependent apoptotic pathway in 3OC12-HSL-treated cells. In conclusion, 3OC12-HSL induced endothelial cell apoptosis via the activation of the RIPK1 pathway, independent of LPS toxicity. Inhibition of RIPK1 may act as a therapeutic option for preserving endothelial cell integrity in patients with sepsis by disrupting the mechanism by which quorum-sensing molecules mediate their toxicity.
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Affiliation(s)
- Jungho Shin
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Sun Hee Ahn
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Su Hyun Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Dong-Jin Oh
- Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Goyang, South Korea
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20
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Tobita N, Tsuneto K, Ito S, Yamamoto T. Human TRPV1 and TRPA1 are receptors for bacterial quorum sensing molecules. J Biochem 2021; 170:775-785. [PMID: 34557892 DOI: 10.1093/jb/mvab099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/17/2021] [Indexed: 11/13/2022] Open
Abstract
In this study, we investigated the activation of TRPV1 and TRPA1 by N-acyl homoserine lactones, quorum sensing molecules produced by Gram-negative bacteria, and the inhibitory effect of TRPV1 and TRPA1 by autoinducing peptides, quorum sensing molecules produced by Gram-positive bacteria, using human embryonic kidney 293T cell lines stably expressing human TRPV1 and TRPA1, respectively. As a result, we found that some N-acyl homoserine lactones, such as N-octanoyl-L-homoserine lactone (C8-HSL), N-nonanoyl-L-homoserine lactone (C9-HSL) and N-decanoyl-L-homoserine lactone (C10-HSL) activated both TRPV1 and TRPA1. In addition, we clarified that some N-acyl homoserine lactones, for example, N-3-oxo-dodecanoyl-L-homoserine lactone (3-oxo-C12-HSL) only activated TRPV1, and N-acyl homoserine lactones having saturated short acyl chain, such as N-acetyl-L-homoserine lactone (C2-HSL) and N-butyryl-L-homoserine lactone (C4-HSL) only activated TRPA1, respectively. Furthermore, we found that an autoinducing peptide, simple linear peptide CHWPR, inhibited both TRPV1 and TRPA1, and peptide having thiolactone ring DICNAYF, thiolactone ring were formed between C3 to F7, strongly inhibited only the TRPV1. Although the specificity of TRPV1 and TRPA1 for quorum sensing molecules were different, these data suggest that both TRPV1 and TRPA1 would function as receptors for quorum sensing molecule produced by bacteria.
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Affiliation(s)
- Naoya Tobita
- Tobacco Science Research Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan
| | - Kana Tsuneto
- Tobacco Science Research Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan
| | - Shigeaki Ito
- Scientific Product Assessment Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan
| | - Takeshi Yamamoto
- Tobacco Science Research Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba, Yokohama, Kanagawa, 227-8512, Japan
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21
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Zhang X, Liu Y, Lu Y, Li S, Liu J, Zhang Y, Wang L, Li M, Luo Y, Zhang W, Chen C, Li Y. N-3-(oxododecanoyl)-l-homoserine lactone suppresses dendritic cell maturation by upregulating the long noncoding RNA NRIR. J Biosci 2021. [DOI: 10.1007/s12038-021-00186-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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22
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Woo K, Kim DH, Oh MH, Park HS, Choi CH. N-3-Hydroxy Dodecanoyl-DL-homoserine Lactone (OH-dDHL) Triggers Apoptosis of Bone Marrow-Derived Macrophages through the ER- and Mitochondria-Mediated Pathways. Int J Mol Sci 2021; 22:ijms22147565. [PMID: 34299184 PMCID: PMC8305837 DOI: 10.3390/ijms22147565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
Quorum sensing of Acinetobacter nosocomialis for cell-to-cell communication produces N-3-hydroxy dodecanoyl-DL-homoserine lactone (OH-dDHL) by an AnoR/I two-component system. However, OH-dDHL-driven apoptotic mechanisms in hosts have not been clearly defined. Here, we investigated the induction of apoptosis signaling pathways in bone marrow-derived macrophages treated with synthetic OH-dDHL. Moreover, the quorum-sensing system for virulence regulation was evaluated in vivo using wild-type and anoI-deletion mutant strains. OH-dDHL decreased the viability of macrophage and epithelial cells in dose- and time-dependent manners. OH-dDHL induced Ca2+ efflux and caspase-12 activation by ER stress transmembrane protein (IRE1 and ATF6a p50) aggregation and induced mitochondrial dysfunction through reactive oxygen species (ROS) production, which caused cytochrome c to leak. Pretreatment with a pan-caspase inhibitor reduced caspase-3, -8, and -9, which were activated by OH-dDHL. Pro-inflammatory cytokine and paraoxonase-2 (PON2) gene expression were increased by OH-dDHL. We showed that the anoI-deletion mutant strains have less intracellular invasion compared to the wild-type strain, and their virulence, such as colonization and dissemination, was decreased in vivo. Consequently, these findings revealed that OH-dDHL, as a virulence factor, contributes to bacterial infection and survival as well as the modification of host responses in the early stages of infection.
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Affiliation(s)
- Kyungho Woo
- Department of Microbiology and Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea; (K.W.); (D.H.K.); (H.S.P.)
| | - Dong Ho Kim
- Department of Microbiology and Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea; (K.W.); (D.H.K.); (H.S.P.)
| | - Man Hwan Oh
- Department of Microbiology, Dankook University, Cheonan 31116, Korea;
| | - Ho Sung Park
- Department of Microbiology and Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea; (K.W.); (D.H.K.); (H.S.P.)
| | - Chul Hee Choi
- Department of Microbiology and Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea; (K.W.); (D.H.K.); (H.S.P.)
- Correspondence: ; Tel.: +82-42-580-8246
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Yadav VK, Singh PK, Sharma D, Pandey H, Singh SK, Agarwal V. Autoinducer N-(3-oxododecanoyl)-l-homoserine lactone induces calcium and reactive oxygen species-mediated mitochondrial damage and apoptosis in blood platelets. Microb Pathog 2021; 154:104792. [PMID: 33636321 DOI: 10.1016/j.micpath.2021.104792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 02/05/2021] [Accepted: 02/05/2021] [Indexed: 01/08/2023]
Abstract
Acylated homoserine lactones (AHL) such as N-(3-oxododecanoyl)-l-homoserine lactone (3-oxo-C12 HSL) and N-butyryl-l-homoserine lactone (C4 HSL) are the most common autoinducer molecules in Pseudomonas aeruginosa. These AHL molecules not only regulate the expression of virulence factors but also have been shown to interfere with the host cell and modulate its functions. Recently, we reported that 3-oxo-C12 HSL but not C4 HSL causes cytosolic Ca2+ rise and ROS production in platelets. In this study, we examined the potential of AHLs to induce apoptosis in the human blood platelet. Our result showed that 3-oxo-C12 HSL but not C4 HSL causes phosphatidylserine (PS) exposure, mitochondrial dysfunction (mitochondrial transmembrane potential loss, and mitochondrial permeability transition pore (mPTP) formation). Besides, 3-oxo-C12 HSL also inhibited thrombin-induced platelet aggregation and clot retraction. The pretreatment of an intracellular calcium chelator BAPTA-AM or ROS inhibitor (DPI) significantly attenuated the 3-oxo-C12 HSL induced apoptotic characters such as PS exposure and mitochondrial dysfunctions. These data, including our previous findings, confirmed that 3-oxo-C12 HSL induced intracellular Ca2+ mediated ROS production results in the activation and subsequent induction of apoptotic features in platelets. Our results demonstrated that the 3-oxo-C12 HSL modulates the functions of platelets that may cause severe thrombotic complications in P. aeruginosa infected individuals.
