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1
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Yang J, Son Y, Kang M, Park W. AamA-mediated epigenetic control of genome-wide gene expression and phenotypic traits in Acinetobacter baumannii ATCC 17978. Microb Genom 2023; 9:mgen001093. [PMID: 37589545 PMCID: PMC10483419 DOI: 10.1099/mgen.0.001093] [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: 12/04/2022] [Accepted: 08/03/2023] [Indexed: 08/18/2023] Open
Abstract
Individual deletions of three genes encoding orphan DNA methyltransferases resulted in the occurrence of growth defect only in the aamA (encoding AcinetobacterAdenine Methylase A) mutant of A. baumannii strain ATCC 17978. Our single-molecule real-time sequencing-based methylome analysis revealed multiple AamA-mediated DNA methylation sites and proposed a potent census target motif (TTTRAATTYAAA). Loss of Dam led to modulation of genome-wide gene expression, and several Dam-target sites including the promoter region of the trmD operon (rpsP, rimM, trmD, and rplS) were identified through our methylome and transcriptome analyses. AamA methylation also appeared to control the expression of many genes linked to membrane functions (lolAB, lpxO), replication (dnaA) and protein synthesis (trmD operon) in the strain ATCC 17978. Interestingly, cellular resistance against several antibiotics and ethidium bromide through functions of efflux pumps diminished in the absence of the aamA gene, and the complementation of aamA gene restored the wild-type phenotypes. Other tested phenotypic traits such as outer-membrane vesicle production, biofilm formation and virulence were also affected in the aamA mutant. Collectively, our data indicated that epigenetic regulation through AamA-mediated DNA methylation of novel target sites mostly in the regulatory regions could contribute significantly to changes in multiple phenotypic traits in A. baumannii ATCC 17978.
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Affiliation(s)
- Jihye Yang
- Laboratory of Molecular Environmental Microbiology, Department of Environmental Science and Ecological Engineering, Korea University, Seoul, Republic of Korea
| | - Yongjun Son
- Laboratory of Molecular Environmental Microbiology, Department of Environmental Science and Ecological Engineering, Korea University, Seoul, Republic of Korea
| | - Mingyeong Kang
- Laboratory of Molecular Environmental Microbiology, Department of Environmental Science and Ecological Engineering, Korea University, Seoul, Republic of Korea
| | - Woojun Park
- Laboratory of Molecular Environmental Microbiology, Department of Environmental Science and Ecological Engineering, Korea University, Seoul, Republic of Korea
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2
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Wang X, Yu D, Chen L. Antimicrobial resistance and mechanisms of epigenetic regulation. Front Cell Infect Microbiol 2023; 13:1199646. [PMID: 37389209 PMCID: PMC10306973 DOI: 10.3389/fcimb.2023.1199646] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 05/26/2023] [Indexed: 07/01/2023] Open
Abstract
The rampant use of antibiotics in animal husbandry, farming and clinical disease treatment has led to a significant issue with pathogen resistance worldwide over the past decades. The classical mechanisms of resistance typically investigate antimicrobial resistance resulting from natural resistance, mutation, gene transfer and other processes. However, the emergence and development of bacterial resistance cannot be fully explained from a genetic and biochemical standpoint. Evolution necessitates phenotypic variation, selection, and inheritance. There are indications that epigenetic modifications also play a role in antimicrobial resistance. This review will specifically focus on the effects of DNA modification, histone modification, rRNA methylation and the regulation of non-coding RNAs expression on antimicrobial resistance. In particular, we highlight critical work that how DNA methyltransferases and non-coding RNAs act as transcriptional regulators that allow bacteria to rapidly adapt to environmental changes and control their gene expressions to resist antibiotic stress. Additionally, it will delve into how Nucleolar-associated proteins in bacteria perform histone functions akin to eukaryotes. Epigenetics, a non-classical regulatory mechanism of bacterial resistance, may offer new avenues for antibiotic target selection and the development of novel antibiotics.
