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Hu X, Li Y, Cao Y, Shi F, Shang L. The role of nitric oxide synthase/ nitric oxide in infection-related cancers: Beyond antimicrobial activity. Biochim Biophys Acta Rev Cancer 2024; 1879:189156. [PMID: 39032540 DOI: 10.1016/j.bbcan.2024.189156] [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: 12/01/2023] [Revised: 07/11/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024]
Abstract
As a free radical and endogenous effector molecule, mammalian endogenous nitric oxide (NO) is mainly derived from nitric oxide synthase (NOS) via L-arginine. NO participates in normal physiological reactions and provides immune responses to prevent the invasion of foreign bacteria. However, NO also has complex and contradictory biological effects. Abnormal NO signaling is involved in the progression of many diseases, such as cancer. In the past decades, cancer research has been closely linked with NOS/ NO, and many tumors with poor prognosis are associated with high expression of NOS. In this review, we give a overview of the biological effects of NOS/ NO. Then we focus on the oncogenic role of iNOS/ NO in HPV, HBV, EBV and H. pylori related tumors. In fact, there is growing evidence that iNOS could be used as a potential therapeutic target in cancer therapy. We emphasize that the pro-tumor effect of NOS/ NO is greater than the anti-tumor effect.
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Affiliation(s)
- Xudong Hu
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Yueshuo Li
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Ya Cao
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Feng Shi
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Li Shang
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China.
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2
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Åberg A, Gideonsson P, Bhat A, Ghosh P, Arnqvist A. Molecular insights into the fine-tuning of pH-dependent ArsR-mediated regulation of the SabA adhesin in Helicobacter pylori. Nucleic Acids Res 2024; 52:5572-5595. [PMID: 38499492 PMCID: PMC11162790 DOI: 10.1093/nar/gkae188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/28/2024] [Accepted: 03/12/2024] [Indexed: 03/20/2024] Open
Abstract
Adaptation to variations in pH is crucial for the ability of Helicobacter pylori to persist in the human stomach. The acid responsive two-component system ArsRS, constitutes the global regulon that responds to acidic conditions, but molecular details of how transcription is affected by the ArsR response regulator remains poorly understood. Using a combination of DNA-binding studies, in vitro transcription assays, and H. pylori mutants, we demonstrate that phosphorylated ArsR (ArsR-P) forms an active protein complex that binds DNA with high specificity in order to affect transcription. Our data showed that DNA topology is key for DNA binding. We found that AT-rich DNA sequences direct ArsR-P to specific sites and that DNA-bending proteins are important for the effect of ArsR-P on transcription regulation. The repression of sabA transcription is mediated by ArsR-P with the support of Hup and is affected by simple sequence repeats located upstream of the sabA promoter. Here stochastic events clearly contribute to the fine-tuning of pH-dependent gene regulation. Our results reveal important molecular aspects for how ArsR-P acts to repress transcription in response to acidic conditions. Such transcriptional control likely mediates shifts in bacterial positioning in the gastric mucus layer.
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Affiliation(s)
- Anna Åberg
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Pär Gideonsson
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Abhayprasad Bhat
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Prachetash Ghosh
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Anna Arnqvist
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
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3
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Dekker JP. Within-Host Evolution of Bacterial Pathogens in Acute and Chronic Infection. ANNUAL REVIEW OF PATHOLOGY 2024; 19:203-226. [PMID: 37832940 DOI: 10.1146/annurev-pathmechdis-051122-111408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2023]
Abstract
Bacterial pathogens undergo remarkable adaptive change in response to the selective forces they encounter during host colonization and infection. Studies performed over the past few decades have demonstrated that many general evolutionary processes can be discerned during the course of host adaptation, including genetic diversification of lineages, clonal succession events, convergent evolution, and balanced fitness trade-offs. In some cases, elevated mutation rates resulting from mismatch repair or proofreading deficiencies accelerate evolution, and active mobile genetic elements or phages may facilitate genome plasticity. The host immune response provides another critical component of the fitness landscapes guiding adaptation, and selection operating on pathogens at this level may lead to immune evasion and the establishment of chronic infection. This review summarizes recent advances in this field, with a special focus on different forms of bacterial genome plasticity in the context of infection, and considers clinical consequences of adaptive changes for the host.
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Affiliation(s)
- John P Dekker
- Bacterial Pathogenesis and Antimicrobial Resistance Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA;
- National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
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4
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Bugaytsova JA, Moonens K, Piddubnyi A, Schmidt A, Edlund JO, Lisiutin G, Brännström K, Chernov YA, Thorel K, Tkachenko I, Sharova O, Vikhrova I, Butsyk A, Shubin P, Chyzhma R, Johansson DX, Marcotte H, Sjöström R, Shevtsova A, Bylund G, Rakhimova L, Lundquist A, Berhilevych O, Kasianchuk V, Loboda A, Ivanytsia V, Hultenby K, Persson MAA, Gomes J, Matos R, Gartner F, Reis CA, Whitmire JM, Merrell DS, Pan-Hammarström Q, Landström M, Oscarson S, D’Elios MM, Agreus L, Ronkainen J, Aro P, Engstrand L, Graham DY, Kachkovska V, Mukhopadhyay A, Chaudhuri S, Karmakar BC, Paul S, Kravets O, Camorlinga M, Torres J, Berg DE, Moskalenko R, Haas R, Remaut H, Hammarström L, Borén T. Helicobacter pylori attachment-blocking antibodies protect against duodenal ulcer disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.24.542096. [PMID: 37292721 PMCID: PMC10245814 DOI: 10.1101/2023.05.24.542096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The majority of the world population carry the gastric pathogen Helicobacter pylori. Fortunately, most individuals experience only low-grade or no symptoms, but in many cases the chronic inflammatory infection develops into severe gastric disease, including duodenal ulcer disease and gastric cancer. Here we report on a protective mechanism where H. pylori attachment and accompanying chronic mucosal inflammation can be reduced by antibodies that are present in a vast majority of H. pylori carriers. These antibodies block binding of the H. pylori attachment protein BabA by mimicking BabA's binding to the ABO blood group glycans in the gastric mucosa. However, many individuals demonstrate low titers of BabA blocking antibodies, which is associated with an increased risk for duodenal ulceration, suggesting a role for these antibodies in preventing gastric disease.
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Affiliation(s)
- Jeanna A. Bugaytsova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
| | - Kristof Moonens
- Structural and Molecular Microbiology, VIB Department of Structural Biology, VIB, 1050 Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Present address: Ablynx, a Sanofi Company, Technologiepark 21, 9052 Zwijnaarde, Belgium
| | - Artem Piddubnyi
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Alexej Schmidt
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital, SE14186 Huddinge, Sweden
- Present address: Department of Medical Biosciences, Umeå University, SE90185 Umeå, Sweden
| | - Johan Olofsson Edlund
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- The Biochemical Imaging Center Umeå (BICU), Umeå University, SE90187 Umeå, Sweden
| | - Gennadii Lisiutin
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Microbiology, Virology and Biotechnology, Odesa Mechnikov National University, 65082 Odesa, Ukraine
| | - Kristoffer Brännström
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- The Biochemical Imaging Center Umeå (BICU), Umeå University, SE90187 Umeå, Sweden
- Present address: Pfizer Worldwide R&D, BioMedicine Design, 10 555 Science Center Drive, San Diego CA, 92121 USA
| | - Yevgen A. Chernov
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
| | - Kaisa Thorel
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Iryna Tkachenko
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Oleksandra Sharova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Pediatrics, Medical Institute, Sumy State University, 40018 Sumy, Ukraine
| | - Iryna Vikhrova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Pediatrics, Medical Institute, Sumy State University, 40018 Sumy, Ukraine
| | - Anna Butsyk
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Pavlo Shubin
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Ruslana Chyzhma
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Daniel X. Johansson
- Department of Clinical Neuroscience, Karolinska Institutet at Center for Molecular Medicine, Karolinska University Hospital, Solna, SE17176 Stockholm, Sweden
| | - Harold Marcotte
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital, SE14186 Huddinge, Sweden
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Rolf Sjöström
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
| | - Anna Shevtsova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
| | - Göran Bylund
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
| | - Lena Rakhimova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Present address: Department of Odontology, Umeå University, SE90187 Umeå, Sweden
| | - Anders Lundquist
- Department of Statistics, USBE, Umeå University, SE90187 Umeå, Sweden
- Umeå Center for Functional Brain Imaging, Umeå University, SE90187 Umeå, Sweden
| | - Oleksandra Berhilevych
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Victoria Kasianchuk
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Andrii Loboda
- Department of Pediatrics, Medical Institute, Sumy State University, 40018 Sumy, Ukraine
| | - Volodymyr Ivanytsia
- Department of Microbiology, Virology and Biotechnology, Odesa Mechnikov National University, 65082 Odesa, Ukraine
| | - Kjell Hultenby
- Departments of Laboratory Medicine, Division of Biomolecular and Cellular Medicine, Karolinska Institutet at Karolinska University Hospital, SE14186 Huddinge, Sweden
| | - Mats A. A. Persson
- Department of Clinical Neuroscience, Karolinska Institutet at Center for Molecular Medicine, Karolinska University Hospital, Solna, SE17176 Stockholm, Sweden
| | - Joana Gomes
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Rita Matos
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Fátima Gartner
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Celso A. Reis
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | | | - D. Scott Merrell
- Department of Microbiology and Immunology, USUHS, Bethesda, MD 20814, USA
| | - Qiang Pan-Hammarström
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Maréne Landström
- Present address: Department of Medical Biosciences, Umeå University, SE90185 Umeå, Sweden
| | - Stefan Oscarson
- Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
| | - Mario M. D’Elios
- Department of Experimental and Clinical Medicine, Largo Brambilla 3, 50134 Firenze, Italy
| | - Lars Agreus
- Division of Family Medicine and Primary Care, Karolinska Institutet, SE14183 Huddinge, Sweden
| | - Jukka Ronkainen
- University of Oulu, Center for Life Course Health Research and Primary Health Care Center, Tornio Finland
| | - Pertti Aro
- University of Oulu, Center for Life Course Health Research and Primary Health Care Center, Tornio Finland
| | - Lars Engstrand
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE17177 Stockholm, Sweden
- Present address: Science for Life Laboratory, SE17165, Solna, Sweden
| | - David Y. Graham
- Department of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine, Michael E. DeBakey VAMC, 2002 Holcombe Blvd. Houston, TX, 77030 USA
| | - Vladyslava Kachkovska
- Department of Internal Medicine, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Asish Mukhopadhyay
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases P 33, CIT Road, Scheme XM, Kolkata 700010, India
| | - Sujit Chaudhuri
- Department of Gastroenterology, AMRI Hospital, Salt Lake City. Kolkata, West Bengal 700098, India
| | - Bipul Chandra Karmakar
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases P 33, CIT Road, Scheme XM, Kolkata 700010, India
| | - Sangita Paul
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases P 33, CIT Road, Scheme XM, Kolkata 700010, India
| | - Oleksandr Kravets
- Department of Surgery, Traumatology, Orthopedics and Physiology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Margarita Camorlinga
- Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatria, CMN SXXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Javier Torres
- Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatria, CMN SXXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Douglas E. Berg
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Roman Moskalenko
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Rainer Haas
- German Center for Infection Research (DZIF), Munich Site, 80336 Munich, Germany
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer-Institute, Faculty of Medicine, LMU Munich, Germany
| | - Han Remaut
- Structural and Molecular Microbiology, VIB Department of Structural Biology, VIB, 1050 Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Lennart Hammarström
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Thomas Borén
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Lead contact
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5
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Suerbaum S, Ailloud F. Genome and population dynamics during chronic infection with Helicobacter pylori. Curr Opin Immunol 2023; 82:102304. [PMID: 36958230 DOI: 10.1016/j.coi.2023.102304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 02/21/2023] [Accepted: 02/22/2023] [Indexed: 03/25/2023]
Abstract
Helicobacter pylori is responsible for one of the most prevalent bacterial infections worldwide. Chronic infection typically leads to chronic active gastritis. Clinical sequelae, including peptic ulcers, mucosa-associated lymphoid tissue lymphoma or, most importantly, gastric adenocarcinoma develop in 10-15% of cases. H. pylori is characterized by extensive inter-strain diversity which is the result of a high mutation rate, recombination, and a large repertoire of restriction-modification systems. This diversity is thought to be a major contributor to H. pylori's persistence and exceptional aptitude to adapt to the gastric environment and evade the immune system. This review covers efforts in the last decade to characterize and understand the multiple layers of H. pylori's diversity in different biological contexts.