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Affiliation(s)
- Vivek Kumar Yadav
- Department of Biotechnology Motilal Nehru National Institute of Technology, Allahabad, India
| | - Pradeep Kumar Singh
- Department of Biotechnology Motilal Nehru National Institute of Technology, Allahabad, India; Maharana Pratap Government Post Graduate College Gadarwara, Madhya Pradesh, India
| | - Deepmala Sharma
- Department of Mathematics National Institute of Technology, Raipur, India
| | - Himanshu Pandey
- Faculty of Sowa Rigpa Central Institute of Higher Tibetan Studies Sarnath, Varanasi, India
| | - Sunil Kumar Singh
- Department of Zoology, Central University of Punjab, Bathinda, India.
| | - Vishnu Agarwal
- Department of Biotechnology Motilal Nehru National Institute of Technology, Allahabad, India.
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Peyrottes A, Coquant G, Brot L, Rainteau D, Seksik P, Grill JP, Mallet JM. Anti-Inflammatory Effects of Analogues of N-Acyl Homoserine Lactones on Eukaryotic Cells. Int J Mol Sci 2020; 21:E9448. [PMID: 33322538 PMCID: PMC7764250 DOI: 10.3390/ijms21249448] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Since acyl-homoserine lactone (AHL) profiling has been described in the gut of healthy subjects and patients with inflammatory bowel disease (IBD), the potential effects of these molecules on host cells have raised interest in the medical community. In particular, natural AHLs such as the 3-oxo-C12-HSL exhibit anti-inflammatory properties. Our study aimed at finding stable 3-oxo-C12-HSL-derived analogues with improved anti-inflammatory effects on epithelial and immune cells. METHODS We first studied the stability and biological properties of the natural 3-oxo-C12-HSL on eukaryotic cells and a bacterial reporter strain. We then constructed and screened a library of 22 AHL-derived molecules. Anti-inflammatory effects were assessed by cytokine release in an epithelial cell model, Caco-2, and a murine macrophage cell line, RAW264.7, (respectively, IL-8 and IL-6) upon exposure to the molecule and after appropriate stimulation (respectively, TNF-α 50 ng/mL and IFN-γ 50 ng/mL, and LPS 10 ng/mL and IFN-γ 20 U/mL). RESULTS We found two molecules of interest with amplified anti-inflammatory effects on mammalian cells without bacterial-activating properties in the reporter strain. The molecules furthermore showed improved stability in biological medium compared to the native 3-oxo-C12-HSL. CONCLUSIONS We provide new bio-inspired AHL analogues with strong anti-inflammatory properties that will need further study from a therapeutic perspective.
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Affiliation(s)
- Agathe Peyrottes
- Laboratoire des Biomolécules (LBM), Département de chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 75005 Paris, France; (A.P.); (J.-M.M.)
- INSERM, Centre de Recherche Saint-Antoine, APHP, Hôpital Saint-Antoine, Microbiote Intestin et Inflammation, Sorbonne Université, 75005 Paris, France; (G.C.); (L.B.); (D.R.); (J.-P.G.)
| | - Garance Coquant
- INSERM, Centre de Recherche Saint-Antoine, APHP, Hôpital Saint-Antoine, Microbiote Intestin et Inflammation, Sorbonne Université, 75005 Paris, France; (G.C.); (L.B.); (D.R.); (J.-P.G.)
| | - Loïc Brot
- INSERM, Centre de Recherche Saint-Antoine, APHP, Hôpital Saint-Antoine, Microbiote Intestin et Inflammation, Sorbonne Université, 75005 Paris, France; (G.C.); (L.B.); (D.R.); (J.-P.G.)
| | - Dominique Rainteau
- INSERM, Centre de Recherche Saint-Antoine, APHP, Hôpital Saint-Antoine, Microbiote Intestin et Inflammation, Sorbonne Université, 75005 Paris, France; (G.C.); (L.B.); (D.R.); (J.-P.G.)
| | - Philippe Seksik
- INSERM, Centre de Recherche Saint-Antoine, APHP, Hôpital Saint-Antoine, Microbiote Intestin et Inflammation, Sorbonne Université, 75005 Paris, France; (G.C.); (L.B.); (D.R.); (J.-P.G.)
- Service de Gastroentérologie et Nutrition, Hôpital Saint-Antoine, APHP, 75012 Paris, France
| | - Jean-Pierre Grill
- INSERM, Centre de Recherche Saint-Antoine, APHP, Hôpital Saint-Antoine, Microbiote Intestin et Inflammation, Sorbonne Université, 75005 Paris, France; (G.C.); (L.B.); (D.R.); (J.-P.G.)
| | - Jean-Maurice Mallet
- Laboratoire des Biomolécules (LBM), Département de chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 75005 Paris, France; (A.P.); (J.-M.M.)
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25
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Pessione E. The Russian Doll Model: How Bacteria Shape Successful and Sustainable Inter-Kingdom Relationships. Front Microbiol 2020; 11:573759. [PMID: 33193180 PMCID: PMC7606975 DOI: 10.3389/fmicb.2020.573759] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/31/2020] [Indexed: 12/20/2022] Open
Abstract
Successful inter-kingdom relationships are based upon a dynamic balance between defense and cooperation. A certain degree of competition is necessary to guarantee life spread and development. On the other hand, cooperation is a powerful tool to ensure a long lasting adaptation to changing environmental conditions and to support evolution to a higher level of complexity. Bacteria can interact with their (true or potential) parasites (i.e., phages) and with their multicellular hosts. In these model interactions, bacteria learnt how to cope with their inner and outer host, transforming dangerous signals into opportunities and modulating responses in order to achieve an agreement that is beneficial for the overall participants, thus giving rise to a more complex "organism" or ecosystem. In this review, particular attention will be addressed to underline the minimal energy expenditure required for these successful interactions [e.g., moonlighting proteins, post-translational modifications (PTMs), and multitasking signals] and the systemic vision of these processes and ways of life in which the system proves to be more than the sum of the single components. Using an inside-out perspective, I will examine the possibility of multilevel interactions, in which viruses help bacteria to cope with the animal host and bacteria support the human immune system to counteract viral infection in a circular vision. In this sophisticated network, bacteria represent the precious link that insures system stability with relative low energy expenditure.
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Affiliation(s)
- Enrica Pessione
- Department of Life Sciences and Systems Biology, School of Nature Sciences, Università degli Studi di Torino, Turin, Italy
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26
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Shrestha A, Schikora A. AHL-priming for enhanced resistance as a tool in sustainable agriculture. FEMS Microbiol Ecol 2020; 96:5957528. [DOI: 10.1093/femsec/fiaa226] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/04/2020] [Indexed: 01/28/2023] Open
Abstract
ABSTRACTBacteria communicate with each other through quorum sensing (QS) molecules. N-acyl homoserine lactones (AHL) are one of the most extensively studied groups of QS molecules. The role of AHL molecules is not limited to interactions between bacteria; they also mediate inter-kingdom interaction with eukaryotes. The perception mechanism of AHL is well-known in bacteria and several proteins have been proposed as putative receptors in mammalian cells. However, not much is known about the perception of AHL in plants. Plants generally respond to short-chained AHL with modification in growth, while long-chained AHL induce AHL-priming for enhanced resistance. Since plants may host several AHL-producing bacteria and encounter multiple AHL at once, a coordinated response is required. The effect of the AHL combination showed relatively low impact on growth but enhanced resistance. Microbial consortium of bacterial strains that produce different AHL could therefore be an interesting approach in sustainable agriculture. Here, we review the molecular and genetical basis required for AHL perception. We highlight recent advances in the field of AHL-priming. We also discuss the recent discoveries on the impact of combination(s) of multiple AHL on crop plants and the possible use of this knowledge in sustainable agriculture.
