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Su F, Su M, Wei W, Wu J, Chen L, Sun X, Liu M, Sun S, Mao R, Bourgonje AR, Hu S. Integrating multi-omics data to reveal the host-microbiota interactome in inflammatory bowel disease. Gut Microbes 2025; 17:2476570. [PMID: 40063366 PMCID: PMC11901428 DOI: 10.1080/19490976.2025.2476570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/14/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
Numerous studies have accelerated the knowledge expansion on the role of gut microbiota in inflammatory bowel disease (IBD). However, the precise mechanisms behind host-microbe cross-talk remain largely undefined, due to the complexity of the human intestinal ecosystem and multiple external factors. In this review, we introduce the interactome concept to systematically summarize how intestinal dysbiosis is involved in IBD pathogenesis in terms of microbial composition, functionality, genomic structure, transcriptional activity, and downstream proteins and metabolites. Meanwhile, this review also aims to present an updated overview of the relevant mechanisms, high-throughput multi-omics methodologies, different types of multi-omics cohort resources, and computational methods used to understand host-microbiota interactions in the context of IBD. Finally, we discuss the challenges pertaining to the integration of multi-omics data in order to reveal host-microbiota cross-talk and offer insights into relevant future research directions.
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Affiliation(s)
- Fengyuan Su
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Meng Su
- The First Clinical Medical School, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Wenting Wei
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Jiayun Wu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Leyan Chen
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Xiqiao Sun
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Moyan Liu
- Amsterdam UMC location Academic Medical Center, Department of Experimental Vascular Medicine, Amsterdam, The Netherlands
| | - Shiqiang Sun
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Arno R. Bourgonje
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shixian Hu
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Clyne M, Ó Cróinín T. Pathogenicity and virulence of Helicobacter pylori: A paradigm of chronic infection. Virulence 2025; 16:2438735. [PMID: 39725863 DOI: 10.1080/21505594.2024.2438735] [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: 05/13/2024] [Revised: 11/18/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Infection with Helicobacter pylori is one of the most common infections of mankind. Infection typically occurs in childhood and persists for the lifetime of the host unless eradicated with antimicrobials. The organism colonizes the stomach and causes gastritis. Most infected individuals are asymptomatic, but infection also causes gastric and duodenal ulceration, and gastric cancer. H. pylori possesses an arsenal of virulence factors, including a potent urease enzyme for protection from acid, flagella that mediate motility, an abundance of outer membrane proteins that can mediate attachment, several immunomodulatory proteins, and an ability to adapt to specific conditions in individual human stomachs. The presence of a type 4 secretion system that injects effector molecules into gastric cells and subverts host cell signalling is associated with virulence. In this review we discuss the interplay of H. pylori colonization and virulence factors with host and environmental factors to determine disease outcome in infected individuals.
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Affiliation(s)
- Marguerite Clyne
- School of Medicine, University College Dublin, Dublin, Ireland
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Tadhg Ó Cróinín
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
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3
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Hsu CY, Jasim SA, Rasool KH, H M, Kaur J, Jabir MS, Alhajlah S, Kumar A, Jawad SF, Husseen B. Divergent functions of TLRs in gastrointestinal (GI) cancer: Overview of their diagnostic, prognostic and therapeutic value. Semin Oncol 2025; 52:152344. [PMID: 40347779 DOI: 10.1016/j.seminoncol.2025.152344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 05/14/2025]
Abstract
The relationship between the innate immune signal and the start of the adaptive immune response is the central idea of this theory. By controlling the inflammatory and tissue-repair reactions to damage, the Toll-like receptors (TLRs), as a family of PRRs, have attracted increasing attention for its function in protecting the host against infection and preserving tissue homeostasis. Microbial infection, damage, inflammation, and tissue healing have all been linked to the development of malignancies, especially gastrointestinal (GI) cancers. Recently, increased studies on TLR recognition and binding, as well as their ligands, have significantly advanced our knowledge of the various TLR signaling pathways and offered therapy options for GI malignancies. Upon activation by pathogen-associated or damage-associated molecular patterns (DAMPs and PAMPs), TLRs trigger key pathways like NF-κB, MAPK, and IRF. NF-κB activation promotes inflammation, cell survival, and proliferation, often contributing to tumor growth, metastasis, and therapy resistance. MAPK pathways similarly drive uncontrolled cell growth and invasion, while IRF pathways modulate interferon production, yielding both anti-tumor and protumor effects. The resulting chronic inflammatory environment within tumors can foster progression, yet TLR activation can also stimulate beneficial anti-tumor immune responses. However, the functions of TLR expression in GI cancers and their diagnostic and prognostic along with therapeutic value have not yet entirely been elucidated. Understanding how TLR activation contributes to anti-cancer immunity against GI malignancies may hasten immunotherapy developments and increase patient survival.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona, USA
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-maarif University College, Anbar, Iraq; Biotechnology Department, College of Applied Science, Fallujah University, Fallujah, Iraq
| | - Khetam Habeeb Rasool
- Department of Biology, College of Science, University of Mustansiriyah, Mustansiriyah, Iraq
| | - Malathi H
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Jaswinder Kaur
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Mohali, Punjab, India
| | - Majid S Jabir
- Department of Applied Sciences, University of Technology, Anbar, Iraq
| | - Sharif Alhajlah
- Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia.
| | - Abhinav Kumar
- Department of Nuclear and Renewable Energy, Ural Federal University Named after the First President of Russia Boris Yeltsin, Ekaterinburg, Russia; Centre for Research Impact & Outcome, Chitkara University, Rajpura, Punjab, India; Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, India
| | - Sabrean F Jawad
- Department of Pharmacy, Al-Mustaqbal University College, Hillah, Babylon, Iraq
| | - Beneen Husseen
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq; Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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4
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Wizenty J, Sigal M. Helicobacter pylori, microbiota and gastric cancer - principles of microorganism-driven carcinogenesis. Nat Rev Gastroenterol Hepatol 2025; 22:296-313. [PMID: 40011753 DOI: 10.1038/s41575-025-01042-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2025] [Indexed: 02/28/2025]
Abstract
The demonstration that Helicobacter pylori is a pathogenic bacterium with marked carcinogenic potential has paved the way for new preventive approaches for gastric cancer. Although decades of research have uncovered complex interactions of H. pylori with epithelial cells, current insights have refined our view on H. pylori-associated carcinogenesis. Specifically, the cell-type-specific effects on gastric stem and progenitor cells deep in gastric glands provide a new view on the ability of the bacteria to colonize long-term, manipulate host responses and promote gastric pathology. Furthermore, new, large-scale epidemiological data have shed light on factors that determine why only a subset of carriers progress to gastric cancer. Currently, technological advances have brought yet another revelation: H. pylori is far from the only microorganism able to colonize the stomach. Instead, the stomach is colonized by a diverse gastric microbiota, and there is emerging evidence for the occurrence and pathological effect of dysbiosis resulting from an aberrant interplay between H. pylori and the gastric mucosa. With the weight of this evidence mounting, here we consider how the lessons learned from H. pylori research inform and synergize with this emerging field to bring a more comprehensive understanding of the role of microbes in gastric carcinogenesis.
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Affiliation(s)
- Jonas Wizenty
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy and BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
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Fulton KM, Mendoza-Barberà E, Tomás JM, Twine SM, Smith JC, Merino S. Polar flagellin glycan heterogeneity of Aeromonas hydrophila strain ATCC 7966 T. Bioorg Chem 2025; 158:108300. [PMID: 40058227 DOI: 10.1016/j.bioorg.2025.108300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/08/2025] [Accepted: 02/18/2025] [Indexed: 03/19/2025]
Abstract
Motile pathogens often rely upon flagellar motility as an essential virulence factor and in many species the structural flagellin protein is glycosylated. Flagellin glycosylation has been shown to be important for proper function of the flagellar filament in a number of bacterial species. Aeromonas hydrophila is a ubiquitous aquatic pathogen with a constitutively expressed polar flagellum. Using a suite of mass spectrometry techniques, the flagellin FlaA and FlaB structural proteins of A. hydrophila strain ATCC 7966T were shown to be glycosylated with significant microheterogeneity, macroheterogeneity, and metaheterogeneity. The primary linking sugar in this strain was a novel and previously unreported pseudaminic acid derivative with a mass of 422 Da. The pseudaminic acid derivative was followed in sequence by two hexoses, an N-acetylglucosamine (with additional variable secondary modification), and a deoxy N-acetylglucosamine derivative. These pentasaccharide glycans were observed modifying all eight modification sites. Hexasaccharides, which included an additional N-acetylhexosamine residue as the capping sugar, were observed exclusively modifying a pair of isobaric peptides from FlaA and FlaB. Interestingly, these isobaric peptides are immediately adjacent to a toll-like receptor 5 binding site in both protein sequences. Glycosylation status was also linked to motility, a critical bacterial virulence factor.