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Affiliation(s)
- Xinrui Wang
- Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
- National Health Commission Key Laboratory of Technical Evaluation of Fertility Regulation for Non-Human Primate, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, China
| | - Donghong Yu
- Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
- National Health Commission Key Laboratory of Technical Evaluation of Fertility Regulation for Non-Human Primate, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, China
| | - Lu Chen
- Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
- National Health Commission Key Laboratory of Technical Evaluation of Fertility Regulation for Non-Human Primate, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, China
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3
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Nahar N, Tram G, Jen FEC, Phillips ZN, Weinert L, Bossé J, Jabbari J, Gouil Q, Du MM, Ritchie M, Bowden R, Langford P, Tucker A, Jennings M, Turni C, Blackall P, Atack J. Actinobacillus pleuropneumoniae encodes multiple phase-variable DNA methyltransferases that control distinct phasevarions. Nucleic Acids Res 2023; 51:3240-3260. [PMID: 36840716 PMCID: PMC10123105 DOI: 10.1093/nar/gkad091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/26/2023] Open
Abstract
Actinobacillus pleuropneumoniae is the cause of porcine pleuropneumonia, a severe respiratory tract infection that is responsible for major economic losses to the swine industry. Many host-adapted bacterial pathogens encode systems known as phasevarions (phase-variable regulons). Phasevarions result from variable expression of cytoplasmic DNA methyltransferases. Variable expression results in genome-wide methylation differences within a bacterial population, leading to altered expression of multiple genes via epigenetic mechanisms. Our examination of a diverse population of A. pleuropneumoniae strains determined that Type I and Type III DNA methyltransferases with the hallmarks of phase variation were present in this species. We demonstrate that phase variation is occurring in these methyltransferases, and show associations between particular Type III methyltransferase alleles and serovar. Using Pacific BioSciences Single-Molecule, Real-Time (SMRT) sequencing and Oxford Nanopore sequencing, we demonstrate the presence of the first ever characterised phase-variable, cytosine-specific Type III DNA methyltransferase. Phase variation of distinct Type III DNA methyltransferase in A. pleuropneumoniae results in the regulation of distinct phasevarions, and in multiple phenotypic differences relevant to pathobiology. Our characterisation of these newly described phasevarions in A. pleuropneumoniae will aid in the selection of stably expressed antigens, and direct and inform development of a rationally designed subunit vaccine against this major veterinary pathogen.
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Affiliation(s)
- Nusrat Nahar
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Greg Tram
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Freda E-C Jen
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Zachary N Phillips
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Lucy A Weinert
- Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK
| | - Janine T Bossé
- Section of Paediatric Infectious Disease, Imperial College London, St Mary's Campus, London W2 1PG, UK
| | - Jafar S Jabbari
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Quentin Gouil
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Mei R M Du
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - Matthew E Ritchie
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Rory Bowden
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Paul R Langford
- Section of Paediatric Infectious Disease, Imperial College London, St Mary's Campus, London W2 1PG, UK
| | - Alexander W Tucker
- Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK
| | - Michael P Jennings
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Conny Turni
- Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, St. Lucia, Queensland 4072, Australia
| | - Patrick J Blackall
- Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, St. Lucia, Queensland 4072, Australia
| | - John M Atack
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
- School of Environment and Science, Griffith University, Gold Coast, Queensland 4222, Australia
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4
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Vital JS, Tanoeiro L, Lopes-Oliveira R, Vale FF. Biomarker Characterization and Prediction of Virulence and Antibiotic Resistance from Helicobacter pylori Next Generation Sequencing Data. Biomolecules 2022; 12:691. [PMID: 35625618 PMCID: PMC9138241 DOI: 10.3390/biom12050691] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/02/2022] [Accepted: 05/07/2022] [Indexed: 02/06/2023] Open
Abstract
The Gram-negative bacterium Helicobacter pylori colonizes c.a. 50% of human stomachs worldwide and is the major risk factor for gastric adenocarcinoma. Its high genetic variability makes it difficult to identify biomarkers of early stages of infection that can reliably predict its outcome. Moreover, the increasing antibiotic resistance found in H. pylori defies therapy, constituting a major human health problem. Here, we review H. pylori virulence factors and genes involved in antibiotic resistance, as well as the technologies currently used for their detection. Furthermore, we show that next generation sequencing may lead to faster characterization of virulence factors and prediction of the antibiotic resistance profile, thus contributing to personalized treatment and management of H. pylori-associated infections. With this new approach, more and permanent data will be generated at a lower cost, opening the future to new applications for H. pylori biomarker identification and antibiotic resistance prediction.