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Affiliation(s)
- Abhishek Shrestha
- Julius Kühn Institute (JKI) - Federal Research Centre for Cultivated Plants, Institute for Epidemiology and Pathogen Diagnostics, Messeweg 11/12, 38104 Braunschweig, Germany
| | - Adam Schikora
- Julius Kühn Institute (JKI) - Federal Research Centre for Cultivated Plants, Institute for Epidemiology and Pathogen Diagnostics, Messeweg 11/12, 38104 Braunschweig, Germany
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27
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Coquant G, Grill JP, Seksik P. Impact of N-Acyl-Homoserine Lactones, Quorum Sensing Molecules, on Gut Immunity. Front Immunol 2020; 11:1827. [PMID: 32983093 PMCID: PMC7484616 DOI: 10.3389/fimmu.2020.01827] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/08/2020] [Indexed: 01/02/2023] Open
Abstract
Among numerous molecules found in the gut ecosystem, quorum sensing (QS) molecules represent an overlooked part that warrants highlighting. QS relies on the release of small molecules (auto-inducers) by bacteria that accumulate in the environment depending on bacterial cell density. These molecules not only are sensed by the microbial community but also interact with host cells and contribute to gut homeostasis. It therefore appears entirely appropriate to highlight the role of these molecules on the immune system in dysbiosis-associated inflammatory conditions where the bacterial populations are imbalanced. Here, we intent to focus on one of the most studied QS molecule family, namely, the type I auto-inducers represented by N-acyl-homoserine lactones (AHL). First described in pathogens such as Pseudomonas aeruginosa, these molecules have also been found in commensals and have been recently described within the complex microbial communities of the mammalian intestinal tract. In this mini-review, we will expound on this emergent field of research. We will first recall evidence on AHL structure, synthesis, receptors, and functions regarding interbacterial communication. Then, we will discuss their interactions with the host and particularly with agents of the innate and adaptive gut mucosa immunity. This will reveal how this new set of molecules, driven by microbial imbalance, can interact with inflammation pathways and could be a potential target in inflammatory bowel disease (IBD). The discovery of the general impact of these compounds on the detection of the bacterial quorum and on the dynamic and immune responses of eukaryotic cells opens up a new field of pathophysiology.
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Affiliation(s)
- Garance Coquant
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Hôpital Saint Antoine, Paris, France
| | - Jean-Pierre Grill
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Hôpital Saint Antoine, Paris, France
| | - Philippe Seksik
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Hôpital Saint Antoine, Paris, France
- Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
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28
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Guo J, Wang Z, Weng Y, Yuan H, Yoshida K, Ikegame M, Uchibe K, Kamioka H, Ochiai K, Okamura H, Qiu L. N-(3-oxododecanoyl)-homoserine lactone regulates osteoblast apoptosis and differentiation by mediating intracellular calcium. Cell Signal 2020; 75:109740. [PMID: 32818672 DOI: 10.1016/j.cellsig.2020.109740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 08/14/2020] [Accepted: 08/14/2020] [Indexed: 02/06/2023]
Abstract
Pseudomonas aeruginosa (P. aeruginosa) is associated with periapical periodontitis. The lesions are characterized by a disorder in osteoblast metabolism. Quorum sensing molecular N-(3-oxododecanoyl)-homoserine lactone (AHL) is secreted by P. aeruginosa and governs the expression of numerous virulence factors. AHL can trigger intracellular calcium ([Ca2+]i) fluctuations in many host cells. However, it is unclear whether AHL can regulate osteoblast metabolism by affecting [Ca2+]i changes or its spatial correlation. We explored AHL-induced apoptosis and differentiation in pre-osteoblastic MC3T3-E1 cells and evaluated [Ca2+]i mobilization using several extraction methods. The spatial distribution pattern of [Ca2+]i among cells was investigated by Moran's I, an index of spatial autocorrelation. We found that 30 μM and 50 μM AHL triggered opposing osteoblast fates. At 50 μM, AHL inhibited osteoblast differentiation by promoting mitochondrial-dependent apoptosis and negatively regulating osteogenic marker genes, including Runx2, Osterix, bone sialoprotein (Bsp), and osteocalcin (OCN). In contrast, prolonged treatment with 30 μM AHL promoted osteoblast differentiation concomitantly with cell apoptosis. The elevation of [Ca2+]i levels in osteoblasts treated with 50 μM AHL was spatially autocorrelated, while no such phenomenon was observed in 30 μM AHL-treated osteoblasts. The blocking of cell-to-cell spatial autocorrelation in the osteoblasts provoked by 50 μM AHL significantly inhibited apoptosis and partially restored differentiation. Our observations suggest that AHL affects the fate of osteoblasts (apoptosis and differentiation) by affecting the spatial correlation of [Ca2+]i changes. Thus, AHL acts as a double-edged sword for osteoblast function.
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Affiliation(s)
- Jiajie Guo
- School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China; Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Ziyi Wang
- Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Yao Weng
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Haoze Yuan
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kaya Yoshida
- Department of Oral Healthcare Education, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Mika Ikegame
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kenta Uchibe
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hiroshi Kamioka
- Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kazuhiko Ochiai
- Laboratory of Veterinary Hygiene, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Hirohiko Okamura
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
| | - Lihong Qiu
- School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China.
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29
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Josephson H, Ntzouni M, Skoglund C, Linder S, Turkina MV, Vikström E. Pseudomonas aeruginosa N-3-Oxo-Dodecanoyl-Homoserine Lactone Impacts Mitochondrial Networks Morphology, Energetics, and Proteome in Host Cells. Front Microbiol 2020; 11:1069. [PMID: 32523583 PMCID: PMC7261938 DOI: 10.3389/fmicb.2020.01069] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/29/2020] [Indexed: 01/10/2023] Open
Abstract
Mitochondria play crucial roles in cellular metabolism, signaling, longevity, and immune defense. Recent evidences have revealed that the host microbiota, including bacterial pathogens, impact mitochondrial behaviors and activities in the host. The pathogenicity of Pseudomonas aeruginosa requires quorum sensing (QS) cell-cell communication allowing the bacteria to sense population density and collectively control biofilm development, virulence traits, adaptation and interactions with the host. QS molecules, like N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C12-HSL), can also modulate the behavior of host cells, e.g., epithelial barrier properties and innate immune responses. Here, in two types of cells, fibroblasts and intestinal epithelial cells, we investigated whether and how P. aeruginosa 3O-C12-HSL impacts the morphology of mitochondrial networks and their energetic characteristics, using high-resolution transmission electron microscopy, fluorescence live-cell imaging, assay for mitochondrial bioenergetics, and quantitative mass spectrometry for mitoproteomics and bioinformatics. We found that 3O-C12-HSL induced fragmentation of mitochondria, disruption of cristae and inner membrane ultrastructure, altered major characteristics of respiration and energetics, and decreased mitochondrial membrane potential, and that there are distinct cell-type specific details of these effects. Moreover, this was mechanistically accompanied by differential expression of both common and cell-type specific arrays of components in the mitochondrial proteome involved in their structural organization, electron transport chain complexes and response to stress. We suggest that this effect of 3O-C12-HSL on mitochondria may represent one of the events in the interaction between P. aeruginosa and host mitochondria and may have an impact on the pathogens strategy to hijack host cell activities to support their own survival and spreading.