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Affiliation(s)
- Kelly M Fulton
- Department of Chemistry, Faculty of Science, Carleton University, 1125 Colonel By Dr., Ottawa, Ontario, K1S 5B6, Canada; Human Health Therapeutics Research Centre, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario, K1N 5A2, Canada.
| | - Elena Mendoza-Barberà
- Departamento de Biologia, Sanidad y Medio Ambiente, Facultad de Farmacia y Ciencias de la Alimentación, Universidad de Barcelona, C/ Joan XXIII, 27, 08028 Barcelona, Barcelona, Spain; Instituto de Investigación en Nutrición y Seguridad Alimentaria (INSA), Universidad de Barcelona, Av. Prat de la Riba, 171, 08921, Santa Coloma de Gramenet, Barcelona, Spain
| | - Juan M Tomás
- Instituto de Investigación en Nutrición y Seguridad Alimentaria (INSA), Universidad de Barcelona, Av. Prat de la Riba, 171, 08921, Santa Coloma de Gramenet, Barcelona, Spain; Departamento de Genética, Microbiología y Estadística, Facultad de Biología, Universidad de Barcelona, Avd. Diagonal 643, 08028 Barcelona, Barcelona, Spain
| | - Susan M Twine
- Human Health Therapeutics Research Centre, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario, K1N 5A2, Canada; Department of Biology, Faculty of Science, Carleton University, 1125 Colonel By Dr., Ottawa, Ontario, K1S 5B6, Canada
| | - Jeffrey C Smith
- Department of Chemistry, Faculty of Science, Carleton University, 1125 Colonel By Dr., Ottawa, Ontario, K1S 5B6, Canada
| | - Susana Merino
- Instituto de Investigación en Nutrición y Seguridad Alimentaria (INSA), Universidad de Barcelona, Av. Prat de la Riba, 171, 08921, Santa Coloma de Gramenet, Barcelona, Spain; Departamento de Genética, Microbiología y Estadística, Facultad de Biología, Universidad de Barcelona, Avd. Diagonal 643, 08028 Barcelona, Barcelona, Spain
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Villarroel-Espíndola F, Jaupi L, Reyes J, Barrientos C, Podestá C, Selman C, Bizama C, Corvalan A, Gonzalez-Stegmaier R, Jara-Rosales S, Bascur P. Spatial Study of TLR4, TLR5 and TLR9 in Gastric Premalignant Lesions Before and After Helicobacter pylori Eradication. Int J Mol Sci 2025; 26:4059. [PMID: 40362298 PMCID: PMC12072049 DOI: 10.3390/ijms26094059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The histological changes in the gastric epithelium are crucial in the progression from premalignant to neoplastic lesions. TLR4, TLR5 and TLR9 have been localized in the gastric epithelium and studied separately using conventional histological techniques without a focus on the protein or cell interactions within the microenvironment. Therefore, we developed a multiplex immunohistochemistry/immunofluorescence (mIHC/IF) technology for the simultaneous detection of TLR4, TLR5 and TLR9 on a single tissue section of human gastric biopsies from 10 paired cases collected in two independent visits, and its correlation with the OLGA/OLGIM scoring and H. pylori status after eradication. The results confirmed that mIHC/IF is useful for simultaneously interrogating six biomarkers and demonstrated that TLR4 and TLR9 are significantly associated with H. pylori infection. However, only TLR9 is positively related to the presence of intestinal metaplasia. TLR5 was mainly present in goblet cells (TFF3+) but did not show any significant association with H. pylori or the presence of intestinal metaplasia. Our results suggest that a more comprehensive strategy to interrogate the tissue microenvironment in premalignant lesions may improve the interpretation of the earned risk of gastric cancer in patients with chronic gastritis and evidence of failure in H. pylori eradication.
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Affiliation(s)
- Franz Villarroel-Espíndola
- Translational Medicine Unit, Fundación Arturo López Pérez (FALP) Cancer Center, Santiago 7500921, Chile; (L.J.); (J.R.); (R.G.-S.); (S.J.-R.); (P.B.)
- Advanced Center for Chronic Diseases (ACCDIS), Santiago 8331150, Chile; (C.B.); (A.C.)
- PhD Program in Chronic Diseases, Faculty of Medicine and Science, Universidad San Sebastián, Los Leones Campus, Santiago 7510157, Chile
- PhD Program in Medical Sciences, Faculty of Medicine, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Leyla Jaupi
- Translational Medicine Unit, Fundación Arturo López Pérez (FALP) Cancer Center, Santiago 7500921, Chile; (L.J.); (J.R.); (R.G.-S.); (S.J.-R.); (P.B.)
| | - Joaquín Reyes
- Translational Medicine Unit, Fundación Arturo López Pérez (FALP) Cancer Center, Santiago 7500921, Chile; (L.J.); (J.R.); (R.G.-S.); (S.J.-R.); (P.B.)
| | - Carlos Barrientos
- Endoscopy Unit, Fundación Arturo López Pérez (FALP) Cancer Center, Santiago 7500921, Chile; (C.B.); (C.P.)
| | - Celia Podestá
- Endoscopy Unit, Fundación Arturo López Pérez (FALP) Cancer Center, Santiago 7500921, Chile; (C.B.); (C.P.)
| | - Carolina Selman
- Molecular Diagnosis Laboratory, Diagnostic Units, Fundación Arturo López Pérez (FALP) Cancer Center, Santiago 7500921, Chile;
| | - Carolina Bizama
- Advanced Center for Chronic Diseases (ACCDIS), Santiago 8331150, Chile; (C.B.); (A.C.)
- Department of Pathology, UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Alejandro Corvalan
- Advanced Center for Chronic Diseases (ACCDIS), Santiago 8331150, Chile; (C.B.); (A.C.)
- Department of Pathology, UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Roxana Gonzalez-Stegmaier
- Translational Medicine Unit, Fundación Arturo López Pérez (FALP) Cancer Center, Santiago 7500921, Chile; (L.J.); (J.R.); (R.G.-S.); (S.J.-R.); (P.B.)
| | - Sergio Jara-Rosales
- Translational Medicine Unit, Fundación Arturo López Pérez (FALP) Cancer Center, Santiago 7500921, Chile; (L.J.); (J.R.); (R.G.-S.); (S.J.-R.); (P.B.)
- PhD Program in Chronic Diseases, Faculty of Medicine and Science, Universidad San Sebastián, Los Leones Campus, Santiago 7510157, Chile
- Faculty of Health Care Sciences, School of Midwifery, Universidad San Sebastián, Los Leones Campus, Santiago 7510157, Chile
| | - Pia Bascur
- Translational Medicine Unit, Fundación Arturo López Pérez (FALP) Cancer Center, Santiago 7500921, Chile; (L.J.); (J.R.); (R.G.-S.); (S.J.-R.); (P.B.)
- PhD Program in Medical Sciences, Faculty of Medicine, Universidad Austral de Chile, Valdivia 5090000, Chile
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Chen D, Wang W, Chen X, Liang N, Li J, Ding W, Zhang H, Yang Z, Zhao H, Liu Z. Plant-derived extracts or compounds for Helicobacter-associated gastritis: a systematic review of their anti-Helicobacter activity and anti-inflammatory effect in animal experiments. Chin Med 2025; 20:53. [PMID: 40264171 PMCID: PMC12013188 DOI: 10.1186/s13020-025-01093-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 03/10/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Helicobacter infection, which is the leading cause of gastritis and stomach cancer, has become common worldwide. Almost all Helicobacter-infected patients have chronic active gastritis, also known as Helicobacter-associated gastritis (HAG). However, the eradication rate of Helicobacter is decreasing due to the poor efficacy of current medications, which causes infection to recur, inflammation to persist, and stomach cancer to develop. Natural components have robust antibacterial activity and anti-inflammatory capacity, as confirmed by many studies of alternative natural medicines. PURPOSE This article aimed to conduct a comprehensive search and meta-analysis to evaluate the efficacy of anti-Helicobacter and anti-inflammatory activities of plant-derived extracts or compounds that can treat HAG in animal experiments. We intended to provide detailed preclinical-research foundation including plant and compound information, as well as the mechanisms by which these plant-derived substances inhibit the progression of Helicobacter infection, gastritis and neoplasms for future study. METHODS The systematic review is aligned with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the protocol was registered in PROSPERO (CRD42024527889). An extensive search was performed across multiple databases, including PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal database (VIP), the Wanfang database, and the China biomedical literature service system (SinoMed), up until November 2023. Meta-analysis on Review Manager software (RevMan 5.4) estimating anti-Helicobacter and anti-inflammatory activity was performed. We used the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias tool to evaluate the risk of bias of each study included. RESULTS Our study encompassed 61 researches, comprised 36 extracts and 37 compounds improving HAG by inhibiting Helicobacter infection, the inflammatory response, oxidative stress, and regulating apoptosis and proliferation. Sixteen families especially Asteraceae, Fabaceae and Rosaceae and nine classes including Terpenoids, Alkaloids, Phenols, and Flavonoids may be promising directions for valuable new drugs. The Meta-analyse demonstrated the plant-base substance treatments possess significant anti-Helicobacter and anti-inflammation activity comparing to control groups. The included plants and compounds confirmed that signaling pathways NF-κB, JAK2/STAT3, MAPK, TLR4/MyD88, PI3K/AKT, NLRP3/Caspase-1 and NRF2/HO-1 play a key role in the progression of HAG. CONCLUSION Plant-derived extracts or compounds actively improve HAG by modulating relevant mechanisms and signaling pathways, particularly through the anti-Helicobacter and inflammatory regulation ways. Further researches to apply these treatments in humans are needed, which will provide direction for the future development of therapeutic drugs to increase eradication rate and alleviate gastritis.