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Affiliation(s)
- Sebastian Suerbaum
- Max von Pettenkofer Institute for Hygiene and Medical Microbiology, Medical Faculty, LMU Munich, Pettenkoferstr. 9a, 80336 Munich, Germany; DZIF German Centre for Infection Research, Munich Partner Site, Pettenkoferstr. 9a, 80336 Munich, Germany; German National Reference Centre for Helicobacter pylori, Pettenkoferstr. 9a, 80336 Munich, Germany.
| | - Florent Ailloud
- Max von Pettenkofer Institute for Hygiene and Medical Microbiology, Medical Faculty, LMU Munich, Pettenkoferstr. 9a, 80336 Munich, Germany; DZIF German Centre for Infection Research, Munich Partner Site, Pettenkoferstr. 9a, 80336 Munich, Germany
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6
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Yamaoka Y, Saruuljavkhlan B, Alfaray RI, Linz B. Pathogenomics of Helicobacter pylori. Curr Top Microbiol Immunol 2023; 444:117-155. [PMID: 38231217 DOI: 10.1007/978-3-031-47331-9_5] [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: 01/18/2024]
Abstract
The human stomach bacterium Helicobacter pylori, the causative agent of gastritis, ulcers and adenocarcinoma, possesses very high genetic diversity. H. pylori has been associated with anatomically modern humans since their origins over 100,000 years ago and has co-evolved with its human host ever since. Predominantly intrafamilial and local transmission, along with genetic isolation, genetic drift, and selection have facilitated the development of distinct bacterial populations that are characteristic for large geographical areas. H. pylori utilizes a large arsenal of virulence and colonization factors to mediate the interaction with its host. Those include various adhesins, the vacuolating cytotoxin VacA, urease, serine protease HtrA, the cytotoxin-associated genes pathogenicity island (cagPAI)-encoded type-IV secretion system and its effector protein CagA, all of which contribute to disease development. While many pathogenicity-related factors are present in all strains, some belong to the auxiliary genome and are associated with specific phylogeographic populations. H. pylori is naturally competent for DNA uptake and recombination, and its genome evolution is driven by extraordinarily high recombination and mutation rates that are by far exceeding those in other bacteria. Comparative genome analyses revealed that adaptation of H. pylori to individual hosts is associated with strong selection for particular protein variants that facilitate immune evasion, especially in surface-exposed and in secreted virulence factors. Recent studies identified single-nucleotide polymorphisms (SNPs) in H. pylori that are associated with the development of severe gastric disease, including gastric cancer. Here, we review the current knowledge about the pathogenomics of H. pylori.
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Affiliation(s)
- Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu Oita, 879-5593, Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Batsaikhan Saruuljavkhlan
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu Oita, 879-5593, Japan
| | - Ricky Indra Alfaray
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu Oita, 879-5593, Japan
- Helicobacter pylori and Microbiota Study Group, Universitas Airlangga, Surabaya, 60286, East Java, Indonesia
| | - Bodo Linz
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
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7
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Prevalence of Helicobacter pylori Virulence Genes and Their Association with Chronic Gastritis in Beijing, China. Curr Microbiol 2022; 80:33. [PMID: 36482124 DOI: 10.1007/s00284-022-03135-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori is closely related to chronic gastritis. The aim of the study was to investigate the correlation between H. pylori virulence genes and chronic gastritis in order to determine the pathogenic role of H. pylori virulence genes in chronic gastritis. Gastric mucosal tissues were obtained from 142 patients with chronic gastritis at three Beijing hospitals. The presence of virulence genes was determined by polymerase chain reaction (PCR) from H. pylori DNA. Multilocus sequence typing (MLST) and a phylogenetic tree were performed to characterize the overall genetic diversity. 91 new sequence types were identified by MLST in this study, and all strains showed high genetic diversity. The H. pylori isolates were divided into three types: hspEAsia strains (61 strains), hpEurope strains (15 strains), and mixed strains (16 strains). Some virulence genes were found to be significantly different between strains. The highest positive rates were found for dupA in chronic atrophic gastritis (AG), iceA1 in chronic non-atrophic gastritis with erosions, and iceA2 in chronic non-atrophic gastritis. The presence of dupA was found to be inversely related to the risk of AG. The H. pylori strains display high genetic diversity. Some virulence genes were found to be significantly different between diseases. The detection of various virulence genes is critical for screening high-risk populations for precancerous lesions and for the early prevention and control of gastric cancer.
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8
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Thorpe HA, Tourrette E, Yahara K, Vale FF, Liu S, Oleastro M, Alarcon T, Perets TT, Latifi-Navid S, Yamaoka Y, Martinez-Gonzalez B, Karayiannis I, Karamitros T, Sgouras DN, Elamin W, Pascoe B, Sheppard SK, Ronkainen J, Aro P, Engstrand L, Agreus L, Suerbaum S, Thorell K, Falush D. Repeated out-of-Africa expansions of Helicobacter pylori driven by replacement of deleterious mutations. Nat Commun 2022; 13:6842. [PMID: 36369175 PMCID: PMC9652371 DOI: 10.1038/s41467-022-34475-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 10/26/2022] [Indexed: 11/13/2022] Open
Abstract
Helicobacter pylori lives in the human stomach and has a population structure resembling that of its host. However, H. pylori from Europe and the Middle East trace substantially more ancestry from modern African populations than the humans that carry them. Here, we use a collection of Afro-Eurasian H. pylori genomes to show that this African ancestry is due to at least three distinct admixture events. H. pylori from East Asia, which have undergone little admixture, have accumulated many more non-synonymous mutations than African strains. European and Middle Eastern bacteria have elevated African ancestry at the sites of these mutations, implying selection to remove them during admixture. Simulations show that population fitness can be restored after bottlenecks by migration and subsequent admixture of small numbers of bacteria from non-bottlenecked populations. We conclude that recent spread of African DNA has been driven by deleterious mutations accumulated during the original out-of-Africa bottleneck.
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Affiliation(s)
- Harry A Thorpe
- Department of Biostatistics, University of Oslo, Oslo, Norway
| | - Elise Tourrette
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Koji Yahara
- Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Filipa F Vale
- Pathogen Genome Bioinformatics and Computational Biology, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Siqi Liu
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Mónica Oleastro
- National Reference Laboratory for Gastrointestinal Infections, Department of Infectious Diseases, National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal
| | - Teresa Alarcon
- Department of Microbiology, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
| | - Tsachi-Tsadok Perets
- Gastroenterology Laboratory, Rabin Medical Center, Petah Tikva, Israel
- Department of Digital Medical Technologies, Holon Institute of Technology, Holon, Israel
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan
- Department of Medicine-Gastroenterology, Baylor College of Medicine, Houston, TX, USA
| | | | - Ioannis Karayiannis
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece
| | | | | | - Wael Elamin
- G42 Healthcare, Abu Dhabi, UAE
- Elrazi University, Khartoum, Sudan
| | - Ben Pascoe
- Department of Biology, University of Oxford, Oxford, UK
| | - Samuel K Sheppard
- Ineos Oxford Institute, Department of Biology, University of Oxford, Oxford, UK
| | - Jukka Ronkainen
- Center for Life Course Health Research, University of Oulu, Oulu, Finland
- Primary Health Care Center, Tornio, Finland
| | | | - Lars Engstrand
- Center for Translational Microbiome Research, Department for Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Lars Agreus
- Division of Family Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sebastian Suerbaum
- Department of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, Germany
- Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hanover, Germany
- DZIF German Center for Infection Research, Hannover-Braunschweig and Munich Partner Sites, Munich, Germany
| | - Kaisa Thorell
- Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Daniel Falush
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
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9
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Moeller AH. Loyal gut microbes. Science 2022; 377:1263-1264. [PMID: 36108001 DOI: 10.1126/science.ade2879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Bacterial strains in the gut microbiota diversified as humans spread across the globe.
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Affiliation(s)
- Andrew H Moeller
- Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY, USA
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10
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Suzuki TA, Fitzstevens JL, Schmidt VT, Enav H, Huus KE, Ngwese MM, Grießhammer A, Pfleiderer A, Adegbite BR, Zinsou JF, Esen M, Velavan TP, Adegnika AA, Song LH, Spector TD, Muehlbauer AL, Marchi N, Kang H, Maier L, Blekhman R, Ségurel L, Ko G, Youngblut ND, Kremsner P, Ley RE. Codiversification of gut microbiota with humans. Science 2022; 377:1328-1332. [PMID: 36108023 PMCID: PMC10777373 DOI: 10.1126/science.abm7759] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
Abstract
The gut microbiomes of human populations worldwide have many core microbial species in common. However, within a species, some strains can show remarkable population specificity. The question is whether such specificity arises from a shared evolutionary history (codiversification) between humans and their microbes. To test for codiversification of host and microbiota, we analyzed paired gut metagenomes and human genomes for 1225 individuals in Europe, Asia, and Africa, including mothers and their children. Between and within countries, a parallel evolutionary history was evident for humans and their gut microbes. Moreover, species displaying the strongest codiversification independently evolved traits characteristic of host dependency, including reduced genomes and oxygen and temperature sensitivity. These findings all point to the importance of understanding the potential role of population-specific microbial strains in microbiome-mediated disease phenotypes.
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Affiliation(s)
- Taichi A. Suzuki
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen, Germany
| | - J. Liam Fitzstevens
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen, Germany
| | - Victor T. Schmidt
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen, Germany
| | - Hagay Enav
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen, Germany
| | - Kelsey E. Huus
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen, Germany
| | - Mirabeau Mbong Ngwese
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen, Germany
| | - Anne Grießhammer
- Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany
| | - Anne Pfleiderer
- Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany
| | - Bayode R. Adegbite
- Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
| | - Jeannot F. Zinsou
- Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
| | - Meral Esen
- Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany
- German Center for Infection Research, Tübingen, Germany
- Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany
| | - Thirumalaisamy P. Velavan
- Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany
- Vietnamese German Center for Medical Research, Hanoi, Vietnam
| | - Ayola A. Adegnika
- Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- German Center for Infection Research, Tübingen, Germany
- Fondation pour la Recherche Scientifique, Cotonou, Bénin
| | - Le Huu Song
- Vietnamese German Center for Medical Research, Hanoi, Vietnam
- 108 Military Central Hospital, Hanoi, Vietnam
| | - Timothy D. Spector
- Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
| | - Amanda L. Muehlbauer
- Department of Ecology, Evolution, and Behavior, University of Minnesota, Minneapolis, MN, USA
| | - Nina Marchi
- Eco-anthropologie, Muséum National d’Histoire Naturelle, CNRS, Université de Paris, Paris, France
| | - Hyena Kang
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
| | - Lisa Maier
- Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany
- Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany
| | - Ran Blekhman
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
| | - Laure Ségurel
- Eco-anthropologie, Muséum National d’Histoire Naturelle, CNRS, Université de Paris, Paris, France
- Laboratoire de Biométrie et Biologie Evolutive, CNRS, Université Lyon 1, Villeurbanne, France
| | - GwangPyo Ko
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
| | - Nicholas D. Youngblut
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen, Germany
| | - Peter Kremsner
- Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany
- Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
- German Center for Infection Research, Tübingen, Germany
- Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany
| | - Ruth E. Ley
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen, Germany
- Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany
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11
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The Helicobacter pylori UvrC Nuclease Is Essential for Chromosomal Microimports after Natural Transformation. mBio 2022; 13:e0181122. [PMID: 35876509 PMCID: PMC9426483 DOI: 10.1128/mbio.01811-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Helicobacter pylori is a Gram-negative bacterial carcinogenic pathogen that infects the stomachs of half of the human population. It is a natural mutator due to a deficient DNA mismatch repair pathway and is naturally competent for transformation. As a result, it is one of the most genetically diverse human bacterial pathogens. The length of chromosomal imports in H. pylori follows an unusual bimodal distribution consisting of macroimports with a mean length of 1,645 bp and microimports with a mean length of 28 bp. The mechanisms responsible for this import pattern were unknown. Here, we used a high-throughput whole-genome transformation assay to elucidate the role of nucleotide excision repair pathway (NER) components on import length distribution. The data show that the integration of microimports depended on the activity of the UvrC endonuclease, while none of the other components of the NER pathway was required. Using H. pylori site-directed mutants, we showed that the widely conserved UvrC nuclease active sites, while essential for protection from UV light, one of the canonical NER functions, are not required for generation of microimports. A quantitative analysis of recombination patterns based on over 1,000 imports from over 200 sequenced recombinant genomes showed that microimports occur frequently within clusters of multiple imports, strongly suggesting they derive from a single strand invasion event. We propose a hypothetical model of homologous recombination in H. pylori, involving a novel function of UvrC, that reconciles the available experimental data about recombination patterns in H. pylori. IMPORTANCE Helicobacter pylori is one of the most common and genetically diverse human bacterial pathogens. It is responsible for chronic gastritis and represents the main risk factor for gastric cancer. In H. pylori, DNA fragments can be imported by recombination during natural transformation. The length of those fragments determines how many potentially beneficial or deleterious alleles are acquired and thus influences adaptation to the gastric niche. Here, we used a transformation assay to examine imported fragments across the chromosome. We show that UvrC, an endonuclease involved in DNA repair, is responsible for the specific integration of short DNA fragments. This suggests that short and long fragments are imported through distinct recombination pathways. We also show that short fragments are frequently clustered with longer fragments, suggesting that both pathways may be mechanistically linked. These findings provide a novel basis to explain how H. pylori can fine-tune the genetic diversity acquired by transformation.