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Affiliation(s)
- Henrik Josephson
- Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Maria Ntzouni
- Core Facility, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Camilla Skoglund
- Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Stig Linder
- Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Maria V Turkina
- Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Elena Vikström
- Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
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30
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Guo J, Yoshida K, Ikegame M, Okamura H. Quorum sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone: An all-rounder in mammalian cell modification. J Oral Biosci 2020; 62:16-29. [DOI: 10.1016/j.job.2020.01.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 01/09/2020] [Accepted: 01/14/2020] [Indexed: 01/17/2023]
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31
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Small talk: chemical conversations with bacteria. CHEMTEXTS 2020. [DOI: 10.1007/s40828-020-0102-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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32
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He C, Lin HY, Wang CC, Zhang M, Lin YY, Huang FY, Lin YZ, Tan GH. Exopolysaccharide from Paecilomyces lilacinus modulates macrophage activities through the TLR4/NF‑κB/MAPK pathway. Mol Med Rep 2019; 20:4943-4952. [PMID: 31638207 PMCID: PMC6854591 DOI: 10.3892/mmr.2019.10746] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 09/26/2019] [Indexed: 01/02/2023] Open
Abstract
Multiple exopolysaccharides (EPSs) have been isolated from various organisms in extreme environments and have yielded a variety of activities. The present study evaluated the immunomodulatory capabilities of an EPS (termed PH‑EPS) derived from the fungus Paecilomyces lilacinus PH0016, which was isolated from a tropical and hyperhaline environment in southern China. The macrophage RAW 264.7 cell line was used to investigate the mechanism of PH‑EPS‑induced macrophage activation. The results indicated that RAW 264.7 macrophages were activated by PH‑EPS, in an effect slightly inferior to lipopolysaccharide (LPS), as evidenced by secretion of interleukin (IL)‑1β, tumor necrosis factor (TNF)‑α and nitric oxide (NO), and by significantly increased phagocytosis in the cells treated with PH‑EPS. Nuclear factor (NF)‑κB p65 was significantly translocated into the nucleus in the PH‑EPS‑treated cells. In addition, expression of inducible NO synthase (iNOS) and IκB‑α degradation were enhanced in PH‑EPS‑treated cells. The phosphorylation levels of p38, JNK and ERK were also significantly increased in the PH‑EPS‑treated cells. Furthermore, IL‑1β and TNF‑α production was markedly decreased in PH‑EPS‑treated cells when the mitogen‑activated protein kinase (MAPK) pathways were blocked by the inhibitor Dectin‑1 and by antibodies against Toll‑like receptor 4 (TLR4). The present results indicated that PH‑EPS from Paecilomyces lilacinus possessed the capability of activating RAW 264.7 cells via the TLR4/NF‑κB/MAPKs signaling pathway.
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Affiliation(s)
- Chao He
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, Hainan 571199, P.R. China
| | - Hai-Yan Lin
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, Hainan 571199, P.R. China
| | - Cai-Chun Wang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, Hainan 571199, P.R. China
| | - Ming Zhang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, Hainan 571199, P.R. China
| | - Ying-Ying Lin
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, Hainan 571199, P.R. China
| | - Feng-Ying Huang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, Hainan 571199, P.R. China
| | - Ying-Zi Lin
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, Hainan 571199, P.R. China
| | - Guang-Hong Tan
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, Hainan 571199, P.R. China
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Vivas W, Leonhardt I, Hünniger K, Häder A, Marolda A, Kurzai O. Multiple Signaling Pathways Involved in Human Dendritic Cell Maturation Are Affected by the Fungal Quorum-Sensing Molecule Farnesol. THE JOURNAL OF IMMUNOLOGY 2019; 203:2959-2969. [DOI: 10.4049/jimmunol.1900431] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 09/25/2019] [Indexed: 01/30/2023]
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Kufer TA, Creagh EM, Bryant CE. Guardians of the Cell: Effector-Triggered Immunity Steers Mammalian Immune Defense. Trends Immunol 2019; 40:939-951. [PMID: 31500957 DOI: 10.1016/j.it.2019.08.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 07/31/2019] [Accepted: 08/08/2019] [Indexed: 12/14/2022]
Abstract
The mammalian innate immune system deals with invading pathogens and stress by activating pattern-recognition receptors (PRRs) in the host. Initially proposed to be triggered by the discrimination of defined molecular signatures from pathogens rather than from self, it is now clear that PRRs can also be activated by endogenous ligands, bacterial metabolites and, following pathogen-induced alterations of cellular processes, changes in the F-actin cytoskeleton. These processes are collectively referred to as effector-triggered immunity (ETI). Here, we summarize the molecular and conceptual advances in our understanding of cell autonomous innate immune responses against bacterial pathogens, and discuss how classical activation of PRRs and ETI interplay to drive inflammatory responses.
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Affiliation(s)
- Thomas A Kufer
- Institute of Nutritional Medicine, Department of Immunology, University of Hohenheim, Stuttgart, Germany.
| | - Emma M Creagh
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
| | - Clare E Bryant
- Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
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Maurice NM, Bedi B, Sadikot RT. Pseudomonas aeruginosa Biofilms: Host Response and Clinical Implications in Lung Infections. Am J Respir Cell Mol Biol 2019; 58:428-439. [PMID: 29372812 DOI: 10.1165/rcmb.2017-0321tr] [Citation(s) in RCA: 237] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Pseudomonas aeruginosa is a major health challenge that causes recalcitrant multidrug-resistant infections, especially in immunocompromised and hospitalized patients. P. aeruginosa is an important cause of nosocomial and ventilator-associated pneumonia characterized by high prevalence and fatality rates. P. aeruginosa also causes chronic lung infections in individuals with cystic fibrosis. Multidrug- and totally drug-resistant strains of P. aeruginosa are increasing threats that contribute to high mortality in these patients. The pathogenesis of many P. aeruginosa infections depends on its ability to form biofilms, structured bacterial communities that can coat mucosal surfaces or invasive devices. These biofilms make conditions more favorable for bacterial persistence, as embedded bacteria are inherently more difficult to eradicate than planktonic bacteria. The molecular mechanisms that underlie P. aeruginosa biofilm pathogenesis and the host response to P. aeruginosa biofilms remain to be fully defined. However, it is known that biofilms offer protection from the host immune response and are also extremely recalcitrant to antimicrobial therapy. Therefore, development of novel therapeutic strategies specifically aimed at biofilms is urgently needed. Here, we review the host response, key clinical implications of P. aeruginosa biofilms, and novel therapeutic approaches to treat biofilms relevant to lung infections. Greater understanding of P. aeruginosa biofilms will elucidate novel avenues to improve outcomes for P. aeruginosa pulmonary infections.
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Affiliation(s)
- Nicholas M Maurice
- 1 Atlanta Veterans Affairs Medical Center, Decatur, Georgia; and.,2 Department of Medicine Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, Georgia
| | - Brahmchetna Bedi
- 1 Atlanta Veterans Affairs Medical Center, Decatur, Georgia; and
| | - Ruxana T Sadikot
- 1 Atlanta Veterans Affairs Medical Center, Decatur, Georgia; and.,2 Department of Medicine Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, Georgia
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Yadav VK, Singh PK, Sharma D, Singh SK, Agarwal V. Mechanism underlying N-(3-oxo-dodecanoyl)-L-homoserine lactone mediated intracellular calcium mobilization in human platelets. Blood Cells Mol Dis 2019; 79:102340. [PMID: 31207554 DOI: 10.1016/j.bcmd.2019.102340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/19/2019] [Accepted: 05/19/2019] [Indexed: 10/26/2022]
Abstract
Acyl-homoserine lactones (AHLs), are the key autoinducer molecules that mediate Pseudomonas aeruginosa associated quorum sensing. P. aeruginosa produces two types of AHLs; N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12 HSL) and N-butyryl-L-homoserine lactone (C4 HSL). AHLs are not only regulating the virulence gene of bacteria but also influence the host cell functions by interkingdom signaling. In this study, we explored the mechanism of AHLs induced calcium mobilization in human platelets. We found that 3-oxo-C12 HSL but not C4 HSL induces intracellular calcium release. 3-oxo-C12 HSL induced calcium mobilization was majorly contributed from the dense tubular system (DTS). Furthermore, 3-oxo-C12 HSL also stimulates the store-operated Ca2+ entry (SOCE) in platelet. Intracellular calcium rise was significantly lowered in rotenone, and bafilomycin pre-treated platelets suggesting partial involvement of mitochondria and acidic vacuoles. The significant effect of 3-oxo-C12 HSL on calcium mobilization can alter the platelet functions that might results in thrombotic disorders in individuals infected with P. aeruginosa.