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Affiliation(s)
- Danni Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wenlai Wang
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China
| | - Xiangyun Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Ning Liang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jiawang Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wei Ding
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Hongrui Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhen Yang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China.
| | - Hongxia Zhao
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China.
| | - Zhenhong Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China.
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China.
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8
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Leitner M, Murigneux V, Etebari K, Asgari S. Wolbachia elevates host methyltransferase expression and alters the m 6A methylation landscape in Aedes aegypti mosquito cells. BMC Microbiol 2025; 25:164. [PMID: 40128692 PMCID: PMC11934717 DOI: 10.1186/s12866-025-03898-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 03/17/2025] [Indexed: 03/26/2025] Open
Abstract
Wolbachia pipientis is an intracellular endosymbiotic bacterium that blocks the replication of several arboviruses in transinfected Aedes aegypti mosquitoes, yet its antiviral mechanism remains unknown. For the first time, we employed Nanopore direct RNA sequencing technology to investigate the impact of wAlbB strain of Wolbachia on the host's N6-methyladenosine (m6A) machinery and post-transcriptional modification landscape. Our study revealed that Wolbachia infection elevates the expression of genes involved in the mosquito's m6A methyltransferase complex. However, knocking down these m6A-related genes did not affect Wolbachia density. Nanopore sequencing identified 1,392 differentially modified m6A DRACH motifs on mosquito transcripts, with 776 showing increased and 616 showing decreased m6A levels due to Wolbachia. These m6A sites were predominantly enriched in coding sequences and 3'-untranslated regions. Gene Ontology analysis revealed that genes with reduced m6A levels were over-represented in functional GO terms associated with purine nucleotide binding functions critical in the post-transcriptional modification process of m6A. Differential gene expression analysis of the Nanopore data uncovered that a total of 643 protein-coding genes were significantly differentially expressed, 427 were downregulated, and 216 were upregulated. Several classical and non-classical immune-related genes were amongst the downregulated DEGs. Notably, it revealed a critical host factor, transmembrane protein 41B (TMEM41B), which is required for flavivirus infection, was upregulated and methylated in the presence of Wolbachia. Indeed, there is a strong correlation between gene expression being upregulated in genes with both increased and decreased levels of m6A modification, respectively. Our findings underscore Wolbachia's ability to modulate many intracellular aspects of its mosquito host by influencing post-transcriptional m6A modifications and gene expression, and it unveils a potential link behind its antiviral properties.
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Affiliation(s)
- Michael Leitner
- School of the Environment, The University of Queensland, Brisbane, Australia
| | - Valentine Murigneux
- QCIF Facility for Advanced Bioinformatics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Kayvan Etebari
- School of Agriculture and Food Sustainability, The University of Queensland, Brisbane, Australia
| | - Sassan Asgari
- School of the Environment, The University of Queensland, Brisbane, Australia.
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9
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Wu O, Gao J, Zhang X, Liu W, Zhang H, Khederzadeh S, Lu X, Wu Y. TLR5's Role in Obesity-related Hypertension: Updated Evidence and Prospects. Angiology 2025:33197251326384. [PMID: 40079382 DOI: 10.1177/00033197251326384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2025]
Abstract
Toll-like receptor 5 (TLR5), integral to the immune system as a primary sensor for flagellin, is central to the link between innate and adaptive immunity, modulating immune responses and cytokine production essential for defense against flagellated pathogens and immune tolerance. This review consolidates the understanding of TLR5's structural and signaling mechanisms and its interactions with flagellin, shedding light on its dual role in immune responses and its promise as a therapeutic target. It highlights TLR5's intricate role in the pathogenesis of obesity-related hypertension, a growing global health concern that correlates with rising obesity rates and is characterized by a complex interplay of immune responses and metabolic dysregulation. Despite the current understanding, the impact of TLR5 on obesity-related hypertension is marked by conflicting findings, indicating a need for further exploration. The review critically analyzes the existing literature, providing novel insights from rodent models and human studies that underscore TLR5's therapeutic potential, setting the stage for transformative research in managing obesity-related hypertension. It calls for deeper investigation into TLR5's multifaceted role, emphasizing its promise as a target for managing obesity-related hypertension and the necessity for future research to clarify its complexities and to innovate treatment strategies.
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Affiliation(s)
- Ou Wu
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang, P.R. China
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P.R. China
| | - Jin Gao
- Clinical Laboratory, the Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, P.R. China
| | - Xingyu Zhang
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Wei Liu
- JFIntelligent Healthcare Technology Co. Ltd, Nanchang, Jiangxi, P.R. China
| | - Hu Zhang
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital Affiliated with Medical College of Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Saber Khederzadeh
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, P.R. China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, P.R. China
| | - Xi Lu
- Hangzhou Vocational and Technical College, Hangzhou, Zhejiang, P.R. China
| | - Ya Wu
- Anhui Medical University, Hefei, Anhui, P.R. China
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10
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Elger W, Tegtmeyer N, Rohde M, Linz B, Hirsch C, Backert S. Cultivation and molecular characterization of viable Helicobacter pylori from the root canal of 170 deciduous teeth of children. Cell Commun Signal 2024; 22:578. [PMID: 39627817 PMCID: PMC11613870 DOI: 10.1186/s12964-024-01948-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/16/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Helicobacter pylori is a persistent pathogen in the human stomach. However, the proposed transmission route via the oral cavity is not understood and under intense debate. While dozens of studies have shown by PCR that H. pylori DNA is frequently present in the oral cavity, data on the growth and characterization of viable H. pylori from this compartment are very scarce, and it is unclear whether the bacteria can survive in the oral cavity for longer time periods or even colonize it. METHODS Selective growth methods, scanning electron microscopy, urease assay, Western blotting, PCR, and gene sequencing were applied to identify and examine viable H. pylori in decayed milk teeth. RESULTS Here, we studied viable H. pylori in the plaque and root canals of 170 endodontically infected deciduous teeth that were extracted from 54 children. While H. pylori DNA was detected in several plaque and many root canal samples by PCR, live bacteria could only be cultivated from 28 root canals, but not from plaque. These 28 isolates have been identified as H. pylori by PCR and sequencing of vacA, cagA and htrA genes, phylogenetic analyses, protein expression of major H. pylori virulence factors, and by signal transduction events during infection of human cell lines. CONCLUSIONS Thus, the microaerobic environment in the root canals of endodontically infected teeth may represent a protected and transient reservoir for live H. pylori, especially in individuals with poor dental hygiene, which could serve as a potential source for re-infection of the stomach after antibiotic therapy or for transmission to other individuals.
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Affiliation(s)
- Wieland Elger
- Department of Paediatric Dentistry, University School of Dental Medicine, University of Leipzig, Leipzig, Germany
| | - Nicole Tegtmeyer
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Manfred Rohde
- Central Facility for Microscopy, Helmholtz Centre for Infection Research, Brunswick, Germany
| | - Bodo Linz
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Hirsch
- Department of Paediatric Dentistry, University School of Dental Medicine, University of Leipzig, Leipzig, Germany.
| | - Steffen Backert
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
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11
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Xi Y, Li X, Liu L, Xiu F, Yi X, Chen H, You X. Sneaky tactics: Ingenious immune evasion mechanisms of Bartonella. Virulence 2024; 15:2322961. [PMID: 38443331 PMCID: PMC10936683 DOI: 10.1080/21505594.2024.2322961] [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: 12/18/2023] [Accepted: 02/20/2024] [Indexed: 03/07/2024] Open
Abstract
Gram-negative Bartonella species are facultative intracellular bacteria that can survive in the harsh intracellular milieu of host cells. They have evolved strategies to evade detection and degradation by the host immune system, which ensures their proliferation in the host. Following infection, Bartonella alters the initial immunogenic surface-exposed proteins to evade immune recognition via antigen or phase variation. The diverse lipopolysaccharide structures of certain Bartonella species allow them to escape recognition by the host pattern recognition receptors. Additionally, the survival of mature erythrocytes and their resistance to lysosomal fusion further complicate the immune clearance of this species. Certain Bartonella species also evade immune attacks by producing biofilms and anti-inflammatory cytokines and decreasing endothelial cell apoptosis. Overall, these factors create a challenging landscape for the host immune system to rapidly and effectively eradicate the Bartonella species, thereby facilitating the persistence of Bartonella infections and creating a substantial obstacle for therapeutic interventions. This review focuses on the effects of three human-specific Bartonella species, particularly their mechanisms of host invasion and immune escape, to gain new perspectives in the development of effective diagnostic tools, prophylactic measures, and treatment options for Bartonella infections.