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12
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Loh JT, Shuman JHB, Lin AS, Favret N, Piazuelo MB, Mallal S, Chopra A, McClain MS, Cover TL. Positive Selection of Mutations in the Helicobacter pylori katA 5' Untranslated Region in a Mongolian Gerbil Model of Gastric Disease. Infect Immun 2022; 90:e0000422. [PMID: 35652648 PMCID: PMC9302185 DOI: 10.1128/iai.00004-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 05/11/2022] [Indexed: 01/18/2023] Open
Abstract
To evaluate potential effects of gastric inflammation on Helicobacter pylori diversification and evolution within the stomach, we experimentally infected Mongolian gerbils with an H. pylori strain in which Cag type IV secretion system (T4SS) activity is controlled by a TetR/tetO system. Gerbils infected with H. pylori under conditions in which Cag T4SS activity was derepressed had significantly higher levels of gastric inflammation than gerbils infected under conditions with repressed Cag T4SS activity. Mutations in the 5' untranslated region (UTR) of katA (encoding catalase) were detected in strains cultured from 8 of the 17 gerbils infected with Cag T4SS-active H. pylori and none of the strains from 17 gerbils infected with Cag T4SS-inactive H. pylori. Catalase enzymatic activity, steady-state katA transcript levels, and katA transcript stability were increased in strains with these single nucleotide polymorphisms (SNPs) compared to strains in which these SNPs were absent. Moreover, strains harboring these SNPs exhibited increased resistance to bactericidal effects of hydrogen peroxide, compared to control strains. Experimental introduction of the SNPs into the wild-type katA 5' UTR resulted in increased katA transcript stability, increased katA steady-state levels, and increased catalase enzymatic activity. Based on site-directed mutagenesis and modeling of RNA structure, increased katA transcript levels were correlated with higher predicted thermal stability of the katA 5' UTR secondary structure. These data suggest that high levels of gastric inflammation positively select for H. pylori strains producing increased levels of catalase, which may confer survival advantages to the bacteria in an inflammatory gastric environment.
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Affiliation(s)
- John T. Loh
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Jennifer H. B. Shuman
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Aung Soe Lin
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Natalie Favret
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Simon Mallal
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Abha Chopra
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Mark S. McClain
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennesse, USA
| | - Timothy L. Cover
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennesse, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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13
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Mosaic Evolution of Beta-Barrel-Porin-Encoding Genes in Escherichia coli. Appl Environ Microbiol 2022; 88:e0006022. [PMID: 35285711 DOI: 10.1128/aem.00060-22] [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] [Indexed: 11/20/2022] Open
Abstract
Bacterial porin-encoding genes are often found under positive selection. Local recombination has also been identified in a few of them to facilitate bacterial rapid adaptation, although it remains unknown whether it is a common evolutionary mechanism for the porins or outer membrane proteins in Gram-negative bacteria. In this study, we investigated the beta-barrel (β-barrel) porin-encoding genes in Escherichia coli that were reported under positive Darwinian selection. Besides fhuA that was found with ingenic local recombination previously, we identified four other genes, i.e., lamB, ompA, ompC, and ompF, all showing the similar mosaic evolution patterns. Comparative analysis of the protein sequences disclosed a list of highly variable regions in each family, which are mostly located in the convex of extracellular loops and coinciding with the binding sites of bacteriophages. For each of the porin families, mosaic recombination leads to unique combinations of the variable regions with different sequence patterns, generating diverse protein groups. Structural modeling indicated a conserved global topology among the different porins, with the extracellular surface varying a lot due to individual or combinatorial variable regions. The conservation of global tertiary structure would ensure the channel activity, while the wide diversity of variable regions may represent selection to avoid the invasion of phages, antibiotics or immune surveillance factors. Our study identified multiple bacterial porin genes with mosaic evolution. We hypothesize that this could be generalized strategy for outer membrane proteins to both maintain normal life processes and evade the attack of unfavored factors rapidly. IMPORTANCE Microevolution studies can disclose more elaborate evolutionary mechanisms of genes, appearing especially important for genes with multifaceted function such as those encoding outer membrane proteins. However, in most cases, the gene is considered as a whole unit, and the evolutionary patterns are disclosed. Here, we report that multiple bacterial porin proteins follow mosaic evolution, with local ingenic recombination combined with spontaneous mutations based on positive Darwinian selection, and conservation for most structural regions. This could represent a common mechanism for bacterial outer membrane proteins. The variable regions within each porin family showed large coincidence with the binding sites of bacteriophages, antibiotics, and immune factors and therefore would represent effective targets for the development of new antibacterial agents or vaccines.
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14
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Wei S, Li X, Wang J, Wang Y, Zhang C, Dai S, Wang X, Deng X, Zhao L, Shan B. Outer Membrane Vesicles Secreted by Helicobacter pylori Transmitting Gastric Pathogenic Virulence Factors. ACS OMEGA 2022; 7:240-258. [PMID: 35036696 PMCID: PMC8756444 DOI: 10.1021/acsomega.1c04549] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/03/2021] [Indexed: 06/14/2023]
Abstract
Helicobacter pylori (H. pylori) is known to be a major pathogen causing gastric diseases through its direct localization in gastric epithelium cells. H. pylori releases outer membrane vesicles (OMVs) throughout the growth process. The content, function, and mechanism of H. pylori OMVs in gastric epithelial cells remain unclear. In this study, we extracted and characterized H. pylori OMVs of two strains (standard strain NCTC11637 and clinical strain Hp-400) and analyzed the specific content by proteomic technology. We identified more than 400 proteins in H. pylori OMVs. In addition, we investigated the impact of H. pylori OMVs on cellular functions by detecting proteomic changes in GES1 cells. GES1 cells cocultured with increasing concentrations of H. pylori OMVs were subjected to quantitative proteomic analyses using label-free methods for relative quantitation. The results showed that a total of 4261 proteins were verified, 153 of which were significantly altered in abundance when cocultured with NCTC11637 OMVs, and a total of 4234 proteins in Hp-400 OMVs, 390 of which were significantly altered. Gene ontology analysis and Kyoto encyclopedia of genes and genomes pathway mapping identified significantly altered inflammatory and cancer signaling pathways, including metabolic pathways and the PI3K-Akt signaling pathway. Furthermore, we explored the proteomic changes in GES1 cells induced by H. pylori. Bioinformatics analysis showed that changes in multiple pathways coincided with OMV-mediated proteomic changes. Based on these results, H. pylori induced pathogenicity in epithelial cells at least partially by secreting OMVs that mediated dramatic and specific proteomic changes in host cells. Data are available via ProteomeXchange with identifiers PXD025216, PXD025259, and PXD025281.
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Affiliation(s)
- Sisi Wei
- Research
Center, Hebei Medical University Fourth
Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei Province 050011, China
| | - Xiaoya Li
- Research
Center, Hebei Medical University Fourth
Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei Province 050011, China
| | - Jingjing Wang
- Research
Center, Hebei Medical University Fourth
Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei Province 050011, China
| | - Yaojie Wang
- Research
Center, Hebei Medical University Fourth
Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei Province 050011, China
| | - Cong Zhang
- Research
Center, Hebei Medical University Fourth
Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei Province 050011, China
| | - Suli Dai
- Research
Center, Hebei Medical University Fourth
Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei Province 050011, China
| | - Xian Wang
- Shijiazhuang
Center for Disease Control and Prevention, Shijiazhuang, Hebei Province 050011, China
| | - Xiaoqing Deng
- Research
Center, Hebei Medical University Fourth
Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei Province 050011, China
| | - Lianmei Zhao
- Research
Center, Hebei Medical University Fourth
Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei Province 050011, China
| | - Baoen Shan
- Research
Center, Hebei Medical University Fourth
Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, Hebei Province 050011, China
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15
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Jang S, Hansen LM, Su H, Solnick JV, Cha JH. Host immune response mediates changes in cagA copy number and virulence potential of Helicobacter pylori. Gut Microbes 2022; 14:2044721. [PMID: 35289715 PMCID: PMC8928821 DOI: 10.1080/19490976.2022.2044721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/15/2022] [Indexed: 02/04/2023] Open
Abstract
Helicobacter pylori is the major risk factor for gastric cancer. H. pylori harboring the type IV secretion system (T4SS) and its effector CagA encoded on the cag pathogenicity Island (cagPAI) increases the risk. H. pylori PMSS1 has a multi-cagA genotype, modulating cagA copy number dynamically from zero to four copies. To examine the effect of the immune response on cagA copy number change, we utilized a mouse model with different immune status. PMSS1 recovered from Rag1-/- mice, lacking functional T or B cells, retained more cagA copies. PMSS1 recovered from Il10-/- mice, showing intense inflammation, had fewer cagA copies compared to those recovered from wild-type mice. Moreover, cagA copy number of PMSS1 recovered from wild-type and Il10-/- mice was positively correlated with the capacity to induce IL-8 secretion at four weeks of infection. Since recombination in cagY influences T4SS function, including CagA translocation and IL-8 induction, we constructed a multiple linear regression model to predict H. pylori-induced IL-8 expression based on cagA copy number and cagY recombination status; H. pylori induces more IL-8 secretion when the strain has more cagA copies and intact cagY. This study shows that H. pylori PMSS1 in mice with less intense immune response possess higher cagA copy number than those infected in mice with more intense immune response and thus the multi-cagA genotype, along with cagY recombination, functions as an immune-sensitive regulator of H. pylori virulence.
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Affiliation(s)
- Sungil Jang
- Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Four Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Department of Oral Biochemistry, School of Dentistry, Jeonbuk National University, Jeonju, Republic of Korea
| | - Lori M. Hansen
- Center for Immunology and Infectious Diseases; Departments of Medicine and of Microbiology and Immunology, School of Medicine; University of California Davis, Davis, CA, USA
| | - Hanfu Su
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Jay V. Solnick
- Center for Immunology and Infectious Diseases; Departments of Medicine and of Microbiology and Immunology, School of Medicine; University of California Davis, Davis, CA, USA
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Four Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
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16
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Characterization of East-Asian Helicobacter pylori encoding Western EPIYA-ABC CagA. J Microbiol 2021; 60:207-214. [PMID: 34757586 DOI: 10.1007/s12275-022-1483-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/24/2022]
Abstract
The polymorphic bacterial oncoprotein, CagA shows geography-dependent variation in the C-terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs; East-Asian H. pylori isolates carry the ABD type while Western isolates carry the ABC type. In Western isolates, the EPIYA-C motif is sometimes found in multi-copy and this genotype is associated with disease severity. Interestingly, a small number of East-Asian H. pylori isolates have been found to carry Western ABC-type CagA. To gain a better understanding of these unusual isolates, the genomes of four Korean H. pylori clinical isolates carrying ABC-type CagA were sequenced via third generation (Pac-Bio SMRT) sequencing technology. The obtained data were utilized for phylogenetic analysis as well as comparison of additional virulence factors that are known to show geographic-dependent polymorphisms. Three of four isolates indeed belonged to the hpEastAsia group and showed typical East-Asian polymorphism in virulence factors such as homA/B/C, babA/B/C, and oipA. One isolate grouped to HpAfrica and showed typical Western polymorphism of virulence factors such as cagA, homA/B/C, and oipA. To understand the occurrence of the multi-copy EPIYA-C motif genotype in an East-Asian H. pylori background, the Korean clinical isolate, K154 was analyzed; this strain belonged to hpEastAsia but encoded CagA EPIYA-ABCCCC. Based on DNA sequence homology within the CagA multimerization (CM) sequence that flanked the EPIYA-C motifs, we predicted that the number of C motifs might change via homologous recombination. To test this hypothesis, K154 was cultured for one generation and 287 single colonies were analyzed for the number of EPIYA-C motifs using PCR-based screening and DNA sequencing verification. Three out of 284 (1%) single colony isolates showed changes in the number of EPIYA-C motifs in vitro; one isolate increased to five EPIYA-C motifs, one decreased to three EPIYA-C motifs, and one completely deleted the EPIYA-C motifs. The capacity for dynamic changes in the number of EPIYA-C repeats of CagA may play a role in generating important intraspecies diversity in East-Asian H. pylori.
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17
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Ailloud F, Estibariz I, Suerbaum S. Evolved to vary: genome and epigenome variation in the human pathogen Helicobacter pylori. FEMS Microbiol Rev 2021; 45:5900976. [PMID: 32880636 DOI: 10.1093/femsre/fuaa042] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/31/2020] [Indexed: 12/24/2022] Open
Abstract
Helicobacter pylori is a Gram-negative, spiral shaped bacterium that selectively and chronically infects the gastric mucosa of humans. The clinical course of this infection can range from lifelong asymptomatic infection to severe disease, including peptic ulcers or gastric cancer. The high mutation rate and natural competence typical of this species are responsible for massive inter-strain genetic variation exceeding that observed in all other bacterial human pathogens. The adaptive value of such a plastic genome is thought to derive from a rapid exploration of the fitness landscape resulting in fast adaptation to the changing conditions of the gastric environment. Nevertheless, diversity is also lost through recurrent bottlenecks and H. pylori's lifestyle is thus a perpetual race to maintain an appropriate pool of standing genetic variation able to withstand selection events. Another aspect of H. pylori's diversity is a large and variable repertoire of restriction-modification systems. While not yet completely understood, methylome evolution could generate enough transcriptomic variation to provide another intricate layer of adaptive potential. This review provides an up to date synopsis of this rapidly emerging area of H. pylori research that has been enabled by the ever-increasing throughput of Omics technologies and a multitude of other technological advances.