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Affiliation(s)
- Vivek Kumar Yadav
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, India
| | - Pradeep Kumar Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, India
| | - Deepmala Sharma
- Department of Mathematics, National Institute of Technology, Raipur, India
| | - Sunil Kumar Singh
- Department of Animal Sciences, Central University of Punjab, Bathinda, India.
| | - Vishnu Agarwal
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, India.
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The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages. Mediators Inflamm 2019; 2019:3451461. [PMID: 31148944 PMCID: PMC6501241 DOI: 10.1155/2019/3451461] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 01/05/2019] [Accepted: 02/11/2019] [Indexed: 12/20/2022] Open
Abstract
Interleukin-10 (IL-10) is a key anti-inflammatory cytokine, secreted by macrophages and other immune cells to attenuate inflammation. Autocrine type I interferons (IFNs) largely mediate the delayed expression of IL-10 by LPS-stimulated macrophages. We have previously shown that IL-10 is synergistically expressed in macrophages following a costimulus of a TLR agonist and cAMP. We now show that the cAMP pathway directly upregulates IL-10 transcription and plays an important permissive and synergistic role in early, but not late, LPS-stimulated IL-10 mRNA and protein expression in mouse macrophages and in a mouse septic shock model. Our results suggest that the loss of synergism is not due to desensitization of the cAMP inducing signal, and it is not mediated by a positive crosstalk between the cAMP and type I IFN pathways. First, cAMP elevation in LPS-treated cells decreased the secretion of type I IFN. Second, autocrine/paracrine type I IFNs induce IL-10 promoter reporter activity only additively, but not synergistically, with the cAMP pathway. IL-10 promoter reporter activity was synergistically induced by cAMP elevation in macrophages stimulated by an agonist of either TLR4, TLR2/6, or TLR7, receptors which signal via MyD88, but not by an agonist of TLR3 which signals independently of MyD88. Moreover, MyD88 knockout largely reduced the synergistic IL-10 expression, indicating that MyD88 is required for the synergism displayed by LPS with cAMP. This report delineates the temporal regulation of early cAMP-accelerated vs. late type I IFN-dependent IL-10 transcription in LPS-stimulated murine macrophages that can limit inflammation at its onset.
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Song D, Meng J, Cheng J, Fan Z, Chen P, Ruan H, Tu Z, Kang N, Li N, Xu Y, Wang X, Shu F, Mu L, Li T, Ren W, Lin X, Zhu J, Fang X, Amrein MW, Wu W, Yan LT, Lü J, Xia T, Shi Y. Pseudomonas aeruginosa quorum-sensing metabolite induces host immune cell death through cell surface lipid domain dissolution. Nat Microbiol 2019; 4:97-111. [PMID: 30510173 DOI: 10.1038/s41564-018-0290-8] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 10/10/2018] [Indexed: 01/02/2023]
Abstract
Bacterial quorum-sensing autoinducers are small chemicals released to control microbial community behaviours. N-(3-oxo-dodecanoyl) homoserine lactone, the autoinducer of the Pseudomonas aeruginosa LasI-LasR circuitry, triggers significant cell death in lymphocytes. We found that this molecule is incorporated into the mammalian plasma membrane and induces dissolution of eukaryotic lipid domains. This event expels tumour necrosis factor receptor 1 into the disordered lipid phase for its spontaneous trimerization without its ligand and drives caspase 3-caspase 8-mediated apoptosis. In vivo, P. aeruginosa releases N-(3-oxo-dodecanoyl) homoserine lactone to suppress host immunity for its own better survival; conversely, blockage of caspases strongly reduces the severity of the infection. This work reveals an unknown communication method between microorganisms and the mammalian host and suggests interventions of bacterial infections by intercepting quorum-sensing signalling.
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Affiliation(s)
- Dingka Song
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Junchen Meng
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Jie Cheng
- Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
| | - Zheng Fan
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China
| | - Pengyu Chen
- Key Laboratory of Advanced Materials (MOE), Department of Chemical Engineering, Tsinghua University, Beijing, China
| | - Hefei Ruan
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Zhongyuan Tu
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Alberta, Canada
| | - Ning Kang
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Nan Li
- Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Ying Xu
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Xiaobo Wang
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Fei Shu
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Libing Mu
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Tengfei Li
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Wenran Ren
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Xin Lin
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Jun Zhu
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Microbiology, Nanjing Agricultural University, Nanjing, China
| | - Xiaohong Fang
- Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Matthias W Amrein
- Departments of Cell Biology and Anatomy, Snyder Institute, University of Calgary, Calgary, Alberta, Canada
| | - Weihui Wu
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China
| | - Li-Tang Yan
- Key Laboratory of Advanced Materials (MOE), Department of Chemical Engineering, Tsinghua University, Beijing, China
| | - Junhong Lü
- Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
| | - Tie Xia
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China
| | - Yan Shi
- Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China.
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Alberta, Canada.
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Updates on the pathogenicity status of Pseudomonas aeruginosa. Drug Discov Today 2019; 24:350-359. [DOI: 10.1016/j.drudis.2018.07.003] [Citation(s) in RCA: 222] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 07/03/2018] [Accepted: 07/16/2018] [Indexed: 01/06/2023]
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Turkina MV, Vikström E. Bacteria-Host Crosstalk: Sensing of the Quorum in the Context of Pseudomonas aeruginosa Infections. J Innate Immun 2018; 11:263-279. [PMID: 30428481 DOI: 10.1159/000494069] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 09/24/2018] [Indexed: 12/11/2022] Open
Abstract
Cell-to-cell signaling via small molecules is an essential process to coordinate behavior in single species within a community, and also across kingdoms. In this review, we discuss the quorum sensing (QS) systems used by the opportunistic pathogen Pseudomonas aeruginosa to sense bacterial population density and fitness, and regulate virulence, biofilm development, metabolite acquisition, and mammalian host defense. We also focus on the role of N-acylhomoserine lactone-dependent QS signaling in the modulation of innate immune responses connected together via calcium signaling, homeostasis, mitochondrial and cytoskeletal dynamics, and governing transcriptional and proteomic responses of host cells. A future perspective emphasizes the need for multidisciplinary efforts to bring current knowledge of QS into a more detailed understanding of the communication between bacteria and host, as well as into strategies to prevent and treat P. aeruginosa infections and reduce the rate of antibiotic resistance.