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Affiliation(s)
- Yixuan Xi
- Institute of Pathogenic Biology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, China
| | - Xinru Li
- Institute of Pathogenic Biology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, China
| | - Lu Liu
- Institute of Pathogenic Biology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, China
| | - Feichen Xiu
- Institute of Pathogenic Biology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, China
| | - Xinchao Yi
- Institute of Pathogenic Biology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, China
| | - Hongliang Chen
- Chenzhou NO.1 People’s Hospital, The Affiliated Chenzhou Hospital, Hengyang Medical College, University of South China, ChenZhou, China
| | - Xiaoxing You
- Institute of Pathogenic Biology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, China
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12
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Waller AA, Ribardo DA, Hendrixson DR. FlaG competes with FliS-flagellin complexes for access to FlhA in the flagellar T3SS to control Campylobacter jejuni filament length. Proc Natl Acad Sci U S A 2024; 121:e2414393121. [PMID: 39441631 PMCID: PMC11536152 DOI: 10.1073/pnas.2414393121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/26/2024] [Indexed: 10/25/2024] Open
Abstract
Bacteria power rotation of an extracellular flagellar filament for swimming motility. Thousands of flagellin subunits compose the flagellar filament, which extends several microns from the bacterial surface. It is unclear whether bacteria actively control filament length. Many polarly flagellated bacteria produce shorter flagellar filaments than peritrichous bacteria, and FlaG has been reported to limit flagellar filament length in polar flagellates. However, a mechanism for how FlaG may function is unknown. We observed that deletion of flaG in the polarly flagellated pathogens Vibrio cholerae, Pseudomonas aeruginosa, and Campylobacter jejuni caused extension of flagellar filaments to lengths comparable to peritrichous bacteria. Using C. jejuni as a model to understand how FlaG controls flagellar filament length, we found that FlaG and FliS chaperone-flagellin complexes antagonize each other for interactions with FlhA in the flagellar type III secretion system (fT3SS) export gate. FlaG interacted with an understudied region of FlhA, and this interaction appeared to be enhanced in ΔfliS and FlhA FliS-binding mutants. Our data support that FlaG evolved in polarly flagellated bacteria as an antagonist to interfere with the ability of FliS to interact with and deliver flagellins to FlhA in the fT3SS export gate to control flagellar filament length so that these bacteria produce relatively shorter flagella than peritrichous counterparts. This mechanism is similar to how some gatekeepers in injectisome T3SSs prevent chaperones from delivering effector proteins until completion of the T3SS and host contact occurs. Thus, flagellar and injectisome T3SSs have convergently evolved protein antagonists to negatively impact respective T3SSs to secrete their major terminal substrates.
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Affiliation(s)
- Alexis A. Waller
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX75390-9048
| | - Deborah A. Ribardo
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX75390-9048
| | - David R. Hendrixson
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX75390-9048
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13
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Malvino ML. Unraveling the dynamics of Xanthomonas' flagella: insights into host-pathogen interactions. PeerJ 2024; 12:e18204. [PMID: 39465145 PMCID: PMC11505878 DOI: 10.7717/peerj.18204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 09/10/2024] [Indexed: 10/29/2024] Open
Abstract
Understanding the intricate interplay between plants and bacteria is paramount for elucidating mechanisms of immunity and disease. This review synthesizes current knowledge on the role of flagella in bacterial motility and host recognition, shedding light on the molecular mechanisms underlying plant immunity and bacterial pathogenicity. We delve into the sophisticated signaling network of plants, highlighting the pivotal role of pattern recognition receptors (PRRs) in detecting conserved molecular patterns known as microbe-associated molecular patterns (MAMPs), with a particular focus on flagellin as a key MAMP. Additionally, we explore recent discoveries of solanaceous-specific receptors, such as FLAGELLIN SENSING 3 (FLS3), and their implications for plant defense responses. Furthermore, we examine the role of bacterial motility in host colonization and infection, emphasizing the multifaceted relationship between flagella-mediated chemotaxis and bacterial virulence. Through a comprehensive analysis of flagellin polymorphisms within the genus Xanthomonas, we elucidate their potential impact on host recognition and bacterial pathogenicity, offering insights into strategies for developing disease-resistant crops. This review is intended for professionals within the fields of crops sciences and microbiology.
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Affiliation(s)
- Maria L. Malvino
- Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States
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14
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Eser E, Felton VA, Drolia R, Bhunia AK. Salmonella Detection in Food Using a HEK-hTLR5 Reporter Cell-Based Sensor. BIOSENSORS 2024; 14:444. [PMID: 39329819 PMCID: PMC11430776 DOI: 10.3390/bios14090444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 08/31/2024] [Accepted: 09/14/2024] [Indexed: 09/28/2024]
Abstract
The development of a rapid, sensitive, specific method for detecting foodborne pathogens is paramount for supplying safe food to enhance public health safety. Despite the significant improvement in pathogen detection methods, key issues are still associated with rapid methods, such as distinguishing living cells from dead, the pathogenic potential or health risk of the analyte at the time of consumption, the detection limit, and the sample-to-result. Mammalian cell-based assays analyze pathogens' interaction with host cells and are responsive only to live pathogens or active toxins. In this study, a human embryonic kidney (HEK293) cell line expressing Toll-Like Receptor 5 (TLR-5) and chromogenic reporter system (HEK dual hTLR5) was used for the detection of viable Salmonella in a 96-well tissue culture plate. This cell line responds to low concentrations of TLR5 agonist flagellin. Stimulation of TLR5 ligand activates nuclear factor-kB (NF-κB)-linked alkaline phosphatase (AP-1) signaling cascade inducing the production of secreted embryonic alkaline phosphatase (SEAP). With the addition of a ρ-nitrophenyl phosphate as a substrate, a colored end product representing a positive signal is quantified. The assay's specificity was validated with the top 20 Salmonella enterica serovars and 19 non-Salmonella spp. The performance of the assay was also validated with spiked food samples. The total detection time (sample-to-result), including shortened pre-enrichment (4 h) and selective enrichment (4 h) steps with artificially inoculated outbreak-implicated food samples (chicken, peanut kernel, peanut butter, black pepper, mayonnaise, and peach), was 15 h when inoculated at 1-100 CFU/25 g sample. These results show the potential of HEK-DualTM hTLR5 cell-based functional biosensors for the rapid screening of Salmonella.
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Affiliation(s)
- Esma Eser
- Molecular Food Microbiology Laboratory, Department of Food Science, Purdue University, West Lafayette, IN 47907, USA
- Department of Food Engineering, Faculty of Engineering, Canakkale Onsekiz Mart University, Canakkale 17100, Turkey
| | - Victoria A Felton
- Molecular and Cellular Microbiology Laboratory, Department of Biological Science, Old Dominion University, Norfolk, VA 23529, USA
| | - Rishi Drolia
- Molecular Food Microbiology Laboratory, Department of Food Science, Purdue University, West Lafayette, IN 47907, USA
- Molecular and Cellular Microbiology Laboratory, Department of Biological Science, Old Dominion University, Norfolk, VA 23529, USA
- Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA
- Center for Bioelectronics, Old Dominion University, Norfolk, VA 23508, USA
| | - Arun K Bhunia
- Molecular Food Microbiology Laboratory, Department of Food Science, Purdue University, West Lafayette, IN 47907, USA
- Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
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15
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Ishikawa-Ankerhold H, Busch B, Bader A, Maier-Begandt D, Dionisio F, Namineni S, Vladymyrov M, Harrison U, van den Heuvel D, Tomas L, Walzog B, Massberg S, Schulz C, Haas R. Novel multiphoton intravital imaging enables real-time study of Helicobacter pylori interaction with neutrophils and macrophages in the mouse stomach. PLoS Pathog 2024; 20:e1012580. [PMID: 39348445 PMCID: PMC11478878 DOI: 10.1371/journal.ppat.1012580] [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: 12/27/2023] [Revised: 10/15/2024] [Accepted: 09/11/2024] [Indexed: 10/02/2024] Open
Abstract
Helicobacter pylori (H. pylori) is a bacterial pathogen that exclusively colonizes the human gastric mucosa and can cause persistent infection. In this process, H. pylori employs various strategies to avoid recognition by the human immune system. These range from passive defense strategies (e.g., altered LPS or flagellin structures) that prevent recognition by pattern recognition receptors (PRRs) to more active approaches, such as inhibition of IL-2 secretion and proliferation of T cells via VacA. Despite the growing evidence that H. pylori actively manipulates the human immune system for its own benefit, the direct interaction of H. pylori with immune cells in situ is poorly studied. Here, we present a novel intravital imaging model of the murine stomach gastric mucosa and show for the first time the in situ recruitment of neutrophils during infection and a direct H. pylori-macrophage interaction. For this purpose, we applied multiphoton intravital microscopy adapted with live drift correction software (VivoFollow) on LysM-eGFP and CX3CR1-eGFP reporter mice strains in which specific subsets of leukocytes are fluorescently labeled. Multiphoton microscopy is proving to be an excellent tool for characterizing interactions between immune cells and pathogens in vivo.