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Affiliation(s)
- Florent Ailloud
- Max von Pettenkofer Institute, Faculty of Medicine, LMU München, Pettenkoferstr. 9a, 80336 München, Germany
| | - Iratxe Estibariz
- Max von Pettenkofer Institute, Faculty of Medicine, LMU München, Pettenkoferstr. 9a, 80336 München, Germany
| | - Sebastian Suerbaum
- Max von Pettenkofer Institute, Faculty of Medicine, LMU München, Pettenkoferstr. 9a, 80336 München, Germany.,DZIF Deutsches Zentrum für Infektionsforschung, Partner Site Munich, Pettenkoferstr. 9a, 80336 München, Germany.,National Reference Center for Helicobacter pylori, Pettenkoferstr. 9a, 80336 München, Germany
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18
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Menati Rashno M, Mehraban H, Naji B, Radmehr M. Microbiome in human cancers. Access Microbiol 2021; 3:000247. [PMID: 34888478 PMCID: PMC8650843 DOI: 10.1099/acmi.0.000247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 06/17/2021] [Indexed: 12/19/2022] Open
Abstract
A microbiome is defined as the aggregate of all microbiota that reside in human digestive system and other tissues. This microbiota includes viruses, bacteria, fungi that live in various human organs and tissues like stomach, guts, oesophagus, mouth cavity, urinary tract, vagina, lungs, and skin. Almost 20 % of malignant cancers worldwide are related to microbial infections including bacteria, parasites, and viruses. The human body is constantly being attacked by microbes during its lifetime and microbial pathogens that have tumorigenic effects in 15-20 % of reported cancer cases. Recent scientific advances and the discovery of the effect of microbes on cancer as a pathogen or as a drug have significantly contributed to our understanding of the complex relationship between microbiome and cancer. The aim of this study is to overview some microbiomes that reside in the human body and their roles in cancer.
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Affiliation(s)
| | - Hamed Mehraban
- Department of Biology, Payame Noor University (PNU), Tehran, Iran
| | - Behnaz Naji
- Department of Microbiology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Mohadeseh Radmehr
- Department of Microbiology, Damghan Branch, Islamic Azad University, Damghan, Iran
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19
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Saniee P, Jalili S, Ghadersoltani P, Daliri L, Siavoshi F. Individual hosts carry H. pylori isolates with different cagA features - motifs and copy number. INFECTION GENETICS AND EVOLUTION 2021; 93:104961. [PMID: 34119688 DOI: 10.1016/j.meegid.2021.104961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 03/23/2021] [Accepted: 06/02/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND H. pylori strains with different genetic contents may infect different or an individual human host. Genetic diversity of cagA is thought to contribute to differences in H. pylori strains pathogenicity. In this study, diversity of cagA genotype, EPIYA motif and copy number was assessed in H. pylori single colonies isolated from individual patients. MATERIALS AND METHODS Gastric biopsies from 14H. pylori-positive dyspeptic patients were cultured on selective brucella blood agar and incubated at 37 °C under microaerobic conditions. Four single colonies were obtained from each biopsy subculture on brucella blood agar under similar incubation condition. Presence of cagA and types of EPIYA motifs was determined by polymerase chain reaction (PCR) and cagA copy number by quantitative real-time (RT) PCR. RESULTS Single colonies of 5 patients showed no variation in cagA genotype, EPIYA motif and copy number. Out of the remaining 9 patients, 1 patient showed presence or absence of cagA gene, 2 patients had mixed EPIYA motifs, 2 patients had different cagA copy number, 1 patient showed absence or presence of cagA and mixed motifs, 2 patients had cagA genes with different nucleotide sequences, 1 patient showed presence or absence of cagA and difference in cagA nucleotide sequence. Four isolates that contained multiple copies of cagA, carried EPIYA-ABC motif. CONCLUSION Genetic diversity of cagA among single colonies isolated from individual patients represents evidence that gastric mucosa of every individual is colonized with a specific and heterogeneous population of H. pylori. Future studies on patients in different disease groups may elucidate the role of mixed populations of H. pylori in development of gastric diseases.
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Affiliation(s)
- Parastoo Saniee
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G.C, Tehran, Iran.
| | - Shiva Jalili
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G.C, Tehran, Iran
| | - Paria Ghadersoltani
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G.C, Tehran, Iran
| | - Layegheh Daliri
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G.C, Tehran, Iran
| | - Farideh Siavoshi
- Department of Microbiology, School of Biology, University College of Sciences, University of Tehran, Tehran, Iran
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20
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Roberts-Thomson IC. How did the ancient bacterium, Helicobacter pylori, cause an epidemic of chronic duodenal ulceration? JGH OPEN 2021; 5:636-642. [PMID: 34124378 PMCID: PMC8171156 DOI: 10.1002/jgh3.12560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022]
Abstract
The association of Helicobacter pylori with chronic duodenal ulceration was a seminal observation in the short history of gastroenterology. However, H. pylori is now known to be an ancient bacterium, whereas there is persuasive evidence that the epidemic of duodenal ulceration began in the second half of the 19th century and continued into the second half of the 20th century. Possible explanations for the epidemic include genomic changes in the organism and environmental or other influences on the human host. While genomic changes resulted in the appearance of virulence factors, these seem likely to have appeared thousands of years ago with minimal effects on gastritis because of coexisting suppression of gastric immunity. In contrast, the emergence of duodenal ulceration is best explained by a change in the pattern of gastritis from inflammation involving the antrum and body in most individuals to a significant minority (10-20%) with antral gastritis but with relative sparing of the body of the stomach. In the latter group, the increase in serum gastrin (particularly G17) associated with antral gastritis had trophic effects on gastric parietal cells with an increase in the parietal cell mass and hypersecretion of gastric acid. Hypersecretion of acid is seen as the major risk factor for duodenal ulceration with significant contributions from environmental factors including smoking and use of nonsteroidal, anti-inflammatory drugs. Host factors favoring changes in the pattern of gastritis include delayed acquisition of infection and improved nutrition; both with enhancing effects on mucosal immunity.
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Affiliation(s)
- Ian C Roberts-Thomson
- Faculty of Health and Medical Sciences University of Adelaide Adelaide South Australia Australia
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21
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Castillo AI, Almeida RPP. Evidence of gene nucleotide composition favoring replication and growth in a fastidious plant pathogen. G3-GENES GENOMES GENETICS 2021; 11:6170658. [PMID: 33715000 PMCID: PMC8495750 DOI: 10.1093/g3journal/jkab076] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 03/02/2021] [Indexed: 11/13/2022]
Abstract
Nucleotide composition (GC content) varies across bacteria species, genome regions, and specific genes. In Xylella fastidiosa, a vector-borne fastidious plant pathogen infecting multiple crops, GC content ranges between ∼51-52%; however, these values were gathered using limited genomic data. We evaluated GC content variations across X. fastidiosa subspecies fastidiosa (N = 194), subsp. pauca (N = 107), and subsp. multiplex (N = 39). Genomes were classified based on plant host and geographic origin; individual genes within each genome were classified based on gene function, strand, length, ortholog group, Core vs. Accessory, and Recombinant vs. Non-recombinant. GC content was calculated for each gene within each evaluated genome. The effects of genome and gene level variables were evaluated with a mixed effect ANOVA, and the marginal-GC content was calculated for each gene. Also, the correlation between gene-specific GC content vs. natural selection (dN/dS) and recombination/mutation (r/m) was estimated. Our analyses show that intra-genomic changes in nucleotide composition in X. fastidiosa are small and influenced by multiple variables. Higher AT-richness is observed in genes involved in replication and translation, and genes in the leading strand. In addition, we observed a negative correlation between high-AT and dN/dS in subsp. pauca. The relationship between recombination and GC content varied between core and accessory genes. We hypothesize that distinct evolutionary forces and energetic constraints both drive and limit these small variations in nucleotide composition.
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Affiliation(s)
- Andreina I Castillo
- Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720, USA
| | - Rodrigo P P Almeida
- Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720, USA
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22
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Crowley E, Hussey S. Helicobacter pylori in Childhood. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:275-292.e12. [DOI: 10.1016/b978-0-323-67293-1.00027-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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23
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Jackson LK, Potter B, Schneider S, Fitzgibbon M, Blair K, Farah H, Krishna U, Bedford T, Peek RM, Salama NR. Helicobacter pylori diversification during chronic infection within a single host generates sub-populations with distinct phenotypes. PLoS Pathog 2020; 16:e1008686. [PMID: 33370399 PMCID: PMC7794030 DOI: 10.1371/journal.ppat.1008686] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 01/08/2021] [Accepted: 10/22/2020] [Indexed: 12/15/2022] Open
Abstract
Helicobacter pylori chronically infects the stomach of approximately half of the world's population. Manifestation of clinical diseases associated with H. pylori infection, including cancer, is driven by strain properties and host responses; and as chronic infection persists, both are subject to change. Previous studies have documented frequent and extensive within-host bacterial genetic variation. To define how within-host diversity contributes to phenotypes related to H. pylori pathogenesis, this project leverages a collection of 39 clinical isolates acquired prospectively from a single subject at two time points and from multiple gastric sites. During the six years separating collection of these isolates, this individual, initially harboring a duodenal ulcer, progressed to gastric atrophy and concomitant loss of acid secretion. Whole genome sequence analysis identified 1,767 unique single nucleotide polymorphisms (SNPs) across isolates and a nucleotide substitution rate of 1.3x10-4 substitutions/site/year. Gene ontology analysis identified cell envelope genes among the genes with excess accumulation of nonsynonymous SNPs (nSNPs). A maximum likelihood tree based on genetic similarity clusters isolates from each time point separately. Within time points, there is segregation of subgroups with phenotypic differences in bacterial morphology, ability to induce inflammatory cytokines, and mouse colonization. Higher inflammatory cytokine induction in recent isolates maps to shared polymorphisms in the Cag PAI protein, CagY, while rod morphology in a subgroup of recent isolates mapped to eight mutations in three distinct helical cell shape determining (csd) genes. The presence of subgroups with unique genetic and phenotypic properties suggest complex selective forces and multiple niches within the stomach during chronic infection.
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Affiliation(s)
- Laura K. Jackson
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, United States of America
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - Barney Potter
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - Sean Schneider
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - Matthew Fitzgibbon
- Genomics & Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - Kris Blair
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, United States of America
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - Hajirah Farah
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Department of Microbiology, University of Washington School of Medicine, Seattle, WA, United States of America
| | - Uma Krishna
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - Trevor Bedford
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - Nina R. Salama
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, United States of America
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
- Department of Microbiology, University of Washington School of Medicine, Seattle, WA, United States of America
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24
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In Vivo Genome and Methylome Adaptation of cag-Negative Helicobacter pylori during Experimental Human Infection. mBio 2020; 11:mBio.01803-20. [PMID: 32843556 PMCID: PMC7448279 DOI: 10.1128/mbio.01803-20] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Exceptional genetic diversity and variability are hallmarks of Helicobacter pylori, but the biological role of this plasticity remains incompletely understood. Here, we had the rare opportunity to investigate the molecular evolution during the first weeks of H. pylori infection by comparing the genomes and epigenomes of H. pylori strain BCS 100 used to challenge human volunteers in a vaccine trial with those of bacteria reisolated from the volunteers 10 weeks after the challenge. The data provide molecular insights into the process of establishment of this highly versatile pathogen in 10 different human individual hosts, showing, for example, selection for changes in host-interaction molecules as well as changes in epigenetic methylation patterns. The data provide important clues to the early adaptation of H. pylori to new host niches after transmission, which we believe is vital to understand its success as a chronic pathogen and develop more efficient treatments and vaccines. Multiple studies have demonstrated rapid bacterial genome evolution during chronic infection with Helicobacter pylori. In contrast, little was known about genetic changes during the first stages of infection, when selective pressure is likely to be highest. Using single-molecule, real-time (SMRT) and Illumina sequencing technologies, we analyzed genome and methylome evolution during the first 10 weeks of infection by comparing the cag pathogenicity island (cagPAI)-negative H. pylori challenge strain BCS 100 with pairs of H. pylori reisolates from gastric antrum and corpus biopsy specimens of 10 human volunteers who had been infected with this strain as part of a vaccine trial. Most genetic changes detected in the reisolates affected genes with a surface-related role or a predicted function in peptide uptake. Apart from phenotypic changes of the bacterial envelope, a duplication of the catalase gene was observed in one reisolate, which resulted in higher catalase activity and improved survival under oxidative stress conditions. The methylomes also varied in some of the reisolates, mostly by activity switching of phase-variable methyltransferase (MTase) genes. The observed in vivo mutation spectrum was remarkable for a very high proportion of nonsynonymous mutations. Although the data showed substantial within-strain genome diversity in the challenge strain, most antrum and corpus reisolates from the same volunteers were highly similar to each other, indicating that the challenge infection represents a major selective bottleneck shaping the transmitted population. Our findings suggest rapid in vivo selection of H. pylori during early-phase infection providing adaptation to different individuals by common mechanisms of genetic and epigenetic alterations.