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Affiliation(s)
- Maria V Turkina
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Elena Vikström
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden,
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Ben Azzouz E, Boumaza A, Mezouar S, Bardou M, Carlini F, Picard C, Raoult D, Mège JL, Desnues B. Tropheryma whipplei Increases Expression of Human Leukocyte Antigen-G on Monocytes to Reduce Tumor Necrosis Factor and Promote Bacterial Replication. Gastroenterology 2018; 155:1553-1563. [PMID: 30076840 DOI: 10.1053/j.gastro.2018.07.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 07/10/2018] [Accepted: 07/27/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Infection with Tropheryma whipplei has a range of effects-some patients can be chronic carriers without developing any symptoms, whereas others can develop systemic Whipple disease, characterized by a lack a protective inflammatory immune response. Alterations in HLA-G function have been associated with several diseases. We investigated the role of HLA-G during T whipplei infection. METHODS Sera, total RNA, and genomic DNA were collected from peripheral blood from 22 patients with classic Whipple's disease, 19 patients with localized T whipplei infections, and 21 asymptomatic carriers. Levels of soluble HLA-G in sera were measured by enzyme-linked immuosorbent assay, and expressions of HLA-G and its isoforms were monitored by real-time polymerase chain reaction. HLA-G alleles were identified and compared with a population of voluntary bone marrow donors. Additionally, monocytes from healthy subjects were stimulated with T whipplei, and HLA-G expression was monitored by real-time polymerase chain reaction and flow cytometry. Bacterial replication was assessed by polymerase chain reaction in the presence of HLA-G or inhibitor of tumor necrosis factor (TNF) (etanercept). RESULTS HLA-G mRNAs and levels of soluble HLA-G were significantly increased in sera from patients with chronic T whipplei infection compared with sera from asymptomatic carriers and control individuals. No specific HLA-G haplotypes were associated with disease or T whipplei infection. However, T whipplei infection of monocytes induced expression of HLA-G, which was associated with reduced secretion of TNF compared with noninfected monocytes. A neutralizing antibody against HLA-G increased TNF secretion by monocytes in response to T whipplei, and a TNF inhibitor promoted bacteria replication. CONCLUSIONS Levels of HLA-G are increased in sera from patients with T whipplei tissue infections, associated with reduced production of TNF by monocytes. This might promote bacteria colonization in patients.
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Affiliation(s)
- Eya Ben Azzouz
- Aix Marseille Univ, IRD, APHM, MEPHI, IHU-Mediterranee Infection, Marseille, France
| | - Asma Boumaza
- Aix Marseille Univ, IRD, APHM, MEPHI, IHU-Mediterranee Infection, Marseille, France
| | - Soraya Mezouar
- Aix Marseille Univ, IRD, APHM, MEPHI, IHU-Mediterranee Infection, Marseille, France
| | - Matthieu Bardou
- Aix Marseille Univ, IRD, APHM, MEPHI, IHU-Mediterranee Infection, Marseille, France
| | | | - Christophe Picard
- Aix-Marseille Univ, CNRS, EFS, ADES UMR 7268, Marseille, France; Laboratoire d'immunogénétique, Établissement Français du Sang Provence Alpes Côte d'Azur Corse, Marseille, France
| | - Didier Raoult
- Aix Marseille Univ, IRD, APHM, MEPHI, IHU-Mediterranee Infection, Marseille, France
| | - Jean-Louis Mège
- Aix Marseille Univ, IRD, APHM, MEPHI, IHU-Mediterranee Infection, Marseille, France
| | - Benoit Desnues
- Aix Marseille Univ, IRD, APHM, MEPHI, IHU-Mediterranee Infection, Marseille, France.
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Landman C, Grill JP, Mallet JM, Marteau P, Humbert L, Le Balc’h E, Maubert MA, Perez K, Chaara W, Brot L, Beaugerie L, Sokol H, Thenet S, Rainteau D, Seksik P, Quévrain E, on behalf of the Saint Antoine IBD Network. Inter-kingdom effect on epithelial cells of the N-Acyl homoserine lactone 3-oxo-C12:2, a major quorum-sensing molecule from gut microbiota. PLoS One 2018; 13:e0202587. [PMID: 30157234 PMCID: PMC6114859 DOI: 10.1371/journal.pone.0202587] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS N-acyl homoserine lactones (AHLs), which are autoinducer quorum-sensing molecules involved in the bacterial communication network, also interact with eukaryotic cells. Searching for these molecules in the context of inflammatory bowel disease (IBD) is appealing. The aims of our study were to look for AHL molecules in faecal samples from healthy subjects (HS) and IBD patients to correlate AHL profiles with the microbiome and investigate the effect of AHLs of interest on epithelial cells. METHODS Using mass spectrometry, we characterised AHL profiles in faecal samples from HS (n = 26) and IBD patients in remission (n = 24) and in flare (n = 25) and correlated the presence of AHLs of interest with gut microbiota composition obtained by real-time qPCR and 16S sequencing. We synthesised AHLs of interest to test the inflammatory response after IL1β stimulation and paracellular permeability on Caco-2 cells. RESULTS We observed 14 different AHLs, among which one was prominent. This AHL corresponded to 3-oxo-C12:2 and was found significantly less frequently in IBD patients in flare (16%) and in remission (37.5%) versus HS (65.4%) (p = 0.001). The presence of 3-oxo-C12:2 was associated with significantly higher counts of Firmicutes, especially Faecalbacterium prausnitzii, and lower counts of Escherichia coli. In vitro, 3-oxo-C12:2 exerted an anti-inflammatory effect on Caco-2 cells. Interestingly, although 3-oxo-C12, the well-known AHL from Pseudomonas aeruginosa, increased paracellular permeability, 3-oxo-C12:2 did not. CONCLUSIONS We identified AHLs in the human gut microbiota and discovered a new and prominent AHL, 3-oxo-C12:2, which correlates with normobiosis and exerts a protective effect on gut epithelial cells.
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Affiliation(s)
- Cécilia Landman
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Jean-Pierre Grill
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Jean-Maurice Mallet
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Philippe Marteau
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Lydie Humbert
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Eric Le Balc’h
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Marie-Anne Maubert
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Kevin Perez
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Wahiba Chaara
- Sorbonne Universités, INSERM, Immunology-Immunopathology-Immunotherapy (i3), Paris, France
| | - Loic Brot
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Laurent Beaugerie
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Harry Sokol
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Sophie Thenet
- Sorbonne Universités, Centre de Recherche des Cordeliers, PSL University, EPHE, Paris, France
| | - Dominique Rainteau
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Philippe Seksik
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
| | - Elodie Quévrain
- Sorbonne Université, École normale supérieure, PSL University, CNRS, INSERM, APHP, Hôpital Saint-Antoine, Laboratoire des biomolécules, LBM, Paris, France
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Schirmer M, Franzosa EA, Lloyd-Price J, McIver LJ, Schwager R, Poon TW, Ananthakrishnan AN, Andrews E, Barron G, Lake K, Prasad M, Sauk J, Stevens B, Wilson RG, Braun J, Denson LA, Kugathasan S, McGovern DPB, Vlamakis H, Xavier RJ, Huttenhower C. Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat Microbiol 2018; 3:337-346. [PMID: 29311644 PMCID: PMC6131705 DOI: 10.1038/s41564-017-0089-z] [Citation(s) in RCA: 361] [Impact Index Per Article: 51.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 11/28/2017] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a group of chronic diseases of the digestive tract that affects millions of people worldwide. Genetic, environmental and microbial factors have been implicated in the onset and exacerbation of IBD. However, the mechanisms associating gut microbial dysbioses and aberrant immune responses remain largely unknown. The integrative Human Microbiome Project seeks to close these gaps by examining the dynamics of microbiome functionality in disease by profiling the gut microbiomes of >100 individuals sampled over a 1-year period. Here, we present the first results based on 78 paired faecal metagenomes and metatranscriptomes, and 222 additional metagenomes from 59 patients with Crohn's disease, 34 with ulcerative colitis and 24 non-IBD control patients. We demonstrate several cases in which measures of microbial gene expression in the inflamed gut can be informative relative to metagenomic profiles of functional potential. First, although many microbial organisms exhibited concordant DNA and RNA abundances, we also detected species-specific biases in transcriptional activity, revealing predominant transcription of pathways by individual microorganisms per host (for example, by Faecalibacterium prausnitzii). Thus, a loss of these organisms in disease may have more far-reaching consequences than suggested by their genomic abundances. Furthermore, we identified organisms that were metagenomically abundant but inactive or dormant in the gut with little or no expression (for example, Dialister invisus). Last, certain disease-specific microbial characteristics were more pronounced or only detectable at the transcript level, such as pathways that were predominantly expressed by different organisms in patients with IBD (for example, Bacteroides vulgatus and Alistipes putredinis). This provides potential insights into gut microbial pathway transcription that can vary over time, inducing phenotypical changes that are complementary to those linked to metagenomic abundances. The study's results highlight the strength of analysing both the activity and the presence of gut microorganisms to provide insight into the role of the microbiome in IBD.