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Affiliation(s)
- Hellen Ishikawa-Ankerhold
- Department of Internal Medicine I, LMU University Hospital, Munich, Germany
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, LMU University Hospital, Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
| | - Benjamin Busch
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Germany
| | - Almke Bader
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, LMU University Hospital, Munich, Germany
- Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Daniela Maier-Begandt
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, LMU University Hospital, Munich, Germany
- Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Flavio Dionisio
- Department of Internal Medicine I, LMU University Hospital, Munich, Germany
| | - Sukumar Namineni
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Germany
| | - Mykhailo Vladymyrov
- Data Science Lab, Mathematical Institute, University of Bern, Bern, Switzerland
| | - Ute Harrison
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Germany
| | - Dominic van den Heuvel
- Department of Internal Medicine I, LMU University Hospital, Munich, Germany
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, LMU University Hospital, Munich, Germany
| | - Lukas Tomas
- Department of Internal Medicine I, LMU University Hospital, Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
| | - Barbara Walzog
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, LMU University Hospital, Munich, Germany
- Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Steffen Massberg
- Department of Internal Medicine I, LMU University Hospital, Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
| | - Christian Schulz
- Department of Internal Medicine I, LMU University Hospital, Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
- Department of Immunopharmacology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Rainer Haas
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
- German Center for Infection Research (DZIF), LMU Munich, Germany
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16
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Linz B, Sticht H, Tegtmeyer N, Backert S. Cancer-associated SNPs in bacteria: lessons from Helicobacter pylori. Trends Microbiol 2024; 32:847-857. [PMID: 38485609 DOI: 10.1016/j.tim.2024.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/01/2024] [Accepted: 02/02/2024] [Indexed: 09/06/2024]
Abstract
Several single-nucleotide polymorphisms (SNPs) in human chromosomes are known to predispose to cancer. However, cancer-associated SNPs in bacterial pathogens were unknown until discovered in the stomach pathogen Helicobacter pylori. Those include an alanine-threonine polymorphism in the EPIYA-B phosphorylation motif of the injected effector protein CagA that affects cancer risk by modifying inflammatory responses and loss of host cell polarity. A serine-to-leucine change in serine protease HtrA is associated with boosted proteolytic cleavage of epithelial junction proteins and introduction of DNA double-strand breaks (DSBs) in host chromosomes, which co-operatively elicit malignant alterations. In addition, H. pylori genome-wide association studies (GWAS) identified several other SNPs potentially associated with increased gastric cancer (GC) risk. Here we discuss the clinical importance, evolutionary origin, and functional advantage of the H. pylori SNPs. These exciting new data highlight cancer-associated SNPs in bacteria, which should be explored in more detail in future studies.
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Affiliation(s)
- Bodo Linz
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany
| | - Heinrich Sticht
- Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg; 91054 Erlangen, Germany
| | - Nicole Tegtmeyer
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany.
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17
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Bourgonje AR, Hörstke NV, Fehringer M, Innocenti G, Vogl T. Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn's disease and chronic fatigue syndrome. MICROBIOME 2024; 12:141. [PMID: 39075559 DOI: 10.1186/s40168-024-01858-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 06/12/2024] [Indexed: 07/31/2024]
Abstract
BACKGROUND Elevated systemic antibody responses against gut microbiota flagellins are observed in both Crohn's disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting potential serological biomarkers for diagnosis. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) "stimulator" and (2) "silent" flagellins, which bind TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 (involving a C-terminal domain); (3) "evader" flagellins of pathogens, which entirely circumvent TLR5 activation via mutations in the N-terminal TLR5 binding motif. RESULTS Here, we show that both CD and ME/CFS patients exhibit elevated antibody responses against distinct regions of flagellins compared to healthy individuals. N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling "stimulator" and "silent" flagellins more than evaders. However, C-terminal antibody-bound flagellins showed a higher resemblance to the stimulator than to silent flagellins in CD, which was not observed in ME/CFS. CONCLUSIONS These findings suggest that antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Blocking this interaction could lead commensal bacteria to be recognized as pathogenic evaders, potentially contributing to dysregulation in both diseases. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between the diseases. Overall, these results highlight the diagnostic potential of these antibody responses and lay a foundation for deeper mechanistic studies of flagellin/TLR5 interactions and their impact on innate/adaptive immunity balance.
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Affiliation(s)
- Arno R Bourgonje
- The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Nicolai V Hörstke
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Michaela Fehringer
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Gabriel Innocenti
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Thomas Vogl
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
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18
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Guo S, Yang Q, Fan Y, Ran M, Shi Q, Song Z. Characterization and expression profiles of toll-like receptor genes (TLR2 and TLR5) in immune tissues of hybrid yellow catfish under bacterial infection. FISH & SHELLFISH IMMUNOLOGY 2024; 150:109627. [PMID: 38754649 DOI: 10.1016/j.fsi.2024.109627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/23/2024] [Accepted: 05/12/2024] [Indexed: 05/18/2024]
Abstract
The yellow catfish (Pelteobagrus fulvidraco) is one of the most economically important freshwater species in Asia. However, pathogenic bacterial infections often cause high rates of mortality and economic losses in practical aquaculture. Previous studies in mammals have shown that Toll-like receptor 2 (TLR2) and Toll-like receptor 5 (TLR5) are involved in the recognition of cell wall components such as lipopolysaccharides and flagella of various bacteria, thereby acting as key regulators in the innate immunity response. However, TLR2 and TLR5 in yellow catfish have not been characterized. In the present study, TLR2 and TLR5 were examined through comparative genomic approaches. The gene structure, collinearity, protein spatial structure, and phylogenetic relationships were compared with those in multiple representative vertebrates. Meanwhile, quantitative real-time PCR was conducted to explore transcriptional changes in TLR2 and TLR5 in immune tissues after infection with exogenous A. hydrophila and E. tarda. The results demonstrated the presence of TLR2 and TLR5 in yellow catfish. However, a systematic analysis showed that TLR2 was not associated with the arrangement of diverse neighboring genes. The expression of hybrid yellow catfish TLR2 transcripts in multiple tissues (including liver, spleen, kidney, and intestine) was significantly up-regulated after infection with A. hydrophila and E. tarda, suggesting that hybrid yellow catfish TLR2 and TLR5 may participate in the immune process. Taken together, the results indicate that TLR2 and TLR5 are conserved in terms of evolution and possess significant antibacterial activity as well as regulatory properties in immune-related tissues and thus play key roles in host defense against pathogen invasion.
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Affiliation(s)
- Shengtao Guo
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China; Laboratory of Aquatic Genomics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518060, China
| | - Qingzhuoma Yang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Yuxin Fan
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Miling Ran
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Qiong Shi
- Laboratory of Aquatic Genomics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518060, China
| | - Zhaobin Song
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China.
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19
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Kim TS, Ikeuchi T, Theofilou VI, Williams DW, Greenwell-Wild T, June A, Adade EE, Li L, Abusleme L, Dutzan N, Yuan Y, Brenchley L, Bouladoux N, Sakamachi Y, Palmer RJ, Iglesias-Bartolome R, Trinchieri G, Garantziotis S, Belkaid Y, Valm AM, Diaz PI, Holland SM, Moutsopoulos NM. Epithelial-derived interleukin-23 promotes oral mucosal immunopathology. Immunity 2024; 57:859-875.e11. [PMID: 38513665 PMCID: PMC11058479 DOI: 10.1016/j.immuni.2024.02.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 01/05/2024] [Accepted: 02/29/2024] [Indexed: 03/23/2024]
Abstract
At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation.
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Affiliation(s)
- Tae Sung Kim
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tomoko Ikeuchi
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | - Vasileios Ionas Theofilou
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA; Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, MD 21201, USA
| | - Drake Winslow Williams
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | - Teresa Greenwell-Wild
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | - Armond June
- Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, University at Buffalo, Buffalo, NY 14214, USA
| | - Emmanuel E Adade
- Department of Biological Sciences, University at Albany, State University of New York, Albany, NY 12210, USA
| | - Lu Li
- Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, University at Buffalo, Buffalo, NY 14214, USA
| | - Loreto Abusleme
- Department of Pathology and Oral Medicine, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - Nicolas Dutzan
- Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - Yao Yuan
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Laurie Brenchley
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicolas Bouladoux
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yosuke Sakamachi
- Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Robert J Palmer
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ramiro Iglesias-Bartolome
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Giorgio Trinchieri
- Cancer Immunobiology Section, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Stavros Garantziotis
- Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Alex M Valm
- Department of Biological Sciences, University at Albany, State University of New York, Albany, NY 12210, USA
| | - Patricia I Diaz
- Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, University at Buffalo, Buffalo, NY 14214, USA
| | - Steven M Holland
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Niki M Moutsopoulos
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
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20
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Balint D, Brito IL. Human-gut bacterial protein-protein interactions: understudied but impactful to human health. Trends Microbiol 2024; 32:325-332. [PMID: 37805334 PMCID: PMC10990813 DOI: 10.1016/j.tim.2023.09.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 10/09/2023]
Abstract
The human gut microbiome is associated with a wide range of diseases; yet, the mechanisms these microbes use to influence human health are not fully understood. Protein-protein interactions (PPIs) are increasingly identified as a potential mechanism by which gut microbiota influence their human hosts. Similar to some PPIs observed in pathogens, many disease-relevant human-gut bacterial PPIs function by interacting with components of the immune system or the gut barrier. Here, we highlight recent advances in these two areas. It is our opinion that there is a vastly unexplored network of human-gut bacterial PPIs that contribute to the prevention or pathogenesis of various diseases and that future research is warranted to expand PPI discovery.