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25
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Outer inflammatory protein of Helicobacter pylori impacts IL-8 expression, adherence, cell apoptosis and cell cycle of gastric cells independent of its copy number. Med Microbiol Immunol 2020; 209:621-630. [PMID: 32607764 DOI: 10.1007/s00430-020-00688-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 06/23/2020] [Indexed: 12/20/2022]
Abstract
Outer inflammatory protein (OipA) is an important virulence factor of Helicobacter pylori (H. pylori), but the correlation between oipA copy number and its virulence remains unknown. The study was designed to investigate whether the duplicate oipA gene loci showed more virulent than one oipA gene in vitro. H. pylori strain CCS9803 (China Chongqing Strain 9803) that carries duplicate oipA loci was used to construct one or two oipA knockout mutant strain, which was further verified by qPCR and western blot. Gastric epithelial cells AGS and GES-1 were infected with wild-type (WT) or oipA mutants for 6 or 24 h. The expression levels of IL-8, bacterial adhesion, cell apoptosis and cell cycle were performed to analyze the function of oipA. The WT and oipA mutant strains induce significantly higher mRNA and protein levels of IL-8 than the uninfected group (P < 0.05), but only oipA2 mutants induced significantly decreased expression levels than the WT-infected group (P < 0.05). Adherence to gastric cells was significantly decreased by inactivated two oipA loci (P < 0.05). The WT strain caused a significant rising proportion of early apoptosis cell, which had dropped after duplicate oipA genes were both knockout (P < 0.05). WT and oipA1 mutants failed to affect cell cycle; however, the oipA2 mutants increased M phase and reduced S phase when compared to the uninfected group. In conclusion, our study demonstrated that oipA impacts IL-8 expression, adherence, cell apoptosis and cell cycle of gastric cells independent of its gene copy number.
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26
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Detection of Helicobacter pylori Microevolution and Multiple Infection from Gastric Biopsies by Housekeeping Gene Amplicon Sequencing. Pathogens 2020; 9:pathogens9020097. [PMID: 32033301 PMCID: PMC7168683 DOI: 10.3390/pathogens9020097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 01/20/2020] [Accepted: 02/03/2020] [Indexed: 02/06/2023] Open
Abstract
Despite the great efforts devoted to research on Helicobacter pylori, the prevalence of single-strain infection or H. pylori mixed infection and its implications in the mode of transmission of this bacterium are still controversial. In this study, we explored the usefulness of housekeeping gene amplicon sequencing in the detection of H. pylori microevolution and multiple infections. DNA was extracted from five gastric biopsies from four patients infected with distinct histopathological diagnoses. PCR amplification of six H. pylori-specific housekeeping genes was then assessed on each sample. Optimal results were obtained for the cgt and luxS genes, which were selected for amplicon sequencing. A total of 11,833 cgt and 403 luxS amplicon sequences were obtained, 2042 and 112 of which were unique sequences, respectively. All cgt and luxS sequences were clustered at 97% to 9 and 13 operational taxonomic units (OTUs), respectively. For each sample from a different patient, a single OTU comprised the majority of sequences in both genes, but more than one OTU was detected in all samples. These results suggest that multiple infections with a predominant strain together with other minority strains are the main way by which H. pylori colonizes the human stomach.
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27
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Lamichhane B, Wise MJ, Chua EG, Marshall BJ, Tay CY. A novel taxon selection method, aimed at minimizing recombination, clarifies the discovery of a new sub-population of Helicobacter pylori from Australia. Evol Appl 2020; 13:278-289. [PMID: 31993076 PMCID: PMC6976958 DOI: 10.1111/eva.12864] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 07/21/2019] [Accepted: 08/26/2019] [Indexed: 12/16/2022] Open
Abstract
We present a novel method for taxon selection, the aim being to minimize problems arising from highly recombinant species such as Helicobacter pylori. Helicobacter pylori has accompanied modern-human migration out of Africa and is marked by a phylogeographic strain distribution, which has been exploited to add an extra layer of information about human migrations to that obtained from human sources. However, H. pylori's genome has high sequence heterogeneity combined with a very high rate of recombination, causing major allelic diversification across strains. On the other hand, recombination events that have become preserved in sub-populations are a useful source of phylogenetic information. This creates a potential problem in selecting representative strains for particular genetic or phylogeographic clusters and generally ameliorating the impact on analyses of extensive low-level recombination. To address this issue, we perform multiple population structure-based analyses on core genomes to select exemplar strains, called 'quintessents', which exhibit limited recombination. In essence, quintessent strains are representative of their specific phylogenetic clades and can be used to refine the current MLST concatenation-based population structure classification system. The use of quintessents reduces the noise due to local recombination events, while preserving recombination events that have become fixed in sub-populations. We illustrate the method with an analysis of core genome concatenations from 185 H. pylori strains, which reveals a recent speciation event resulting from the recombination of strains from phylogeographic clade hpSahul, carried by Aboriginal Australians, and hpEurope, carried by some of the people who arrived in Australia over the past 200 years. The signal is much clearer when based on quintessent strains, but absent from the analysis based on MLST concatenations.
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Affiliation(s)
- Binit Lamichhane
- Helicobacter pylori Research LaboratoryMarshall Centre for Infectious Disease Research and TrainingSchool of Biomedical SciencesUniversity of Western AustraliaPerthWAAustralia
| | - Michael J. Wise
- Helicobacter pylori Research LaboratoryMarshall Centre for Infectious Disease Research and TrainingSchool of Biomedical SciencesUniversity of Western AustraliaPerthWAAustralia
- Department of Computer Science and Software EngineeringUniversity of Western AustraliaPerthWAAustralia
| | - Eng Guan Chua
- Helicobacter pylori Research LaboratoryMarshall Centre for Infectious Disease Research and TrainingSchool of Biomedical SciencesUniversity of Western AustraliaPerthWAAustralia
| | - Barry J. Marshall
- Helicobacter pylori Research LaboratoryMarshall Centre for Infectious Disease Research and TrainingSchool of Biomedical SciencesUniversity of Western AustraliaPerthWAAustralia
| | - Chin Yen Tay
- Helicobacter pylori Research LaboratoryMarshall Centre for Infectious Disease Research and TrainingSchool of Biomedical SciencesUniversity of Western AustraliaPerthWAAustralia
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28
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Identification of the periplasmic DNA receptor for natural transformation of Helicobacter pylori. Nat Commun 2019; 10:5357. [PMID: 31767852 PMCID: PMC6877725 DOI: 10.1038/s41467-019-13352-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 10/31/2019] [Indexed: 02/08/2023] Open
Abstract
Horizontal gene transfer through natural transformation is a major driver of antibiotic resistance spreading in many pathogenic bacterial species. In the case of Gram-negative bacteria, and in particular of Helicobacter pylori, the mechanisms underlying the handling of the incoming DNA within the periplasm are poorly understood. Here we identify the protein ComH as the periplasmic receptor for the transforming DNA during natural transformation in H. pylori. ComH is a DNA-binding protein required for the import of DNA into the periplasm. Its C-terminal domain displays strong affinity for double-stranded DNA and is sufficient for the accumulation of DNA in the periplasm, but not for DNA internalisation into the cytoplasm. The N-terminal region of the protein allows the interaction of ComH with a periplasmic domain of the inner-membrane channel ComEC, which is known to mediate the translocation of DNA into the cytoplasm. Our results indicate that ComH is involved in the import of DNA into the periplasm and its delivery to the inner membrane translocator ComEC. Some bacteria can take up DNA molecules from the environment. Here, Damke et al. identify a DNA-binding protein in Helicobacter pylori that is required for DNA import into the periplasm and that interacts with an inner-membrane channel that translocates the DNA into the cytoplasm.
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29
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Douglas GM, Langille MGI. Current and Promising Approaches to Identify Horizontal Gene Transfer Events in Metagenomes. Genome Biol Evol 2019; 11:2750-2766. [PMID: 31504488 PMCID: PMC6777429 DOI: 10.1093/gbe/evz184] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2019] [Indexed: 12/16/2022] Open
Abstract
High-throughput shotgun metagenomics sequencing has enabled the profiling of myriad natural communities. These data are commonly used to identify gene families and pathways that were potentially gained or lost in an environment and which may be involved in microbial adaptation. Despite the widespread interest in these events, there are no established best practices for identifying gene gain and loss in metagenomics data. Horizontal gene transfer (HGT) represents several mechanisms of gene gain that are especially of interest in clinical microbiology due to the rapid spread of antibiotic resistance genes in natural communities. Several additional mechanisms of gene gain and loss, including gene duplication, gene loss-of-function events, and de novo gene birth are also important to consider in the context of metagenomes but have been less studied. This review is largely focused on detecting HGT in prokaryotic metagenomes, but methods for detecting these other mechanisms are first discussed. For this article to be self-contained, we provide a general background on HGT and the different possible signatures of this process. Lastly, we discuss how improved assembly of genomes from metagenomes would be the most straight-forward approach for improving the inference of gene gain and loss events. Several recent technological advances could help improve metagenome assemblies: long-read sequencing, determining the physical proximity of contigs, optical mapping of short sequences along chromosomes, and single-cell metagenomics. The benefits and limitations of these advances are discussed and open questions in this area are highlighted.
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Affiliation(s)
- Gavin M Douglas
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Morgan G I Langille
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
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30
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Ram Y, Hadany L. Evolution of Stress-Induced Mutagenesis in the Presence of Horizontal Gene Transfer. Am Nat 2019; 194:73-89. [PMID: 31251650 DOI: 10.1086/703457] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Stress-induced mutagenesis has been observed in multiple species of bacteria and yeast. It has been suggested that in asexual populations, a mutator allele that increases the mutation rate during stress can sweep to fixation with the beneficial mutations it generates. However, even asexual microbes can undergo horizontal gene transfer and rare recombination, which typically interfere with the spread of mutator alleles. Here we examine the effect of horizontal gene transfer on the evolutionary advantage of stress-induced mutator alleles. Our results demonstrate that stress-induced mutator alleles are favored by selection even in the presence of horizontal gene transfer and more so when the mutator alleles also increase the rate of horizontal gene transfer. We suggest that when regulated by stress, mutation and horizontal gene transfer can be complementary rather than competing adaptive strategies and that stress-induced mutagenesis has important implications for evolutionary biology, ecology, and epidemiology, even in the presence of horizontal gene transfer and rare recombination.
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31
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Dominguez RL, Cherry CB, Estevez-Ordonez D, Mera R, Escamilla V, Pawlita M, Waterboer T, Wilson KT, Peek RM, Tavera G, Williams SM, Gulley ML, Emch M, Morgan DR. Geospatial analyses identify regional hot spots of diffuse gastric cancer in rural Central America. BMC Cancer 2019; 19:545. [PMID: 31174492 PMCID: PMC6554991 DOI: 10.1186/s12885-019-5726-x] [Citation(s) in RCA: 2] [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: 05/04/2018] [Accepted: 05/16/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Geospatial technology has facilitated the discovery of disease distributions and etiology and helped target prevention programs. Globally, gastric cancer is the leading infection-associated cancer, and third leading cause of cancer mortality worldwide, with marked geographic variation. Central and South America have a significant burden, particularly in the mountainous regions. In the context of an ongoing population-based case-control study in Central America, our aim was to examine the spatial epidemiology of gastric cancer subtypes and H. pylori virulence factors. METHODS Patients diagnosed with gastric cancer from 2002 to 2013 in western Honduras were identified in the prospective gastric cancer registry at the principal district hospital. Diagnosis was based on endoscopy and confirmatory histopathology. Geospatial methods were applied using the ArcGIS v10.3.1 and SaTScan v9.4.2 platforms to examine regional distributions of the gastric cancer histologic subtypes (Lauren classification), and the H. pylori CagA virulence factor. Getis-Ord-Gi hot spot and Discrete Poisson SaTScan statistics, respectively, were used to explore spatial clustering at the village level (30-50 rural households), with standardization by each village's population. H. pylori and CagA serologic status was determined using the novel H. pylori multiplex assay (DKFZ, Germany). RESULTS Three hundred seventy-eight incident cases met the inclusion criteria (mean age 63.7, male 66.3%). Areas of higher gastric cancer incidence were identified. Significant spatial clustering of diffuse histology adenocarcinoma was revealed both by the Getis-Ord-GI* hot spot analysis (P-value < 0.0015; range 0.00003-0.0014; 99%CI), and by the SaTScan statistic (P-value < 0.006; range 0.0026-0.0054). The intestinal subtype was randomly distributed. H. pylori CagA had significant spatial clustering only in association with the diffuse histology cancer hot spot (Getis-Ord-Gi* P value ≤0.001; range 0.0001-0.0010; SaTScan statistic P value 0.0085). In the diffuse gastric cancer hot spot, the lowest age quartile range was 21-46 years, significantly lower than the intestinal cancers (P = 0.024). CONCLUSIONS Geospatial methods have identified a significant cluster of incident diffuse type adenocarcinoma cases in rural Central America, suggest of a germline genetic association. Further genomic and geospatial analyses to identify potential spatial patterns of genetic, bacterial, and environmental risk factors may be informative.