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Affiliation(s)
- Melanie Schirmer
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Eric A Franzosa
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Jason Lloyd-Price
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Lauren J McIver
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Randall Schwager
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Tiffany W Poon
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Ashwin N Ananthakrishnan
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA
| | - Elizabeth Andrews
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA
| | - Gildardo Barron
- The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kathleen Lake
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Mahadev Prasad
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA, USA
| | - Jenny Sauk
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA
- Vatche and Tamar Manoukian Division of Digestive Disease, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Betsy Stevens
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA
| | - Robin G Wilson
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA
| | - Jonathan Braun
- Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Lee A Denson
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Subra Kugathasan
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA, USA
- Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Dermot P B McGovern
- The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Hera Vlamakis
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Ramnik J Xavier
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA.
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
- Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - Curtis Huttenhower
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
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Singh PK, Yadav VK, Kalia M, Dohare S, Sharma D, Agarwal V. Pseudomonas aeruginosa auto inducer3-oxo-C 12-HSL exerts bacteriostatic effect and inhibits Staphylococcus epidermidis biofilm. Microb Pathog 2017; 110:612-619. [PMID: 28804019 DOI: 10.1016/j.micpath.2017.08.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Revised: 07/25/2017] [Accepted: 08/08/2017] [Indexed: 11/18/2022]
Abstract
Pseudomonas aeruginosa has evolved the 3-oxo-C12-HSL and C4-HSL based quorum sensing system which is responsible for the regulation of various virulence factors and helps to dominates over other bacterial species. Staphylococcus epidermidis has frequently been reported with P. aeruginosa while the role of C4-HSL and 3-oxo-C12-HSL on the S. epidermidis had widely been unexplored, and as per our knowledge, this is the first report on the impact of C4-HSL and 3-oxo-C12-HSL overS. epidermidis growth and biofilm. We found that among the two AHL molecules; only 3-oxo-C12-HSL was able to exert a significant effect in all the experiments including growth and biofilm of S. epidermidis. 3-oxo-C12-HSL at 100 μM and 200 μM concentrations were able to initiate the apparent transient type of planktonic growth inhibition in S. epidermidis. Microscopic analysis and biofilm quantification assay showed the inhibitory effect of 3-oxo-C12-HSL against S. epidermidis biofilm, initial attachment, and EPS production. The study concludes that P. aeruginosa associated 3-oxo-C12-HSL exerts the inhibitory effect on S. epidermidis growth and biofilms and thus it may also help Pseudomonasto dominate under the co-infection conditions.
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Affiliation(s)
- Pradeep Kumar Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
| | - Vivek Kumar Yadav
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
| | - Manmohit Kalia
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
| | - Suhaga Dohare
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
| | - Deepmala Sharma
- Department of Mathematics, National Institute of Technology, Raipur, India
| | - Vishnu Agarwal
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India.
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45
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Bao L, Yu J, Zhong H, Huang D, Lu Q. Expression of toll-like receptors in T lymphocytes stimulated with N
-(3-oxododecanoyl)-L-homoserine lactone from Pseudomonas aeruginosa. APMIS 2017; 125:553-557. [PMID: 28418096 DOI: 10.1111/apm.12690] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Accepted: 01/30/2017] [Indexed: 12/24/2022]
Affiliation(s)
- Lei Bao
- Department of Neonatology; Children's Hospital; Chongqing Medical University; Ministry of Education Key Laboratory of Child Development and Disorders; Key Laboratory of Pediatrics in Chongqing; Chongqing China
| | - Jialin Yu
- Department of Neonatology; Children's Hospital; Chongqing Medical University; Ministry of Education Key Laboratory of Child Development and Disorders; Key Laboratory of Pediatrics in Chongqing; Chongqing China
| | - Haiying Zhong
- Department of Neonatology; Children's Hospital; Chongqing Medical University; Ministry of Education Key Laboratory of Child Development and Disorders; Key Laboratory of Pediatrics in Chongqing; Chongqing China
| | - Daochao Huang
- Department of Neonatology; Children's Hospital; Chongqing Medical University; Ministry of Education Key Laboratory of Child Development and Disorders; Key Laboratory of Pediatrics in Chongqing; Chongqing China
| | - Qi Lu
- Department of Neonatology; Children's Hospital; Chongqing Medical University; Ministry of Education Key Laboratory of Child Development and Disorders; Key Laboratory of Pediatrics in Chongqing; Chongqing China
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46
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Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol 2017; 18:2. [PMID: 28061847 PMCID: PMC5219689 DOI: 10.1186/s12865-016-0187-3] [Citation(s) in RCA: 468] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 12/20/2016] [Indexed: 12/12/2022] Open
Abstract
Background A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health. Methods This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA). Results In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction. Conclusions A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.
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Affiliation(s)
- Lan Lin
- Department of Bioengineering, Medical School, Southeast University, Nanjing, 210009, People's Republic of China.
| | - Jianqiong Zhang
- Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, 210009, People's Republic of China.
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47
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Janus MM, Crielaard W, Zaura E, Keijser BJ, Brandt BW, Krom BP. A novel compound to maintain a healthy oral plaque ecology in vitro. J Oral Microbiol 2016; 8:32513. [PMID: 27476444 PMCID: PMC4967710 DOI: 10.3402/jom.v8.32513] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 06/30/2016] [Accepted: 07/01/2016] [Indexed: 11/14/2022] Open
Abstract
Objective Dental caries is caused by prolonged episodes of low pH due to acid production by oral biofilms. Bacteria within such biofilms communicate via quorum sensing (QS). QS regulates several phenotypic biofilm parameters, such as biofilm formation and the production of virulence factors. In this study, we evaluated the effect of several QS modifiers on growth and the cariogenic potential of microcosm oral biofilms. Methods Biofilms were inoculated with pooled saliva and cultured in the presence of sucrose for 48 and 96 h. QS modifiers (or carrier controls) were continuously present. Lactic acid accumulation capacities were compared to evaluate the cariogenic potential of the biofilms. Subsequently, biofilm growth was quantified by determining colony forming unit counts (CFUs) and their ecology by 16S rDNA-based microbiome analyses. The minimal inhibitory concentration (MIC) for several Streptococcus spp. was determined using microbroth dilution. Results Of the tested QS modifiers only 3-oxo-N-(2-oxocyclohexyl)dodecanamide (3-Oxo-N) completely abolished lactic acid accumulation by the biofilms without affecting biofilm growth. This compound was selected for further investigation. The active range of 3-Oxo-N was 10–100 µM. The homologous QS molecule, acyl homoserine lactone C12, did not counteract the reduction in lactic acid accumulation, suggesting a mechanism other than QS inhibition. Microbial ecology analyses showed a reduction in the relative abundance of Streptococcus spp. in favor of the relative abundance of Veillonella spp. in the 3-Oxo-N exposed biofilms. The MIC of 3-Oxo-N for several streptococcal species varied between 8 and 32 µM. Conclusion 3-Oxo-N changes the ecological homeostasis of in vitro dental plaque. It reduces its cariogenic potential by minimizing lactic acid accumulation. Based on our in vitro data, 3-Oxo-N represents a promising compound in maintaining a healthy, non-cariogenic, ecology in in vivo dental plaque.