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Affiliation(s)
- Diana Balint
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Ilana L Brito
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
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21
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Fields JL, Zhang H, Bellis NF, Petersen HA, Halder SK, Rich-New ST, Wu H, Wang F. Structural diversity and clustering of bacterial flagellar outer domains. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.18.585621. [PMID: 38562817 PMCID: PMC10983879 DOI: 10.1101/2024.03.18.585621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Supercoiled flagellar filaments function as mechanical propellers within the bacterial flagellum complex, playing a crucial role in motility. Flagellin, the building block of the filament, features a conserved inner D0/D1 core domain across different bacterial species. In contrast, approximately half of the flagellins possess additional, highly divergent outer domain(s), suggesting varied functional potential. In this study, we elucidate atomic structures of flagellar filaments from three distinct bacterial species: Cupriavidus gilardii , Stenotrophomonas maltophilia , and Geovibrio thiophilus . Our findings reveal that the flagella from the facultative anaerobic G. thiophilus possesses a significantly more negatively charged surface, potentially enabling adhesion to positively charged minerals. Furthermore, we analyzed all AlphaFold predicted structures for annotated bacterial flagellins, categorizing the flagellin outer domains into 682 structural clusters. This classification provides insights into the prevalence and experimental verification of these outer domains. Remarkably, two of the flagellar structures reported herein belong to a previously unexplored cluster, indicating new opportunities on the study of the functional diversity of flagellar outer domains. Our findings underscore the complexity of bacterial flagellins and open up possibilities for future studies into their varied roles beyond motility.
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22
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Yang J, Wang Y, Hou Y, Sun M, Xia T, Wu X. Evasion of host defense by Brucella. CELL INSIGHT 2024; 3:100143. [PMID: 38250017 PMCID: PMC10797155 DOI: 10.1016/j.cellin.2023.100143] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 01/23/2024]
Abstract
Brucella , an adept intracellular pathogen, causes brucellosis, a zoonotic disease leading to significant global impacts on animal welfare and the economy. Regrettably, there is currently no approved and effective vaccine for human use. The ability of Brucella to evade host defenses is essential for establishing chronic infection and ensuring stable intracellular growth. Brucella employs various mechanisms to evade and undermine the innate and adaptive immune responses of the host through modulating the activation of pattern recognition receptors (PRRs), inflammatory responses, or the activation of immune cells like dendritic cells (DCs) to inhibit antigen presentation. Moreover, it regulates multiple cellular processes such as apoptosis, pyroptosis, and autophagy to establish persistent infection within host cells. This review summarizes the recently discovered mechanisms employed by Brucella to subvert host immune responses and research progress on vaccines, with the aim of advancing our understanding of brucellosis and facilitating the development of more effective vaccines and therapeutic approaches against Brucella .
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Affiliation(s)
- Jinke Yang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Yue Wang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Yuanpan Hou
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Mengyao Sun
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Tian Xia
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Xin Wu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
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23
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Tran SC, Bryant KN, Cover TL. The Helicobacter pylori cag pathogenicity island as a determinant of gastric cancer risk. Gut Microbes 2024; 16:2314201. [PMID: 38391242 PMCID: PMC10896142 DOI: 10.1080/19490976.2024.2314201] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 01/31/2024] [Indexed: 02/24/2024] Open
Abstract
Helicobacter pylori strains can be broadly classified into two groups based on whether they contain or lack a chromosomal region known as the cag pathogenicity island (cag PAI). Colonization of the human stomach with cag PAI-positive strains is associated with an increased risk of gastric cancer and peptic ulcer disease, compared to colonization with cag PAI-negative strains. The cag PAI encodes a secreted effector protein (CagA) and components of a type IV secretion system (Cag T4SS) that delivers CagA and non-protein substrates into host cells. Animal model experiments indicate that CagA and the Cag T4SS stimulate a gastric mucosal inflammatory response and contribute to the development of gastric cancer. In this review, we discuss recent studies defining structural and functional features of CagA and the Cag T4SS and mechanisms by which H. pylori strains containing the cag PAI promote the development of gastric cancer and peptic ulcer disease.
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Affiliation(s)
- Sirena C. Tran
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kaeli N. Bryant
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Timothy L. Cover
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
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24
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Park S, Cho E, Senevirathne A, Chung HJ, Ha S, Kim CH, Kang S, Lee JH. Salmonella vector induces protective immunity against Lawsonia and Salmonella in murine model using prokaryotic expression system. J Vet Sci 2024; 25:e4. [PMID: 38311319 PMCID: PMC10839175 DOI: 10.4142/jvs.23219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 11/18/2023] [Accepted: 11/24/2023] [Indexed: 02/07/2024] Open
Abstract
BACKGROUND Lawsonia intracellularis is the causative agent of proliferative enteropathy and is associated with several outbreaks, causing substantial economic loss to the porcine industry. OBJECTIVES In this study, we focused on demonstrating the protective effect in the mouse model through the immunological bases of two vaccine strains against porcine proliferative enteritis. METHODS We used live-attenuated Salmonella Typhimurium (ST) secreting two selected immunogenic LI antigens (Lawsonia autotransporter A epitopes and flagellin [FliC]-peptidoglycan-associated lipoprotein-FliC) as the vaccine carrier. The constructs were cloned into a Salmonella expression vector (pJHL65) and transformed into the ST strain (JOL912). The expression of immunogenic proteins within Salmonella was evaluated via immunoblotting. RESULTS Immunizing BALB/c mice orally and subcutaneously induced high levels of LI-specific systemic immunoglobulin G and mucosal secretory immunoglobulin A. In immunized mice, there was significant upregulation of interferon-γ and interleukin-4 cytokine mRNA and an increase in the subpopulations of cluster of differentiation (CD) 4+ and CD 8+ T lymphocytes upon splenocytes re-stimulation with LI antigens. We observed significant protection in C57BL/6 mice against challenge with 106.9 times the median tissue culture infectious dose of LI or 2 × 109 colony-forming units of the virulent ST strain. Immunizing mice with either individual vaccine strains or co-mixture inhibited bacterial proliferation, with a marked reduction in the percentage of mice shedding Lawsonia in their feces. CONCLUSIONS Salmonella-mediated LI gene delivery induces robust humoral and cellular immune reactions, leading to significant protection against LI and salmonellosis.
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Affiliation(s)
- Sungwoo Park
- College of Veterinary Medicine, Jeonbuk National University, Iksan Campus, Iksan 54596, Korea
- Swine Science Division, National Institute of Animal Science, Cheonan 31000, Korea
| | - Eunseok Cho
- Swine Science Division, National Institute of Animal Science, Cheonan 31000, Korea
| | - Amal Senevirathne
- College of Veterinary Medicine, Jeonbuk National University, Iksan Campus, Iksan 54596, Korea
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
| | - Hak-Jae Chung
- Swine Science Division, National Institute of Animal Science, Cheonan 31000, Korea
| | - Seungmin Ha
- Dairy Science Division, National Institute of Animal Science, Cheonan 31000, Korea
| | - Chae-Hyun Kim
- Swine Science Division, National Institute of Animal Science, Cheonan 31000, Korea
| | - Seogjin Kang
- Dairy Science Division, National Institute of Animal Science, Cheonan 31000, Korea.
| | - John Hwa Lee
- College of Veterinary Medicine, Jeonbuk National University, Iksan Campus, Iksan 54596, Korea.
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25
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Marzhoseyni Z, Mousavi MJ, Ghotloo S. Helicobacter pylori antigens as immunomodulators of immune system. Helicobacter 2024; 29:e13058. [PMID: 38380545 DOI: 10.1111/hel.13058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 02/07/2024] [Accepted: 02/08/2024] [Indexed: 02/22/2024]
Abstract
Helicobacter pylori (H. pylori) is one of the most prevalent human pathogens and the leading cause of chronic infection in almost half of the population in the world (~59%). The bacterium is a major leading cause of chronic gastritis, gastric and duodenal ulcers, and two type of malignancies, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Despite the immune responses mounted by the host, the bacteria are not cleared from the body resulting in a chronic infection accompanied by a chronic inflammation. Herein, a review of the literature discussing H. pylori antigens modulating the immune responses is presented. The mechanisms that are involved in the modulation of innate immune response, include modulation of recognition by pattern recognition receptors (PRRs) such as modulation of recognition by toll like receptors (TLR)4 and TLR5, modulation of phagocytic function, and modulation of phagocytic killing mediated by reactive oxygen species (ROS) and nitric oxide (NO). On the other hands, H. pylori modulates acquired immune response by the induction of tolerogenic dendritic cells (DCs), modulation of apoptosis, induction of regulatory T cells, modulation of T helper (Th)1 response, and modulation of Th17 response.
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Affiliation(s)
- Zeynab Marzhoseyni
- Department of Paramedicine, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Javad Mousavi
- Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Somayeh Ghotloo
- Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
- Department of Clinical Laboratory Sciences, School of Allied Medical Sciences, Kashan University of Medical Sciences, Kashan, Iran
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26
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Jung MS, Piazuelo MB, Brackman LC, McClain MS, Algood HMS. Essential role of Helicobacter pylori apolipoprotein N-acyltransferase (Lnt) in stomach colonization. Infect Immun 2023; 91:e0036923. [PMID: 37937999 PMCID: PMC10715074 DOI: 10.1128/iai.00369-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 10/17/2023] [Indexed: 11/09/2023] Open
Abstract
Bacterial lipoproteins are post-translationally modified with acyl chains, anchoring these proteins to bacterial membranes. In Gram-negative bacteria, three enzymes complete the modifications. Lgt (which adds two acyl chains) and LspA (which removes the signal peptide) are essential. Lnt (which adds a third acyl chain) is not essential in certain bacteria including Francisella tularensis, Neisseria gonorrhoeae, and Acinetobacter baumannii. Deleting lnt results in mild to severe physiologic changes. We previously showed lnt is not essential for Helicobacter pylori growth in vitro. Here, the physiologic consequences of deleting lnt in H. pylori and the role of Lnt in the host response to H. pylori were examined using in vitro and in vivo models. Comparing wild-type, Δlnt, and complemented mutant H. pylori, no changes in growth rates or sensitivity to acid or antibiotics were observed. Since deleting lnt changes the number of acyl chains on lipoproteins and the number of acyl chains on lipoproteins impacts the innate immune response through Toll-like receptor 2 (TLR2) signaling, primary human gastric epithelial cells were treated with a purified lipoprotein from wild-type or lnt mutant H. pylori. Differential gene expression analysis indicated that lipoprotein from the lnt mutant induced a more robust TLR2 response. In a complementary approach, we infected wild-type and Tlr2-/- mice and found that both the wild-type and complemented mutant strains successfully colonized the animals. However, the lnt mutant strain was unable to colonize either mouse strain. These results show that lnt is essential for H. pylori colonization and identifies lipoprotein synthesis as a target for therapeutic intervention.