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Affiliation(s)
| | - Charlotte B Cherry
- Office of Public Health Informatics & Analytics, Tennessee Department of Public Health, Nashville, TN, USA
| | - Dago Estevez-Ordonez
- Vanderbilt Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, USA
| | - Robertino Mera
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, USA
| | - Veronica Escamilla
- Carolina Population Center, University of North Carolina, Chapel Hill, USA
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tim Waterboer
- Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, USA
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, USA
| | - Gloria Tavera
- Department of Population and Quantitative Health Sciences and Institute of Computational Biology, Case Western Reserve University, Cleveland, USA
| | - Scott M Williams
- Department of Population and Quantitative Health Sciences and Institute of Computational Biology, Case Western Reserve University, Cleveland, USA
| | - Margaret L Gulley
- Department of Pathology, University of North Carolina, Chapel Hill, USA
| | - Michael Emch
- Department of Geography, University of North Carolina, Chapel Hill, USA
| | - Douglas R Morgan
- Vanderbilt Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, USA.
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, USA.
- Division of Gastroenterology and Hepatology, The University of Alabama at Birmingham (UAB), 1808 7th Avenue South, BDB 373, Birmingham, AL, 35233, USA.
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Ailloud F, Didelot X, Woltemate S, Pfaffinger G, Overmann J, Bader RC, Schulz C, Malfertheiner P, Suerbaum S. Within-host evolution of Helicobacter pylori shaped by niche-specific adaptation, intragastric migrations and selective sweeps. Nat Commun 2019; 10:2273. [PMID: 31118420 PMCID: PMC6531487 DOI: 10.1038/s41467-019-10050-1] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 04/10/2019] [Indexed: 02/07/2023] Open
Abstract
The human pathogen Helicobacter pylori displays extensive genetic diversity. While H. pylori is known to evolve during infection, population dynamics inside the gastric environment have not been extensively investigated. Here we obtained gastric biopsies from multiple stomach regions of 16 H. pylori-infected adults, and analyze the genomes of 10 H. pylori isolates from each biopsy. Phylogenetic analyses suggest location-specific evolution and bacterial migration between gastric regions. Migration is significantly more frequent between the corpus and the fundus than with the antrum, suggesting that physiological differences between antral and oxyntic mucosa contribute to spatial partitioning of H. pylori populations. Associations between H. pylori gene polymorphisms and stomach niches suggest that chemotaxis, regulatory functions and outer membrane proteins contribute to specific adaptation to the antral and oxyntic mucosa. Moreover, we show that antibiotics can induce severe population bottlenecks and likely play a role in shaping the population structure of H. pylori.
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Affiliation(s)
- Florent Ailloud
- Department of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, 80336, Munich, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, MHH Hannover Medical School, 30625, Hannover, Germany
- DZIF German Center for Infection Research, Munich Site, Munich, Germany
- DZIF German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany
| | - Xavier Didelot
- School of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK
- Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK
| | - Sabrina Woltemate
- Institute of Medical Microbiology and Hospital Epidemiology, MHH Hannover Medical School, 30625, Hannover, Germany
| | - Gudrun Pfaffinger
- Department of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, 80336, Munich, Germany
| | - Jörg Overmann
- DZIF German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany
- Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, 38124, Braunschweig, Germany
| | - Ruth Christiane Bader
- Department of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, 80336, Munich, Germany
- National Reference Center for Helicobacter pylori, Max von Pettenkofer Institute, 80336, Munich, Germany
| | - Christian Schulz
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University, 39106, Magdeburg, Germany
- Department of Medicine 2, University Hospital, LMU Munich, 81377, Munich, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University, 39106, Magdeburg, Germany
- Department of Medicine 2, University Hospital, LMU Munich, 81377, Munich, Germany
| | - Sebastian Suerbaum
- Department of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, 80336, Munich, Germany.
- Institute of Medical Microbiology and Hospital Epidemiology, MHH Hannover Medical School, 30625, Hannover, Germany.
- DZIF German Center for Infection Research, Munich Site, Munich, Germany.
- DZIF German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany.
- National Reference Center for Helicobacter pylori, Max von Pettenkofer Institute, 80336, Munich, Germany.
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Rizzato C, Torres J, Kasamatsu E, Camorlinga-Ponce M, Bravo MM, Canzian F, Kato I. Potential Role of Biofilm Formation in the Development of Digestive Tract Cancer With Special Reference to Helicobacter pylori Infection. Front Microbiol 2019; 10:846. [PMID: 31110496 PMCID: PMC6501431 DOI: 10.3389/fmicb.2019.00846] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/02/2019] [Indexed: 12/16/2022] Open
Abstract
Bacteria are highly social organisms that communicate via signaling molecules and can assume a multicellular lifestyle to build biofilm communities. Until recently, complications from biofilm-associated infection have been primarily ascribed to increased bacterial resistance to antibiotics and host immune evasion, leading to persistent infection. In this theory and hypothesis article we present a relatively new argument that biofilm formation has potential etiological role in the development of digestive tract cancer. First, we summarize recent new findings suggesting the potential link between bacterial biofilm and various types of cancer to build the foundation of our hypothesis. To date, evidence has been particularly convincing for colorectal cancer and its precursor, i.e., polyps, pointing to several key individual bacterial species, such as Bacteroides fragilis, Fusobacterium nucleatum, and Streptococcus gallolyticus subsp. Gallolyticus. Then, we further extend this hypothesis to one of the most common bacterial infection in humans, Helicobacter pylori (Hp), which is considered a major cause of gastric cancer. Thus far, there has been no direct evidence linking in vivo Hp gastric biofilm formation to gastric carcinogenesis. Yet, we synthesize the information to support an argument that biofilm associated-Hp is potentially more carcinogenic, summarizing biological characteristics of biofilm-associated bacteria. We also discuss mechanistic pathways as to how Hp or other biofilm-associated bacteria control biofilm formation and highlight recent findings on Hp genes that influence biofilm formation, which may lead to strain variability in biofilm formation. This knowledge may open a possibility of developing targeted intervention. We conclude, however, that this field is still in its infancy. To test the hypothesis rigorously and to link it ultimately to gastric pathologies (e.g., premalignant lesions and cancer), studies are needed to learn more about Hp biofilms, such as compositions and biological properties of extracellular polymeric substance (EPS), presence of non-Hp microbiome and geographical distribution of biofilms in relation to gastric gland types and structures. Identification of specific Hp strains with enhanced biofilm formation would be helpful not only for screening patients at high risk for sequelae from Hp infection, but also for development of new antibiotics to avoid resistance, regardless of its association with gastric cancer.
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Affiliation(s)
- Cosmeri Rizzato
- Department of Translation Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, Unidades Médicas de Alta Especialidad Pediatría, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Elena Kasamatsu
- Instituto de Investigaciones en Ciencias de la Salud, National University of Asunción, Asunción, Paraguay
| | - Margarita Camorlinga-Ponce
- Unidad de Investigación en Enfermedades Infecciosas, Unidades Médicas de Alta Especialidad Pediatría, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Maria Mercedes Bravo
- Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología, Bogotá, Colombia
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ikuko Kato
- Department of Oncology and Pathology, Wayne State University School of Medicine, Detroit, MI, United States
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Estibariz I, Overmann A, Ailloud F, Krebes J, Josenhans C, Suerbaum S. The core genome m5C methyltransferase JHP1050 (M.Hpy99III) plays an important role in orchestrating gene expression in Helicobacter pylori. Nucleic Acids Res 2019; 47:2336-2348. [PMID: 30624738 PMCID: PMC6412003 DOI: 10.1093/nar/gky1307] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 12/18/2018] [Accepted: 12/21/2018] [Indexed: 12/20/2022] Open
Abstract
Helicobacter pylori encodes a large number of restriction-modification (R-M) systems despite its small genome. R-M systems have been described as 'primitive immune systems' in bacteria, but the role of methylation in bacterial gene regulation and other processes is increasingly accepted. Every H. pylori strain harbours a unique set of R-M systems resulting in a highly diverse methylome. We identified a highly conserved GCGC-specific m5C MTase (JHP1050) that was predicted to be active in all of 459 H. pylori genome sequences analyzed. Transcriptome analysis of two H. pylori strains and their respective MTase mutants showed that inactivation of the MTase led to changes in the expression of 225 genes in strain J99, and 29 genes in strain BCM-300. Ten genes were differentially expressed in both mutated strains. Combining bioinformatic analysis and site-directed mutagenesis, we demonstrated that motifs overlapping the promoter influence the expression of genes directly, while methylation of other motifs might cause secondary effects. Thus, m5C methylation modifies the transcription of multiple genes, affecting important phenotypic traits that include adherence to host cells, natural competence for DNA uptake, bacterial cell shape, and susceptibility to copper.
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Affiliation(s)
- Iratxe Estibariz
- Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, München, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Munich Site, Munich, Germany
| | - Annemarie Overmann
- Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, München, Germany
| | - Florent Ailloud
- Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, München, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Munich Site, Munich, Germany
| | - Juliane Krebes
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Christine Josenhans
- Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, München, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Munich Site, Munich, Germany
| | - Sebastian Suerbaum
- Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, München, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Munich Site, Munich, Germany
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The Story of Helicobacter pylori: Depicting Human Migrations from the Phylogeography. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:1-16. [PMID: 31016625 DOI: 10.1007/5584_2019_356] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori is a spiral-shaped Gram-negative bacterium, which has infected more than half of the human population. Besides its colonisation capability, the genetic diversity of H. pylori is exceptionally well structured and belongs to several distinct genetic populations, depicting various prehistorical human migration events. The evolutionary relationship of H. pylori with its host had been started at least ~100,000 years ago. In addition, the discovery of the ancient H. pylori genome from a European Copper Age glacier mummy, "The Iceman", gave the idea that the second out of Africa migration resulted in the recombinant population of hpEurope at least about 5300 years ago. The advancement of next-generation genome sequencing discovered the prophage of H. pylori and could discriminate the big population of hpEurope into two different subpopulations. In addition, the implementation of the chromopainter/fineSTRUCTURE algorithm to the whole genome analysis of H. pylori provides a finer resolution population genetics of H. pylori; therefore it could also depict the recent migrations within the past 500 years after colonial expansion. This discovery shows that the genetic recombination of H. pylori strains is far more dynamic compared to its human host, but still maintains the similarity to its host, suggesting that H. pylori is a handy tool to reconstruct the human migration both in the past and the recent.
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Chattopadhyay S, Chi PB, Minin VN, Berg DE, Sokurenko EV. Recombination-independent rapid convergent evolution of the gastric pathogen Helicobacter pylori. BMC Genomics 2018; 19:835. [PMID: 30463511 PMCID: PMC6249973 DOI: 10.1186/s12864-018-5231-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Accepted: 11/07/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Helicobacter pylori is a human stomach pathogen, naturally-competent for DNA uptake, and prone to homologous recombination. Extensive homoplasy (i.e., phylogenetically-unlinked identical variations) observed in H. pylori genes is considered a hallmark of such recombination. However, H. pylori also exhibits a high mutation rate. The relative adaptive role of homologous recombination and mutation in species diversity is a highly-debated issue in biology. Recombination results in homoplasy. While convergent mutation can also account for homoplasy, its contribution is thought to be minor. We demonstrate here that, contrary to dogma, convergent mutation is a key contributor to Helicobacter pylori homoplasy, potentially driven by adaptive evolution of proteins. RESULTS Our present genome-wide analysis shows that homoplastic nonsynonymous (amino acid replacement) changes are not typically accompanied by homoplastic synonymous (silent) variations. Moreover, the majority of the codon positions with homoplastic nonsynonymous changes also contain different (i.e. non-homoplastic) nonsynonymous changes arising from mutation only. This indicates that, to a considerable extent, nonsynonymous homoplasy is due to convergent mutations. High mutation rate or limited availability of evolvable sites cannot explain this excessive convergence, as suggested by our simulation studies. Rather, the genes with convergent mutations are overrepresented in distinct functional categories, suggesting possible selective responses to conditions such as distinct micro-niches in single hosts, and to differences in host genotype, physiology, habitat and diet. CONCLUSIONS We propose that mutational convergence is a key player in H. pylori's adaptation and extraordinary persistence in human hosts. High frequency of mutational convergence could be due to saturation of evolvable sites capable of responding to selection pressures, while the number of mutable residues is far from saturation. We anticipate a similar scenario of mutational vs. recombinational genome dynamics or plasticity for other naturally competent microbes where strong positive selection could favor frequent convergent mutations in adaptive protein evolution.
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Affiliation(s)
| | - Peter B Chi
- Department of Mathematics and Statistics, Villanova University, Villanova, PA, USA
| | - Vladimir N Minin
- Department of Statistics, University of California, Irvine, California, USA
| | - Douglas E Berg
- Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Evgeni V Sokurenko
- Department of Microbiology, University of Washington, Seattle, Washington, USA
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Noto JM, Chopra A, Loh JT, Romero-Gallo J, Piazuelo MB, Watson M, Leary S, Beckett AC, Wilson KT, Cover TL, Mallal S, Israel DA, Peek RM. Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments. Gut 2018; 67:1793-1804. [PMID: 28924022 PMCID: PMC5857411 DOI: 10.1136/gutjnl-2017-313863] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 06/30/2017] [Accepted: 07/15/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Helicobacter pylori is the strongest risk factor for gastric cancer; however, the majority of infected individuals do not develop disease. Pathological outcomes are mediated by complex interactions among bacterial, host and environmental constituents, and two dietary factors linked with gastric cancer risk are iron deficiency and high salt. We hypothesised that prolonged adaptation of H. pylori to in vivo carcinogenic microenvironments results in genetic modification important for disease. DESIGN Whole genome sequencing of genetically related H. pylori strains that differ in virulence and targeted H. pylori sequencing following prolonged exposure of bacteria to in vitro carcinogenic conditions were performed. RESULTS A total of 180 unique single nucleotide polymorphisms (SNPs) were identified among the collective genomes when compared with a reference H. pylori genome. Importantly, common SNPs were identified in isolates harvested from iron-depleted and high salt carcinogenic microenvironments, including an SNP within fur (FurR88H). To investigate the direct role of low iron and/or high salt, H. pylori was continuously cultured in vitro under low iron or high salt conditions to assess fur genetic variation. Exposure to low iron or high salt selected for the FurR88H variant after only 5 days. To extend these results, fur was sequenced in 339 clinical H. pylori strains. Among the isolates examined, 17% (40/232) of strains isolated from patients with premalignant lesions harboured the FurR88H variant, compared with only 6% (6/107) of strains from patients with non-atrophic gastritis alone (p=0.0034). CONCLUSION These results indicate that specific genetic variation arises within H. pylori strains during in vivo adaptation to conditions conducive for gastric carcinogenesis.