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Affiliation(s)
- Marleen M Janus
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, Amsterdam, The Netherlands.,Top Institute Food and Nutrition, Wageningen, The Netherlands
| | - Wim Crielaard
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, Amsterdam, The Netherlands.,Top Institute Food and Nutrition, Wageningen, The Netherlands
| | - Egija Zaura
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, Amsterdam, The Netherlands.,Top Institute Food and Nutrition, Wageningen, The Netherlands
| | - Bart J Keijser
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, Amsterdam, The Netherlands.,Top Institute Food and Nutrition, Wageningen, The Netherlands.,Microbiology and Systems Biology, TNO Earth, Environmental and Life Sciences, Zeist, The Netherlands
| | - Bernd W Brandt
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, Amsterdam, The Netherlands.,Top Institute Food and Nutrition, Wageningen, The Netherlands
| | - Bastiaan P Krom
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, Amsterdam, The Netherlands.,Top Institute Food and Nutrition, Wageningen, The Netherlands;
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48
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Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma. Infect Immun 2016; 84:1975-1985. [PMID: 27091928 DOI: 10.1128/iai.00164-16] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/11/2016] [Indexed: 02/06/2023] Open
Abstract
The pathogenic profile of Pseudomonas aeruginosa is related to its ability to secrete a variety of virulence factors. Quorum sensing (QS) is a mechanism wherein small diffusible molecules, specifically acyl-homoserine lactones, are produced by P. aeruginosa to promote virulence. We show here that macrophage clearance of P. aeruginosa (PAO1) is enhanced by activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ). Macrophages treated with a PPARγ agonist (pioglitazone) showed enhanced phagocytosis and bacterial killing of PAO1. It is known that PAO1 QS molecules are inactivated by PON-2. QS molecules are also known to inhibit activation of PPARγ by competitively binding PPARγ receptors. In accord with this observation, we found that infection of macrophages with PAO1 inhibited expression of PPARγ and PON-2. Mechanistically, we show that PPARγ induces macrophage paraoxonase 2 (PON-2), an enzyme that degrades QS molecules produced by P. aeruginosa Gene silencing studies confirmed that enhanced clearance of PAO1 in macrophages by PPARγ is PON-2 dependent. Further, we show that PPARγ agonists also enhance clearance of P. aeruginosa from lungs of mice infected with PAO1. Together, these data demonstrate that P. aeruginosa impairs the ability of host cells to mount an immune response by inhibiting PPARγ through secretion of QS molecules. These studies define a novel mechanism by which PPARγ contributes to the host immunoprotective effects during bacterial infection and suggest a role for PPARγ immunotherapy for P. aeruginosa infections.
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49
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Holm A, Magnusson KE, Vikström E. Pseudomonas aeruginosa N-3-oxo-dodecanoyl-homoserine Lactone Elicits Changes in Cell Volume, Morphology, and AQP9 Characteristics in Macrophages. Front Cell Infect Microbiol 2016; 6:32. [PMID: 27047801 PMCID: PMC4805602 DOI: 10.3389/fcimb.2016.00032] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 03/07/2016] [Indexed: 12/21/2022] Open
Abstract
Quorum sensing (QS) communication allows Pseudomonas aeruginosa to collectively control its population density and the production of biofilms and virulence factors. QS signal molecules, like N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C12-HSL), can also affect the behavior of host cells, e.g., by modulating the chemotaxis, migration, and phagocytosis of human leukocytes. Moreover, host water homeostasis and water channels aquaporins (AQP) are critical for cell morphology and functions as AQP interact indirectly with the cell cytoskeleton and signaling cascades. Here, we investigated how P. aeruginosa 3O-C12-HSL affects cell morphology, area, volume and AQP9 expression and distribution in human primary macrophages, using quantitative PCR, immunoblotting, two- and three-dimensional live imaging, confocal and nanoscale imaging. Thus, 3O-C12-HSL enhanced cell volume and area and induced cell shape and protrusion fluctuations in macrophages, processes tentatively driven by fluxes of water across cell membrane through AQP9, the predominant AQP in macrophages. Moreover, 3O-C12-HSL upregulated the expression of AQP9 at both the protein and mRNA levels. This was accompanied with enhanced whole cell AQP9 fluorescent intensity and redistribution of AQP9 to the leading and trailing regions, in parallel with increased cell area in the macrophages. Finally, nanoscopy imaging provided details on AQP9 dynamics and architecture within the lamellipodial area of 3O-C12-HSL-stimulated cells. We suggest that these novel events in the interaction between P. aeruginosa and macrophage may have an impact on the effectiveness of innate immune cells to fight bacteria, and thereby resolve the early stages of infections and inflammations.
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Affiliation(s)
- Angelika Holm
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University Linköping, Sweden
| | - Karl-Eric Magnusson
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University Linköping, Sweden
| | - Elena Vikström
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University Linköping, Sweden
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50
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Wu B, Capilato J, Pham MP, Walker J, Spur B, Rodriguez A, Perez LJ, Yin K. Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition. FASEB J 2016; 30:2400-10. [PMID: 26965685 DOI: 10.1096/fj.201500029r] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 02/29/2016] [Indexed: 12/13/2022]
Abstract
Bacterial infections can quickly turn into sepsis, with its attendant clinical sequelae of inflammation, tissue injury, and organ failure. Paradoxically, sustained inflammation in sepsis may lead to immune suppression, because of which the host is unable to clear the existing infection. Use of agents that suppress the inflammatory response may accelerate host immune suppression, whereas use of traditional antibiotics does not significantly affect inflammation. In this study, we investigated whether lipoxin A4 (LXA4), a specialized, proresolution lipid mediator, could increase neutrophil phagocytic activity as well as reduce bacterial virulence. Using the mouse cecal ligation and puncture (CLP) model of sepsis, the administration of LXA4 (7 μg/kg i.v.) 1 h after surgery increased neutrophil phagocytic ability and Fcγ receptor I (CD64) expression. Ex vivo studies have confirmed that the direct addition of LXA4 to CLP neutrophils increased phagocytic ability but not CD64 expression. LXA4 did not affect neutrophils taken from control mice in which CD64 expression was minimal. Taken together with in vivo data, these results suggest that LXA4 directly augments CD64-mediated neutrophil phagocytic ability but does not directly increase neutrophil CD64 expression. Bacterial communication and virulence is regulated by quorum sensing inducers. In Pseudomonas aeruginosa, virulence is induced with release of various virulence factors, by N-3-oxododecanolyl homoserine lactone binding to the quorum sensing receptor, LasR. We show that LXA4 is an inhibitor of LasR in P. aeruginosa and that it decreases the release of pyocyanin exotoxin. These results suggest that LXA4 has the novel dual properties of increasing host defense and decreasing pathogen virulence by inhibiting quorum sensing.-Wu, B., Capilato, J., Pham, M. P., Walker, J., Spur, B., Rodriguez, A., Perez, L. J., Yin, K. Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition.
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Affiliation(s)
- Benedict Wu
- Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA; and
| | - Joseph Capilato
- Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey, USA
| | - Michelle P Pham
- Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey, USA
| | - Jean Walker
- Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA; and
| | - Bernd Spur
- Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA; and
| | - Ana Rodriguez
- Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA; and
| | - Lark J Perez
- Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey, USA
| | - Kingsley Yin
- Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA; and
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