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Affiliation(s)
- Joana S. Vital
- Pathogen Genome Bioinformatics and Computational Biology, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal; (J.S.V.); (L.T.); (R.L.-O.)
| | - Luís Tanoeiro
- Pathogen Genome Bioinformatics and Computational Biology, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal; (J.S.V.); (L.T.); (R.L.-O.)
| | - Ricardo Lopes-Oliveira
- Pathogen Genome Bioinformatics and Computational Biology, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal; (J.S.V.); (L.T.); (R.L.-O.)
| | - Filipa F. Vale
- Pathogen Genome Bioinformatics and Computational Biology, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal; (J.S.V.); (L.T.); (R.L.-O.)
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5
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Ben-Assa N, Coyne MJ, Fomenkov A, Livny J, Robins WP, Muniesa M, Carey V, Carasso S, Gefen T, Jofre J, Roberts RJ, Comstock LE, Geva-Zatorsky N. Analysis of a phase-variable restriction modification system of the human gut symbiont Bacteroides fragilis. Nucleic Acids Res 2020; 48:11040-11053. [PMID: 33045731 PMCID: PMC7641763 DOI: 10.1093/nar/gkaa824] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 09/10/2020] [Accepted: 10/06/2020] [Indexed: 11/28/2022] Open
Abstract
The genomes of gut Bacteroidales contain numerous invertible regions, many of which contain promoters that dictate phase-variable synthesis of surface molecules such as polysaccharides, fimbriae, and outer surface proteins. Here, we characterize a different type of phase-variable system of Bacteroides fragilis, a Type I restriction modification system (R-M). We show that reversible DNA inversions within this R-M locus leads to the generation of eight specificity proteins with distinct recognition sites. In vitro grown bacteria have a different proportion of specificity gene combinations at the expression locus than bacteria isolated from the mammalian gut. By creating mutants, each able to produce only one specificity protein from this region, we identified the R-M recognition sites of four of these S-proteins using SMRT sequencing. Transcriptome analysis revealed that the locked specificity mutants, whether grown in vitro or isolated from the mammalian gut, have distinct transcriptional profiles, likely creating different phenotypes, one of which was confirmed. Genomic analyses of diverse strains of Bacteroidetes from both host-associated and environmental sources reveal the ubiquity of phase-variable R-M systems in this phylum.
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Affiliation(s)
- Nadav Ben-Assa
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Technion Integrated Cancer Center (TICC), Haifa, 3525422 Israel
| | - Michael J Coyne
- Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | | | - Jonathan Livny
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - William P Robins
- Department of Microbiology, Harvard Medical School, Boston, 02115, MA, USA
| | - Maite Muniesa
- Department of Genetics, Microbiology and Statistics, School of Biology, University of Barcelona, Avda. Diagonal 643 08028 Barcelona Spain
| | - Vincent Carey
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Shaqed Carasso
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Technion Integrated Cancer Center (TICC), Haifa, 3525422 Israel
| | - Tal Gefen
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Technion Integrated Cancer Center (TICC), Haifa, 3525422 Israel
| | - Juan Jofre
- Department of Genetics, Microbiology and Statistics, School of Biology, University of Barcelona, Avda. Diagonal 643 08028 Barcelona Spain
| | | | - Laurie E Comstock
- Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Naama Geva-Zatorsky
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Technion Integrated Cancer Center (TICC), Haifa, 3525422 Israel.,Canadian Institute for Advanced Research (CIFAR) Azrieli Global Scholar, MaRS Centre, West Tower 661 University Ave., Suite 505 Toronto, ON M5G 1M1, Canada
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6
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Seib KL, Srikhanta YN, Atack JM, Jennings MP. Epigenetic Regulation of Virulence and Immunoevasion by Phase-Variable Restriction-Modification Systems in Bacterial Pathogens. Annu Rev Microbiol 2020; 74:655-671. [PMID: 32689914 DOI: 10.1146/annurev-micro-090817-062346] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Human-adapted bacterial pathogens use a mechanism called phase variation to randomly switch the expression of individual genes to generate a phenotypically diverse population to adapt to challenges within and between human hosts. There are increasing reports of restriction-modification systems that exhibit phase-variable expression. The outcome of phase variation of these systems is global changes in DNA methylation. Analysis of phase-variable Type I and Type III restriction-modification systems in multiple human-adapted bacterial pathogens has demonstrated that global changes in methylation regulate the expression of multiple genes. These systems are called phasevarions (phase-variable regulons). Phasevarion switching alters virulence phenotypes and facilitates evasion of host immune responses. This review describes the characteristics of phasevarions and implications for pathogenesis and immune evasion. We present and discuss examples of phasevarion systems in the major human pathogens Haemophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, Helicobacter pylori, Moraxella catarrhalis, and Streptococcus pneumoniae.