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Affiliation(s)
- Jennifer M Noto
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Abha Chopra
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - John T Loh
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Judith Romero-Gallo
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mark Watson
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Shay Leary
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Amber C Beckett
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Keith T Wilson
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Timothy L Cover
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA,Department of Medicine, Division of Infectious Diseases, Vanderbilt University, Nashville, Tennessee, USA
| | - Simon Mallal
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia,Department of Medicine, Division of Infectious Diseases, Vanderbilt University, Nashville, Tennessee, USA
| | - Dawn A Israel
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard M Peek
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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38
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Overmann J, Huang S, Nübel U, Hahnke RL, Tindall BJ. Relevance of phenotypic information for the taxonomy of not-yet-cultured microorganisms. Syst Appl Microbiol 2018; 42:22-29. [PMID: 30197212 DOI: 10.1016/j.syapm.2018.08.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 08/15/2018] [Accepted: 08/19/2018] [Indexed: 12/12/2022]
Abstract
To date, far less than 1% of the estimated global species of Bacteria and Archaea have been described and their names validly published. Aside from these quantitative limitations, our understanding of phenotypic and functional diversity of prokaryotes is also highly biased as not a single species has been described for 85 of the 118 phyla that are currently recognized. Due to recent advances in sequencing technology and capacity, metagenomic datasets accumulate at an increasing speed and new bacterial and archaeal genome sequences become available at a faster rate than newly described species. The growing gap between the diversity of Bacteria and Archaea held in pure culture and that detected by molecular methods has led to the proposal to establish a formal nomenclature for not-yet-cultured taxa primarily based on sequence information. According to this proposal, the concept of Candidatus species would be extended to groups of closely related genome sequences and their names validly published following established rules of bacterial nomenclature. The corresponding sequences would be deposited in public databases as the type. The suggested alterations of the International Code of Nomenclature of Prokaryotes raise concerns regarding (1) the reliability and stability of nomenclature, (2) the technological and conceptual limitations as well as availability of reference genomes, (3) the information content of in silico functional predictions, and (4) the recognition of evolutionary units of microbial diversity. These challenges need to be overcome to arrive at a meaningful taxonomy of not-yet-cultured prokaryotes with so far poorly understood phenotypes.
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Affiliation(s)
- Jörg Overmann
- Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen, Inhoffenstraße 7B, 38124 Braunschweig, Germany; Deutsches Zentrum für Infektionsforschung (DZIF), Standort Braunschweig-Hannover, Braunschweig, Germany; German Center for Integrative Biodiversity Research (iDiv) Jena Halle Leipzig, Deutscher Platz 5e, 04103 Leipzig, Germany.
| | - Sixing Huang
- Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen, Inhoffenstraße 7B, 38124 Braunschweig, Germany
| | - Ulrich Nübel
- Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen, Inhoffenstraße 7B, 38124 Braunschweig, Germany; Deutsches Zentrum für Infektionsforschung (DZIF), Standort Braunschweig-Hannover, Braunschweig, Germany
| | - Richard L Hahnke
- Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen, Inhoffenstraße 7B, 38124 Braunschweig, Germany
| | - Brian J Tindall
- Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen, Inhoffenstraße 7B, 38124 Braunschweig, Germany
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Helicobacter pylori Biofilm Formation Is Differentially Affected by Common Culture Conditions, and Proteins Play a Central Role in the Biofilm Matrix. Appl Environ Microbiol 2018; 84:AEM.00391-18. [PMID: 29752266 DOI: 10.1128/aem.00391-18] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 05/02/2018] [Indexed: 12/13/2022] Open
Abstract
The concept of Helicobacter pylori biofilm formation is relatively new. To help provide a foundation for future biofilm studies, we characterized the biofilm formation ability of a common H. pylori lab strain, G27. The goal of this study was to evaluate biofilm formation by G27 in response to common culture conditions and to explore the biofilm matrix. Our results indicate that while various types of growth media did not dramatically affect biofilm formation, surface selection had a significant effect on the final biofilm mass. Furthermore, enzymatic assays and confocal microscopy revealed that proteins appear to be the primary structural component of the H. pylori extracellular matrix; extracellular DNA (eDNA) and polysaccharides were also present but appear to play a secondary role. Finally, we found that two well-characterized antibiofilm cationic peptides differentially affected early and late-stage biofilms. Together these results provide interesting avenues for future investigations that will seek to understand H. pylori biofilm formation.IMPORTANCE The study of H. pylori biofilm formation is still in its infancy. As such, there is great variability in how biofilm assays are performed across labs. While several groups have begun to investigate factors that influence H. pylori biofilm formation, it is not yet understood how H. pylori biofilm formation may vary based on commonly used conditions. These inconsistencies lead to difficulties in interpretation and comparison between studies. Here, we set out to characterize biofilm formation by a commonly available lab strain, G27. Our findings provide novel insight into optimal biofilm conditions, the biofilm matrix, and possible mechanisms to block or disrupt biofilm formation.
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40
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Shapla UM, Raihan J, Islam A, Alam F, Solayman N, Gan SH, Hossen S, Khalil I. Propolis: The future therapy against Helicobacter pylori-mediated gastrointestinal diseases. J Appl Biomed 2018. [DOI: 10.1016/j.jab.2017.10.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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41
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Akita T, Takuno S, Innan H. Coalescent framework for prokaryotes undergoing interspecific homologous recombination. Heredity (Edinb) 2018; 120:474-484. [PMID: 29358726 PMCID: PMC5889408 DOI: 10.1038/s41437-017-0034-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 10/04/2017] [Accepted: 10/23/2017] [Indexed: 12/11/2022] Open
Abstract
Coalescent process for prokaryote species is theoretically considered. Prokaryotes undergo homologous recombination with individuals of the same species (intraspecific recombination) and with individuals of other species (interspecific recombination). This work particularly focuses on interspecific recombination because intraspecific recombination has been well incorporated in coalescent framework. We present a simulation framework for generating SNP (single-nucleotide polymorphism) patterns that allows external DNA integration into host genome from other species. Using this simulation tool, msPro, we observed that the joint processes of intra- and interspecific recombination generate complex SNP patterns. The direct effect of interspecific recombination includes increased polymorphism. Because interspecific recombination is very rare in nature, it generates regions with exceptionally high polymorphism. Following interspecific recombination, intraspecific recombination cuts the integrated external DNA into small fragments, generating a complex SNP pattern that appears as if external DNA was integrated multiple times. The insight gained from our work using the msPro simulator will be useful for understanding and evaluating the relative contributions of intra- and interspecific recombination events in generating complex SNP patters in prokaryotes.
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Affiliation(s)
- Tetsuya Akita
- Graduate University for Advanced Studies, Hayama, Kanagawa, 240-0193, Japan
- National Research Institute of Far Seas Fisheries, Fisheries Research Agency, Yokohama, Kanagawa, 236-8648, Japan
| | - Shohei Takuno
- Graduate University for Advanced Studies, Hayama, Kanagawa, 240-0193, Japan
| | - Hideki Innan
- Graduate University for Advanced Studies, Hayama, Kanagawa, 240-0193, Japan.
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Servetas SL, Kim A, Su H, Cha JH, Merrell DS. Comparative analysis of the Hom family of outer membrane proteins in isolates from two geographically distinct regions: The United States and South Korea. Helicobacter 2018; 23:e12461. [PMID: 29315985 DOI: 10.1111/hel.12461] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Helicobacter pylori encodes numerous outer membrane proteins (OMPs), but only a few have been characterized in depth. Deletion, duplication, and allelic variation of many of the H. pylori OMPs have been reported, which suggests that these proteins may play key roles in host adaptation. Herein, we characterize the variation observed within the Hom family of OMPs in H. pylori obtained from two geographically distinct populations. MATERIALS AND METHODS PCR genotyping of the hom genes was carried out using clinical isolates from South Korea and the United States. A combination of statistical, phylogenetic, and protein modeling analyses was conducted to further characterize the hom variants. RESULTS Variations in the closely related hom genes, homA and homB, occur in regions that are predicted to encode environmentally exposed loops. A similar phenomenon is true for homCS as compared to homCL . Conversely, little variation was observed in homD. Certain variants of the Hom family of proteins were more prominent in isolates from the Korean population as compared to isolates from the United States. CONCLUSION En masse, our data show that the homA, homB, and homC profiles vary based upon the geographic origin of the strain; however, the fourth member of the hom family, homD, is more highly conserved. Additionally, protein topology modeling showed that many of the less well-conserved regions between homA and homB and between homCS and homCL corresponded to predicted environmentally exposed loops, suggesting that the divergence of the Hom family may be due to host adaptation/pressure.
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Affiliation(s)
- Stephanie L Servetas
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Aeryun Kim
- Department of Oral Biology, Oral Science Research Center, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea
| | - Hanfu Su
- Department of Oral Biology, Oral Science Research Center, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea.,Microbiology and Molecular Biology Laboratory, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea.,Microbiology and Molecular Biology Laboratory, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - D Scott Merrell
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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Arnold BJ, Gutmann MU, Grad YH, Sheppard SK, Corander J, Lipsitch M, Hanage WP. Weak Epistasis May Drive Adaptation in Recombining Bacteria. Genetics 2018; 208:1247-1260. [PMID: 29330348 PMCID: PMC5844334 DOI: 10.1534/genetics.117.300662] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 01/01/2018] [Indexed: 11/18/2022] Open
Abstract
The impact of epistasis on the evolution of multi-locus traits depends on recombination. While sexually reproducing eukaryotes recombine so frequently that epistasis between polymorphisms is not considered to play a large role in short-term adaptation, many bacteria also recombine, some to the degree that their populations are described as "panmictic" or "freely recombining." However, whether this recombination is sufficient to limit the ability of selection to act on epistatic contributions to fitness is unknown. We quantify homologous recombination in five bacterial pathogens and use these parameter estimates in a multilocus model of bacterial evolution with additive and epistatic effects. We find that even for highly recombining species (e.g., Streptococcus pneumoniae or Helicobacter pylori), selection on weak interactions between distant mutations is nearly as efficient as for an asexual species, likely because homologous recombination typically transfers only short segments. However, for strong epistasis, bacterial recombination accelerates selection, with the dynamics dependent on the amount of recombination and the number of loci. Epistasis may thus play an important role in both the short- and long-term adaptive evolution of bacteria, and, unlike in eukaryotes, is not limited to strong effect sizes, closely linked loci, or other conditions that limit the impact of recombination.
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Affiliation(s)
- Brian J Arnold
- Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115
| | - Michael U Gutmann
- School of Informatics, University of Edinburgh, EH8 9AB, United Kingdom
| | - Yonatan H Grad
- Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115
| | - Samuel K Sheppard
- Department of Biology and Biochemistry, University of Bath, BA2 7AY, United Kingdom
| | - Jukka Corander
- Department of Biostatistics, University of Oslo, Blindern, 0317, Norway
- Helsinki Institute for Information Technology HIIT, Department of Mathematics and Statistics, University of Helsinki, 00014 Finland
| | - Marc Lipsitch
- Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115
- Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115
| | - William P Hanage
- Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115
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Nell S, Estibariz I, Krebes J, Bunk B, Graham DY, Overmann J, Song Y, Spröer C, Yang I, Wex T, Korlach J, Malfertheiner P, Suerbaum S. Genome and Methylome Variation in Helicobacter pylori With a cag Pathogenicity Island During Early Stages of Human Infection. Gastroenterology 2018; 154:612-623.e7. [PMID: 29066327 DOI: 10.1053/j.gastro.2017.10.014] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 09/22/2017] [Accepted: 10/02/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Helicobacter pylori is remarkable for its genetic variation; yet, little is known about its genetic changes during early stages of human infection, as the bacteria adapt to their new environment. We analyzed genome and methylome variations in a fully virulent strain of H pylori during experimental infection. METHODS We performed a randomized Phase I/II, observer-blind, placebo-controlled study of 12 healthy, H pylori-negative adults in Germany from October 2008 through March 2010. The volunteers were given a prophylactic vaccine candidate (n = 7) or placebo (n = 5) and then challenged with H pylori strain BCM-300. Biopsy samples were collected and H pylori were isolated. Genomes of the challenge strain and 12 reisolates, obtained 12 weeks after (or in 1 case, 62 weeks after) infection were sequenced by single-molecule, real-time technology, which, in parallel, permitted determination of genome-wide methylation patterns for all strains. Functional effects of genetic changes observed in H pylori strains during human infection were assessed by measuring release of interleukin 8 from AGS cells (to detect cag pathogenicity island function), neutral red uptake (to detect vacuolating cytotoxin activity), and adhesion assays. RESULTS The observed mutation rate was in agreement with rates previously determined from patients with chronic H pylori infections, without evidence of a mutation burst. A loss of cag pathogenicity island function was observed in 3 reisolates. In addition, 3 reisolates from the vaccine group acquired mutations in the vacuolating cytotoxin gene vacA, resulting in loss of vacuolization activity. We observed interstrain variation in methylomes due to phase variation in genes encoding methyltransferases. CONCLUSIONS We analyzed adaptation of a fully virulent strain of H pylori to 12 different volunteers to obtain a robust estimate of the frequency of genetic and epigenetic changes in the absence of interstrain recombination. Our findings indicate that the large amount of genetic variation in H pylori poses a challenge to vaccine development. ClinicalTrials.gov no: NCT00736476.