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Affiliation(s)
- Matthew S. Jung
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Lee C. Brackman
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - 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, Tennessee, USA
| | - Holly M. Scott Algood
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Center for Immunobiology, Vanderbilt Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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27
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Zhang X, Zhang K, Yan L, Wang P, Zhao F, Hu S. The role of toll-like receptors in immune tolerance induced by Helicobacter pylori infection. Helicobacter 2023; 28:e13020. [PMID: 37691007 DOI: 10.1111/hel.13020] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/11/2023] [Accepted: 08/29/2023] [Indexed: 09/12/2023]
Abstract
Helicobacter pylori (H. pylori) is a gram-negative, microaerobic bacterium that colonizes the gastric mucosa in about half of the world's population. H. pylori infection can lead to various diseases. Chronic infection by H. pylori exposes the gastric mucosa to bacterial components such as lipopolysaccharide (LPS), outer membrane vesicles (OMVs), and several toxic proteins. Infected with H. pylori activates the release of pro-inflammatory factors and triggers inflammatory responses that damage the gastric mucosa. As the only microorganism that permanently colonizes the human stomach, H. pylori can suppress host immunity to achieve long-term colonization. Toll-like receptors (TLRs) play a crucial role in T-cell activation, promoting innate immune responses and immune tolerance during H. pylori infection. Among the 10 TLRs found in humans, TLR2, TLR4, TLR5, and TLR9 have been thoroughly investigated in relation to H. pylori-linked immune regulation. In the present review, we provide a comprehensive analysis of the various mechanisms employed by different TLRs in the induction of immune tolerance upon H. pylori infection, which will contribute to the research of pathogenic mechanism of H. pylori.
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Affiliation(s)
- Xiulin Zhang
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Ke Zhang
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Linlin Yan
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Pengfei Wang
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Fan Zhao
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Shoukui Hu
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
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28
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Kim HJ, Kim H, Lee JH, Hwangbo C. Toll-like receptor 4 (TLR4): new insight immune and aging. Immun Ageing 2023; 20:67. [PMID: 38001481 PMCID: PMC10668412 DOI: 10.1186/s12979-023-00383-3] [Citation(s) in RCA: 112] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 10/23/2023] [Indexed: 11/26/2023]
Abstract
TLR4, a transmembrane receptor, plays a central role in the innate immune response. TLR4 not only engages with exogenous ligands at the cellular membrane's surface but also interacts with intracellular ligands, initiating intricate intracellular signaling cascades. Through MyD88, an adaptor protein, TLR4 activates transcription factors NF-κB and AP-1, thereby facilitating the upregulation of pro-inflammatory cytokines. Another adapter protein linked to TLR4, known as TRIF, autonomously propagates signaling pathways, resulting in heightened interferon expression. Recently, TLR4 has garnered attention as a significant factor in the regulation of symptoms in aging-related disorders. The persistent inflammatory response triggered by TLR4 contributes to the onset and exacerbation of these disorders. In addition, alterations in TLR4 expression levels play a pivotal role in modifying the manifestations of age-related diseases. In this review, we aim to consolidate the impact of TLR4 on cellular senescence and aging-related ailments, highlighting the potential of TLR4 as a novel therapeutic target that extends beyond immune responses.
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Affiliation(s)
- Hyo-Jin Kim
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Hyemin Kim
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Jeong-Hyung Lee
- Department of Biochemistry (BK21 Four), College of Natural Sciences, Kangwon National University, Chuncheon, 24414, Republic of Korea
| | - Cheol Hwangbo
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea.
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea.
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29
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Dawood AS, Elrashedy A, Nayel M, Salama A, Guo A, Zhao G, Algharib SA, Zaghawa A, Zubair M, Elsify A, Mousa W, Luo W. Brucellae as resilient intracellular pathogens: epidemiology, host-pathogen interaction, recent genomics and proteomics approaches, and future perspectives. Front Vet Sci 2023; 10:1255239. [PMID: 37876633 PMCID: PMC10591102 DOI: 10.3389/fvets.2023.1255239] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 09/15/2023] [Indexed: 10/26/2023] Open
Abstract
Brucellosis is considered one of the most hazardous zoonotic diseases all over the world. It causes formidable economic losses in developed and developing countries. Despite the significant attempts to get rid of Brucella pathogens in many parts of the world, the disease continues to spread widely. Recently, many attempts proved to be effective for the prevention and control of highly contagious bovine brucellosis, which could be followed by others to achieve a prosperous future without rampant Brucella pathogens. In this study, the updated view for worldwide Brucella distribution, possible predisposing factors for emerging Brucella pathogens, immune response and different types of Brucella vaccines, genomics and proteomics approaches incorporated recently in the field of brucellosis, and future perspectives for prevention and control of bovine brucellosis have been discussed comprehensively. So, the current study will be used as a guide for researchers in planning their future work, which will pave the way for a new world without these highly contagious pathogens that have been infecting and threatening the health of humans and terrestrial animals.
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Affiliation(s)
- Ali Sobhy Dawood
- Engineering Laboratory for Tarim Animal Diseases Diagnosis and Control, College of Animal Science and Technology, Tarim University, Alar, Xinjiang, China
- The State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Alyaa Elrashedy
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Mohamed Nayel
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Akram Salama
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Aizhen Guo
- The State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Gang Zhao
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, School of Life Sciences, Ningxia University, Yinchuan, China
| | - Samah Attia Algharib
- Engineering Laboratory for Tarim Animal Diseases Diagnosis and Control, College of Animal Science and Technology, Tarim University, Alar, Xinjiang, China
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues (HZAU), Wuhan, China
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt
| | - Ahmed Zaghawa
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Muhammed Zubair
- Key Laboratory of Veterinary Biological Engineering and Technology, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Ahmed Elsify
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Walid Mousa
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Wanhe Luo
- Engineering Laboratory for Tarim Animal Diseases Diagnosis and Control, College of Animal Science and Technology, Tarim University, Alar, Xinjiang, China
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30
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Mani T, Joshi JB, Priyadharshini R, Sharmila JS, Uthandi S. Flagellin, a plant-defense-activating protein identified from Xanthomonas axonopodis pv. Dieffenbachiae invokes defense response in tobacco. BMC Microbiol 2023; 23:284. [PMID: 37798635 PMCID: PMC10552369 DOI: 10.1186/s12866-023-03028-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 09/22/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Secretome analysis is a valuable tool to study host-pathogen protein interactions and to identify new proteins that are important for plant health. Microbial signatures elicit defense responses in plants, and by that, the plant immune system gets triggered prior to pathogen infection. Functional properties of secretory proteins from Xanthomonas axonopodis pv. dieffenbachiae (Xad1) involved in priming plant immunity was evaluated. RESULTS In this study, the secretome of Xad1 was analyzed under host plant extract-induced conditions, and mass spectroscopic analysis of differentially expressed protein was identified as plant-defense-activating protein viz., flagellin C (FliC). The flagellin and Flg22 peptides both elicited hypersensitive reaction (HR) in non-host tobacco, activated reactive oxygen species (ROS) scavenging enzymes, and increased pathogenesis-related (PR) gene expression viz., NPR1, PR1, and down-regulation of PR2 (β-1,3-glucanase). Protein docking studies revealed the Flg22 epitope of Xad1, a 22 amino acid peptide region in FliC that recognizes plant receptor FLS2 to initiate downstream defense signaling. CONCLUSION The flagellin or the Flg22 peptide from Xad1 was efficient in eliciting an HR in tobacco via salicylic acid (SA)-mediated defense signaling that subsequently triggers systemic immune response epigenetically. The insights from this study can be used for the development of bio-based products (small PAMPs) for plant immunity and health.
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Affiliation(s)
- Tamilarasi Mani
- Biocatalysts Laboratory, Department of Agricultural Microbiology, Directorate of Natural Resource Management, Tamil Nadu Agricultural University, Coimbatore, 641 003, India
| | - J Beslin Joshi
- Biocatalysts Laboratory, Department of Agricultural Microbiology, Directorate of Natural Resource Management, Tamil Nadu Agricultural University, Coimbatore, 641 003, India
- Centre for Water Resources Development and Management, Kozhikode, India
| | - R Priyadharshini
- Biocatalysts Laboratory, Department of Agricultural Microbiology, Directorate of Natural Resource Management, Tamil Nadu Agricultural University, Coimbatore, 641 003, India
- Department of Microbiology, Karpagam Academy of Higher Education, Coimbatore, India
| | - Jeya Sundara Sharmila
- Department of Nano Science and Technology, Directorate of Natural Resource Management, Tamil Nadu Agricultural University, Coimbatore, India
| | - Sivakumar Uthandi
- Biocatalysts Laboratory, Department of Agricultural Microbiology, Directorate of Natural Resource Management, Tamil Nadu Agricultural University, Coimbatore, 641 003, India.