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Affiliation(s)
- Kate L Seib
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia; ,
| | - Yogitha N Srikhanta
- Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia
| | - John M Atack
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia; ,
| | - Michael P Jennings
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia; ,
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7
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Yano H, Alam MZ, Rimbara E, Shibata TF, Fukuyo M, Furuta Y, Nishiyama T, Shigenobu S, Hasebe M, Toyoda A, Suzuki Y, Sugano S, Shibayama K, Kobayashi I. Networking and Specificity-Changing DNA Methyltransferases in Helicobacter pylori. Front Microbiol 2020; 11:1628. [PMID: 32765461 PMCID: PMC7379913 DOI: 10.3389/fmicb.2020.01628] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Epigenetic DNA base methylation plays important roles in gene expression regulation. We here describe a gene expression regulation network consisting of many DNA methyltransferases each frequently changing its target sequence-specificity. Our object Helicobacter pylori, a bacterium responsible for most incidence of stomach cancer, carries a large and variable repertoire of sequence-specific DNA methyltransferases. By creating a dozen of single-gene knockout strains for the methyltransferases, we revealed that they form a network controlling methylome, transcriptome and adaptive phenotype sets. The methyltransferases interact with each other in a hierarchical way, sometimes regulated positively by one methyltransferase but negatively with another. Motility, oxidative stress tolerance and DNA damage repair are likewise regulated by multiple methyltransferases. Their regulation sometimes involves translation start and stop codons suggesting coupling of methylation, transcription and translation. The methyltransferases frequently change their sequence-specificity through gene conversion of their target recognition domain and switch their target sets to remodel the network. The emerging picture of a metamorphosing gene regulation network, or firework, consisting of epigenetic systems ever-changing their specificity in search for adaptation, provides a new paradigm in understanding global gene regulation and adaptive evolution.
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Affiliation(s)
- Hirokazu Yano
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.,Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Md Zobaidul Alam
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Emiko Rimbara
- Department of Bacteriology II, National Institute of Infectious Diseases (NIID), Musashimurayama, Japan
| | | | | | - Yoshikazu Furuta
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.,Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomoaki Nishiyama
- Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
| | | | - Mitsuyasu Hasebe
- National Institute for Basic Biology (NIBB), Okazaki, Japan.,Department of Basic Biology, School of Life Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan
| | - Atsushi Toyoda
- Advanced Genomics Center, National Institute of Genetics, Mishima, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Sumio Sugano
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.,Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Keigo Shibayama
- Department of Bacteriology II, National Institute of Infectious Diseases (NIID), Musashimurayama, Japan
| | - Ichizo Kobayashi
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.,Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Department of Infectious Diseases, School of Medicine, Kyorin University, Mitaka, Japan.,Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Saclay, Gif-sur-Yvette, France.,Research Center for Micro-Nano Technology, Hosei University, Koganei, Japan
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8
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Rogan MR, Patterson LL, Wang JY, McBride JW. Bacterial Manipulation of Wnt Signaling: A Host-Pathogen Tug-of-Wnt. Front Immunol 2019; 10:2390. [PMID: 31681283 PMCID: PMC6811524 DOI: 10.3389/fimmu.2019.02390] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 09/23/2019] [Indexed: 12/27/2022] Open
Abstract
The host-pathogen interface is a crucial battleground during bacterial infection in which host defenses are met with an array of bacterial counter-mechanisms whereby the invader aims to make the host environment more favorable to survival and dissemination. Interestingly, the eukaryotic Wnt signaling pathway has emerged as a key player in the host and pathogen tug-of-war. Although studied for decades as a regulator of embryogenesis, stem cell maintenance, bone formation, and organogenesis, Wnt signaling has recently been shown to control processes related to bacterial infection in the human host. Wnt signaling pathways contribute to cell cycle control, cytoskeleton reorganization during phagocytosis and cell migration, autophagy, apoptosis, and a number of inflammation-related events. Unsurprisingly, bacterial pathogens have evolved strategies to manipulate these Wnt-associated processes in order to enhance infection and survival within the human host. In this review, we examine the different ways human bacterial pathogens with distinct host cell tropisms and lifestyles exploit Wnt signaling for infection and address the potential of harnessing Wnt-related mechanisms to combat infectious disease.