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Affiliation(s)
- Sandra Nell
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany
| | - Iratxe Estibariz
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, München, Germany
| | - Juliane Krebes
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany
| | - Boyke Bunk
- German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
| | - David Y Graham
- Baylor College of Medicine, Michael E. DeBakey VAMC, Houston, Texas
| | - Jörg Overmann
- German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
| | - Yi Song
- Pacific Biosciences, Menlo Park, California
| | - Cathrin Spröer
- German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
| | - Ines Yang
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany
| | - Thomas Wex
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | | | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Sebastian Suerbaum
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, München, Germany; National Reference Center for Helicobacter pylori, München, Germany.
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Delahay RM, Croxall NJ, Stephens AD. Phylogeographic diversity and mosaicism of the Helicobacter pylori tfs integrative and conjugative elements. Mob DNA 2018; 9:5. [PMID: 29416569 PMCID: PMC5785829 DOI: 10.1186/s13100-018-0109-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 01/15/2018] [Indexed: 12/12/2022] Open
Abstract
Background The genome of the gastric pathogen Helicobacter pylori is characterised by considerable variation of both gene sequence and content, much of which is contained within three large genomic islands comprising the cag pathogenicity island (cagPAI) and two mobile integrative and conjugative elements (ICEs) termed tfs3 and tfs4. All three islands are implicated as virulence factors, although whereas the cagPAI is well characterised, understanding of how the tfs elements influence H. pylori interactions with different human hosts is significantly confounded by limited definition of their distribution, diversity and structural representation in the global H. pylori population. Results To gain a global perspective of tfs ICE population dynamics we established a bioinformatics workflow to extract and precisely define the full tfs pan-gene content contained within a global collection of 221 draft and complete H. pylori genome sequences. Complete (ca. 35-55kbp) and remnant tfs ICE clusters were reconstructed from a dataset comprising > 12,000 genes, from which orthologous gene complements and distinct alleles descriptive of different tfs ICE types were defined and classified in comparative analyses. The genetic variation within defined ICE modular segments was subsequently used to provide a complete description of tfs ICE diversity and a comprehensive assessment of their phylogeographic context. Our further examination of the apparent ICE modular types identified an ancient and complex history of ICE residence, mobility and interaction within particular H. pylori phylogeographic lineages and further, provided evidence of both contemporary inter-lineage and inter-species ICE transfer and displacement. Conclusions Our collective results establish a clear view of tfs ICE diversity and phylogeographic representation in the global H. pylori population, and provide a robust contextual framework for elucidating the functional role of the tfs ICEs particularly as it relates to the risk of gastric disease associated with different tfs ICE genotypes. Electronic supplementary material The online version of this article (10.1186/s13100-018-0109-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Robin M Delahay
- 1Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Nicola J Croxall
- 1Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Amberley D Stephens
- 1Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,2Present Address: Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcette Drive, West Cambridge, Cambridge, CB3 0AS UK
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Woodcock DJ, Krusche P, Strachan NJC, Forbes KJ, Cohan FM, Méric G, Sheppard SK. Genomic plasticity and rapid host switching can promote the evolution of generalism: a case study in the zoonotic pathogen Campylobacter. Sci Rep 2017; 7:9650. [PMID: 28851932 PMCID: PMC5575054 DOI: 10.1038/s41598-017-09483-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 07/25/2017] [Indexed: 11/16/2022] Open
Abstract
Horizontal gene transfer accelerates bacterial adaptation to novel environments, allowing selection to act on genes that have evolved in multiple genetic backgrounds. This can lead to ecological specialization. However, little is known about how zoonotic bacteria maintain the ability to colonize multiple hosts whilst competing with specialists in the same niche. Here we develop a stochastic evolutionary model and show how genetic transfer of host segregating alleles, distributed as predicted for niche specifying genes, and the opportunity for host transition could interact to promote the emergence of host generalist lineages of the zoonotic bacterium Campylobacter. Using a modelling approach we show that increasing levels of homologous recombination enhance the efficiency with which selection can fix combinations of beneficial alleles, speeding adaptation. We then show how these predictions change in a multi-host system, with low levels of recombination, consistent with real r/m estimates, increasing the standing variation in the population, allowing a more effective response to changes in the selective landscape. Our analysis explains how observed gradients of host specialism and generalism can evolve in a multihost system through the transfer of ecologically important loci among coexisting strains.
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Affiliation(s)
- Dan J Woodcock
- Warwick Systems Biology Centre, Coventry House, University of Warwick, Coventry, CV47AL, UK
| | - Peter Krusche
- Warwick Systems Biology Centre, Coventry House, University of Warwick, Coventry, CV47AL, UK
| | - Norval J C Strachan
- School of Biological Sciences, University of Aberdeen, Cruickshank Building. St Machar Drive, Aberdeen, AB24 3UU, UK
| | - Ken J Forbes
- School of Medicine and Dentistry, The University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
| | - Frederick M Cohan
- Department of Biology, Wesleyan University, Middletown, CT, 06459-0170, USA
| | - Guillaume Méric
- The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
| | - Samuel K Sheppard
- The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
- Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK.
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Oleastro M, Rocha R, Vale FF. Population genetic structure of Helicobacter pylori strains from Portuguese-speaking countries. Helicobacter 2017; 22. [PMID: 28271597 DOI: 10.1111/hel.12382] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The human gastric colonizer Helicobacter pylori is useful to track human migrations given the agreement between the bacterium phylogeographic distribution and human migrations. As Portugal was an African and Brazilian colonizer for over 400 years, we hypothesized that Portuguese isolates were likely genetically closer with those from countries colonized by Portuguese in the past. We aimed to characterize the population structure of several Portuguese-speaking countries, including Portugal, Brazil, Angola, and Cape Verde. MATERIALS AND METHODS We included strains isolated in Portugal from Portuguese and from former Portuguese colonies. These strains were typed by multilocus sequence typing (MLST) for seven housekeeping genes. We also retrieved from Multi Locus Sequence Typing Web site additional housekeeping gene sequences, namely from Angola and Brazil. RESULTS We provided evidence that strains from Portuguese belong to hpEurope and that the introgression of hpEurope in non-European countries that speak Portuguese is low, except for Brazil and Cape Verde, where hpEurope accounted for one quarter and one half of the population, respectively. We found genetic similarity for all strains from Portuguese-speaking countries that belong to hpEurope population. Moreover, these strains showed a predominance of ancestral Europe 2 (AE2) over ancestral Europe 1 (AE1), followed by ancestral Africa 1. CONCLUSIONS H. pylori is a useful marker even for relative recent human migration events and may become rapidly differentiated from founder populations. H. pylori from Portuguese-speaking countries assigned to hpEurope appears to be a hybrid population resulting from the admixture of AE1, AE2 and ancestral hpAfrica1.
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Affiliation(s)
- Mónica Oleastro
- Department of Infectious Diseases, National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal
| | - Raquel Rocha
- Department of Infectious Diseases, National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal
| | - Filipa F Vale
- Host-Pathogen Interactions Unit, Research Institute for Medicines (iMed-ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Recombination-Driven Genome Evolution and Stability of Bacterial Species. Genetics 2017; 207:281-295. [PMID: 28751420 DOI: 10.1534/genetics.117.300061] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 07/18/2017] [Indexed: 01/21/2023] Open
Abstract
While bacteria divide clonally, horizontal gene transfer followed by homologous recombination is now recognized as an important contributor to their evolution. However, the details of how the competition between clonality and recombination shapes genome diversity remains poorly understood. Using a computational model, we find two principal regimes in bacterial evolution and identify two composite parameters that dictate the evolutionary fate of bacterial species. In the divergent regime, characterized by either a low recombination frequency or strict barriers to recombination, cohesion due to recombination is not sufficient to overcome the mutational drift. As a consequence, the divergence between pairs of genomes in the population steadily increases in the course of their evolution. The species lacks genetic coherence with sexually isolated clonal subpopulations continuously formed and dissolved. In contrast, in the metastable regime, characterized by a high recombination frequency combined with low barriers to recombination, genomes continuously recombine with the rest of the population. The population remains genetically cohesive and temporally stable. Notably, the transition between these two regimes can be affected by relatively small changes in evolutionary parameters. Using the Multi Locus Sequence Typing (MLST) data, we classify a number of bacterial species to be either the divergent or the metastable type. Generalizations of our framework to include selection, ecologically structured populations, and horizontal gene transfer of nonhomologous regions are discussed as well.
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Bernardini G, Figura N, Ponzetto A, Marzocchi B, Santucci A. Application of proteomics to the study of Helicobacter pylori and implications for the clinic. Expert Rev Proteomics 2017; 14:477-490. [PMID: 28513226 DOI: 10.1080/14789450.2017.1331739] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Helicobacter pylori (H. pylori) is a gram-negative bacterium that colonizes the gastric epithelium and mucous layer of more than half the world's population. H. pylori is a primary human pathogen, responsible for the development of chronic gastritis, peptic ulceration and gastric cancer. Proteomics is impacting several aspects of medical research: understanding the molecular basis of infection and disease manifestation, identification of therapeutic targets and discovery of clinically relevant biomarkers. Areas covered: The main aim of the present review is to provide a comprehensive overview of the contribution of proteomics to the study of H. pylori infection pathophysiology. In particular, we focused on the role of the bacterium and its most important virulence factor, CagA, in the progression of gastric cells transformation and cancer progression. We also discussed the proteomic approaches aimed at the investigation of the host response to bacterial infection. Expert commentary: In the field of proteomics of H. pylori, comprehensive analysis of clinically relevant proteins (functional proteomics) rather than entire proteomes will result in important medical outcomes. Finally, we provided an outlook on the potential development of proteomics in H. pylori research.
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Affiliation(s)
- Giulia Bernardini
- a Dipartimento di Biotecnologie , Chimica e Farmacia, Università degli Studi di Siena , Siena , Italy
| | - Natale Figura
- a Dipartimento di Biotecnologie , Chimica e Farmacia, Università degli Studi di Siena , Siena , Italy
| | - Antonio Ponzetto
- b Dipartimento di Scienze Mediche , Università degli Studi di Torino , Torino , Italy
| | - Barbara Marzocchi
- a Dipartimento di Biotecnologie , Chimica e Farmacia, Università degli Studi di Siena , Siena , Italy
| | - Annalisa Santucci
- a Dipartimento di Biotecnologie , Chimica e Farmacia, Università degli Studi di Siena , Siena , Italy
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Abadi ATB. Strategies used by helicobacter pylori to establish persistent infection. World J Gastroenterol 2017; 23:2870-2882. [PMID: 28522905 PMCID: PMC5413782 DOI: 10.3748/wjg.v23.i16.2870] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 02/01/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a Gram-negative and motile bacterium that colonizes the hostile microniche of the human stomach, then persists for the host’s entire life, if not effectively treated. Clinically, H. pylori plays a causative role in the development of a wide spectrum of diseases including chronic active gastritis, peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Due to the global distribution of H. pylori, it is no exaggeration to conclude that smart strategies are contributing to adaptation of the bacterium to its permanent host. Thirty-four years after the discovery of this bacterium, there are still many unanswered questions. For example, which strategies help the bacterium to survive in this inhospitable microniche? This question is slightly easier to answer if we presume the same clinical concept for both persistent infection and disease. Understanding the mechanisms governing H. pylori persistence will improve identification of the increased risk of diseases such as gastric cancer in patients infected with this bacterium. A well-defined and long-term equilibrium between the human host and H. pylori allows bacterial persistence in the gastric microniche; although this coexistence leads to a high risk of severe diseases such as gastric cancer. To escape the bactericidal activity of stomach acid, H. pylori secretes large amounts of surface-associated and cytosolic urease. The potential to avoid acidic conditions and immune evasion are discussed in order to explain the persistence of H. pylori colonization in the gastric mucosa, and data on bacterial genetic diversity are included. Information on the mechanisms related to H. pylori persistence can also provide the direction for future research concerning effective therapy and management of gastroduodenal disorders. The topics presented in the current review are important for elucidating the strategies used by H. pylori to help the bacterium persist in relation to the immune system and the many unfavorable features of living in the gastric microniche.
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