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Affiliation(s)
- Madison R. Rogan
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - LaNisha L. Patterson
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Jennifer Y. Wang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Jere W. McBride
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
- Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, United States
- Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States
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9
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Phillips ZN, Husna AU, Jennings MP, Seib KL, Atack JM. Phasevarions of bacterial pathogens - phase-variable epigenetic regulators evolving from restriction-modification systems. MICROBIOLOGY-SGM 2019; 165:917-928. [PMID: 30994440 DOI: 10.1099/mic.0.000805] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Phase-variable DNA methyltransferases control the expression of multiple genes via epigenetic mechanisms in a wide variety of bacterial species. These systems are called phasevarions, for phase-variable regulons. Phasevarions regulate genes involved in pathogenesis, host adaptation and antibiotic resistance. Many human-adapted bacterial pathogens contain phasevarions. These include leading causes of morbidity and mortality worldwide, such as non-typeable Haemophilus influenzae, Streptococcus pneumoniae and Neisseria spp. Phase-variable methyltransferases and phasevarions have also been discovered in environmental organisms and veterinary pathogens. The existence of many different examples suggests that phasevarions have evolved multiple times as a contingency strategy in the bacterial domain, controlling phenotypes that are important in adapting to environmental change. Many of the organisms that contain phasevarions have existing or emerging drug resistance. Vaccines may therefore represent the best and most cost-effective tool to prevent disease caused by these organisms. However, many phasevarions also control the expression of current and putative vaccine candidates; variable expression of antigens could lead to immune evasion, meaning that vaccines designed using these targets become ineffective. It is therefore essential to characterize phasevarions in order to determine an organism's stably expressed antigenic repertoire, and rationally design broadly effective vaccines.
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Affiliation(s)
- Zachary N Phillips
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Asma-Ul Husna
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Michael P Jennings
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Kate L Seib
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
| | - John M Atack
- Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia
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10
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Payelleville A, Legrand L, Ogier JC, Roques C, Roulet A, Bouchez O, Mouammine A, Givaudan A, Brillard J. The complete methylome of an entomopathogenic bacterium reveals the existence of loci with unmethylated Adenines. Sci Rep 2018; 8:12091. [PMID: 30108278 PMCID: PMC6092372 DOI: 10.1038/s41598-018-30620-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 08/03/2018] [Indexed: 01/01/2023] Open
Abstract
DNA methylation can serve to control diverse phenomena in eukaryotes and prokaryotes, including gene regulation leading to cell differentiation. In bacteria, DNA methylomes (i.e., methylation state of each base of the whole genome) have been described for several species, but methylome profile variation during the lifecycle has rarely been studied, and only in a few model organisms. Moreover, major phenotypic changes have been reported in several bacterial strains with a deregulated methyltransferase, but the corresponding methylome has rarely been described. Here we report the first methylome description of an entomopathogenic bacterium, Photorhabdus luminescens. Eight motifs displaying a high rate of methylation (>94%) were identified. The methylome was strikingly stable over course of growth, but also in a subpopulation responsible for a critical step in the bacterium's lifecycle: successful survival and proliferation in insects. The rare unmethylated GATC motifs were preferentially located in putative promoter regions, and most of them were methylated after Dam methyltransferase overexpression, suggesting that DNA methylation is involved in gene regulation. Our findings bring key insight into bacterial methylomes and encourage further research to decipher the role of loci protected from DNA methylation in gene regulation.
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Affiliation(s)
| | - Ludovic Legrand
- LIPM, Université de Toulouse, INRA, CNRS, Castanet-Tolosan, France
| | | | - Céline Roques
- GeT-PlaGe, INRA, US 1426, Genotoul, Castanet-Tolosan, France
| | - Alain Roulet
- GeT-PlaGe, INRA, US 1426, Genotoul, Castanet-Tolosan, France
| | - Olivier Bouchez
- GeT-PlaGe, INRA, US 1426, Genotoul, Castanet-Tolosan, France
| | - Annabelle Mouammine
- DGIMI, INRA, Univ. Montpellier, Montpellier, France
- Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Quartier UNIL/Sorge, Lausanne, CH1015, Switzerland
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11
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Vaziri F, Tarashi S, Fateh A, Siadat SD. New insights of Helicobacter pylori host-pathogen interactions: The triangle of virulence factors, epigenetic modifications and non-coding RNAs. World J Clin Cases 2018; 6:64-73. [PMID: 29774218 PMCID: PMC5955730 DOI: 10.12998/wjcc.v6.i5.64] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 02/09/2018] [Accepted: 03/07/2018] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a model organism for understanding host-pathogen interactions and infection-mediated carcinogenesis. Gastric cancer and H. pylori colonization indicates the strong correlation. The progression and exacerbation of H. pylori infection are influenced by some factors of pathogen and host. Several virulence factors involved in the proper adherence and attenuation of immune defense to contribute the risk of emerging gastric cancer, therefore analysis of them is very important. H. pylori also modulates inflammatory and autophagy process to intensify its pathogenicity. From the host regard, different genetic factors particularly affect the development of gastric cancer. Indeed, epigenetic modifications, MicroRNA and long non-coding RNA received more attention. Generally, various factors related to pathogen and host that modulate gastric cancer development in response to H. pylori need more attention due to develop an efficacious therapeutic intervention. Therefore, this paper will present a brief overview of host-pathogen interaction especially emphases on bacterial virulence factors, interruption of host cellular signaling, the role of epigenetic modifications and non-coding RNAs.
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Affiliation(s)
- Farzam Vaziri
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Samira Tarashi
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Abolfazl Fateh
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran 1316943551, Iran
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Srikhanta YN, Gorrell RJ, Power PM, Tsyganov K, Boitano M, Clark TA, Korlach J, Hartland EL, Jennings MP, Kwok T. Methylomic and phenotypic analysis of the ModH5 phasevarion of Helicobacter pylori. Sci Rep 2017; 7:16140. [PMID: 29170397 PMCID: PMC5700931 DOI: 10.1038/s41598-017-15721-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 10/31/2017] [Indexed: 12/20/2022] Open
Abstract
The Helicobacter pylori phase variable gene modH, typified by gene HP1522 in strain 26695, encodes a N6-adenosine type III DNA methyltransferase. Our previous studies identified multiple strain-specific modH variants (modH1 – modH19) and showed that phase variation of modH5 in H. pylori P12 influenced expression of motility-associated genes and outer membrane protein gene hopG. However, the ModH5 DNA recognition motif and the mechanism by which ModH5 controls gene expression were unknown. Here, using comparative single molecule real-time sequencing, we identify the DNA site methylated by ModH5 as 5′-Gm6ACC-3′. This motif is vastly underrepresented in H. pylori genomes, but overrepresented in a number of virulence genes, including motility-associated genes, and outer membrane protein genes. Motility and the number of flagella of H. pylori P12 wild-type were significantly higher than that of isogenic modH5 OFF or ΔmodH5 mutants, indicating that phase variable switching of modH5 expression plays a role in regulating H. pylori motility phenotypes. Using the flagellin A (flaA) gene as a model, we show that ModH5 modulates flaA promoter activity in a GACC methylation-dependent manner. These findings provide novel insights into the role of ModH5 in gene regulation and how it mediates epigenetic regulation of H. pylori motility.
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Affiliation(s)
- Yogitha N Srikhanta
- Department of Microbiology, Monash University, Clayton, 3800, Victoria, Australia.,Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, 3010, Victoria, Australia.,Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, 3800, Victoria, Australia
| | - Rebecca J Gorrell
- Department of Microbiology, Monash University, Clayton, 3800, Victoria, Australia.,Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, 3800, Victoria, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Victoria, Australia.,Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, 3800, Victoria, Australia
| | - Peter M Power
- Institute for Glycomics, Griffith University, Gold Coast, Queensland, 4222, Australia
| | - Kirill Tsyganov
- Bioinformatics Platform, Monash University, Clayton, 3800, Victoria, Australia
| | | | | | | | - Elizabeth L Hartland
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, 3010, Victoria, Australia.,Department of Molecular and Translational Science, Hudson Institute of Medical Research, Monash University, Clayton, 3800, Victoria, Australia
| | - Michael P Jennings
- Institute for Glycomics, Griffith University, Gold Coast, Queensland, 4222, Australia.
| | - Terry Kwok
- Department of Microbiology, Monash University, Clayton, 3800, Victoria, Australia. .,Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, 3800, Victoria, Australia. .,Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Victoria, Australia. .,Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, 3800, Victoria, Australia.
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