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31
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Pachathundikandi SK, Tegtmeyer N, Backert S. Masking of typical TLR4 and TLR5 ligands modulates inflammation and resolution by Helicobacter pylori. Trends Microbiol 2023; 31:903-915. [PMID: 37012092 DOI: 10.1016/j.tim.2023.03.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/28/2023] [Accepted: 03/13/2023] [Indexed: 04/03/2023]
Abstract
Helicobacter pylori is a paradigm of chronic bacterial infection and is associated with peptic ulceration and malignancies. H. pylori uses specific masking mechanisms to avoid canonical ligands from activating Toll-like receptors (TLRs), such as lipopolysaccharide (LPS) modification and specific flagellin sequences that are not detected by TLR4 and TLR5, respectively. Thus, it was believed for a long time that H. pylori evades TLR recognition as a crucial strategy for immune escape and bacterial persistence. However, recent data indicate that multiple TLRs are activated by H. pylori and play a role in the pathology. Remarkably, H. pylori LPS, modified through changes in acylation and phosphorylation, is mainly sensed by other TLRs (TLR2 and TLR10) and induces both pro- and anti-inflammatory responses. In addition, two structural components of the cag pathogenicity island-encoded type IV secretion system (T4SS), CagL and CagY, were shown to contain TLR5-activating domains. These domains stimulate TLR5 and enhance immunity, while LPS-driven TLR10 signaling predominantly activates anti-inflammatory reactions. Here, we discuss the specific roles of these TLRs and masking mechanisms during infection. Masking of typical TLR ligands combined with evolutionary shifting to other TLRs is unique for H. pylori and has not yet been described for any other species in the bacterial kingdom. Finally, we highlight the unmasked T4SS-driven activation of TLR9 by H. pylori, which mainly triggers anti-inflammatory responses.
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Affiliation(s)
- Suneesh Kumar Pachathundikandi
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Dept. of Biology, Chair of Microbiology, Staudtstr. 5, 91058 Erlangen, Germany; Babasaheb Bhimrao Ambedkar University, Dept. of Environmental Microbiology, School of Earth and Environmental Sciences, Vidya Vihar, Raebareli Road, Lucknow 226025, India
| | - Nicole Tegtmeyer
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Dept. of Biology, Chair of Microbiology, Staudtstr. 5, 91058 Erlangen, Germany
| | - Steffen Backert
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Dept. of Biology, Chair of Microbiology, Staudtstr. 5, 91058 Erlangen, Germany.
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Liu M, Hu Z, Wang C, Zhang Y. The TLR/MyD88 signalling cascade in inflammation and gastric cancer: the immune regulatory network of Helicobacter pylori. J Mol Med (Berl) 2023; 101:767-781. [PMID: 37195446 DOI: 10.1007/s00109-023-02332-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/18/2023]
Abstract
Helicobacter pylori-induced chronic gastritis represents a well-established risk factor for gastric cancer (GC). However, the mechanism by which chronic inflammation caused by H. pylori induces the development of GC is unclear. H. pylori can influence host cell signalling pathways to induce gastric disease development and mediate cancer promotion and progression. Toll-like receptors (TLRs), as pattern recognition receptors (PRRs), play a key role in the gastrointestinal innate immune response, and their signalling has been implicated in the pathogenesis of an increasing number of inflammation-associated cancers. The core adapter myeloid differentiation factor-88 (MyD88) is shared by most TLRs and functions primarily in H. pylori-triggered innate immune signalling. MyD88 is envisioned as a potential target for the regulation of immune responses and is involved in the regulation of tumourigenesis in a variety of cancer models. In recent years, the TLR/MyD88 signalling pathway has received increasing attention for its role in regulating innate and adaptive immune responses, inducing inflammatory activation and promoting tumour formation. In addition, TLR/MyD88 signalling can manipulate the expression of infiltrating immune cells and various cytokines in the tumour microenvironment (TME). In this review, we discuss the pathogenetic regulatory mechanisms of the TLR/MyD88 signalling cascade pathway and its downstream molecules in H. pylori infection-induced-associated GC. The focus is to elucidate the immunomolecular mechanisms of pathogen recognition and innate immune system activation of H. pylori in the TME of inflammation-associated GC. Ultimately, this study will provide insight into the mechanism of H. pylori-induced chronic inflammation-induced GC development and provide thoughts for GC prevention and treatment strategies.
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Affiliation(s)
- Meiqi Liu
- Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, China
| | - Zhizhong Hu
- Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, China
| | - Chengkun Wang
- Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, China.
| | - Yang Zhang
- Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, China.
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33
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Kashyap D, Rele S, Bagde PH, Saini V, Chatterjee D, Jain AK, Pandey RK, Jha HC. Comprehensive insight into altered host cell-signaling cascades upon Helicobacter pylori and Epstein-Barr virus infections in cancer. Arch Microbiol 2023; 205:262. [PMID: 37310490 DOI: 10.1007/s00203-023-03598-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/14/2023]
Abstract
Cancer is characterized by mutagenic events that lead to disrupted cell signaling and cellular functions. It is one of the leading causes of death worldwide. Literature suggests that pathogens, mainly Helicobacter pylori and Epstein-Barr virus (EBV), have been associated with the etiology of human cancer. Notably, their co-infection may lead to gastric cancer. Pathogen-mediated DNA damage could be the first and crucial step in the carcinogenesis process that modulates numerous cellular signaling pathways. Altogether, it dysregulates the metabolic pathways linked with cell growth, apoptosis, and DNA repair. Modulation in these pathways leads to abnormal growth and proliferation. Several signaling pathways such RTK, RAS/MAPK, PI3K/Akt, NFκB, JAK/STAT, HIF1α, and Wnt/β-catenin are known to be altered in cancer. Therefore, this review focuses on the oncogenic roles of H. pylori, EBV, and its associated signaling cascades in various cancers. Scrutinizing these signaling pathways is crucial and may provide new insights and targets for preventing and treating H. pylori and EBV-associated cancers.
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Affiliation(s)
- Dharmendra Kashyap
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | - Samiksha Rele
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | - Pranit Hemant Bagde
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | - Vaishali Saini
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | | | | | - Rajan Kumar Pandey
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177, Solna, Sweden
| | - Hem Chandra Jha
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India.
- Centre for Rural Development and Technology, Indian Institute of Technology Indore, Madhya Pradesh, 453552, Indore, India.
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Jin X, Gou Y, Xin Y, Li J, Sun J, Li T, Feng J. Advancements in understanding the molecular and immune mechanisms of Bartonella pathogenicity. Front Microbiol 2023; 14:1196700. [PMID: 37362930 PMCID: PMC10288214 DOI: 10.3389/fmicb.2023.1196700] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
Bartonellae are considered to be emerging opportunistic pathogens. The bacteria are transmitted by blood-sucking arthropods, and their hosts are a wide range of mammals including humans. After a protective barrier breach in mammals, Bartonella colonizes endothelial cells (ECs), enters the bloodstream, and infects erythrocytes. Current research primarily focuses on investigating the interaction between Bartonella and ECs and erythrocytes, with recent attention also paid to immune-related aspects. Various molecules related to Bartonella's pathogenicity have been identified. The present review aims to provide a comprehensive overview of the newly described molecular and immune responses associated with Bartonella's pathogenicity.
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Affiliation(s)
- Xiaoxia Jin
- Gansu Provincial Key Laboratory of Evidence Based Medicine and Clinical Translation and Lanzhou Center for Tuberculosis Research, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Yuze Gou
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou, China
| | - Yuxian Xin
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou, China
| | - Jingwei Li
- Gansu Provincial Key Laboratory of Evidence Based Medicine and Clinical Translation and Lanzhou Center for Tuberculosis Research, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Jingrong Sun
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou, China
| | - Tingting Li
- Gansu Provincial Key Laboratory of Evidence Based Medicine and Clinical Translation and Lanzhou Center for Tuberculosis Research, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Jie Feng
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou, China
- State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, China
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35
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Villarroel-Espindola F, Ejsmentewicz T, Gonzalez-Stegmaier R, Jorquera RA, Salinas E. Intersections between innate immune response and gastric cancer development. World J Gastroenterol 2023; 29:2222-2240. [PMID: 37124883 PMCID: PMC10134417 DOI: 10.3748/wjg.v29.i15.2222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/07/2022] [Accepted: 03/13/2023] [Indexed: 04/14/2023] Open
Abstract
Worldwide, gastric cancer (GC) is the fifth most commonly diagnosed malignancy. It has a reduced prevalence but has maintained its poor prognosis being the fourth leading cause of deaths related to cancer. The highest mortality rates occur in Asian and Latin American countries, where cases are usually diagnosed at advanced stages. Overall, GC is viewed as the consequence of a multifactorial process, involving the virulence of the Helicobacter pylori (H. pylori) strains, as well as some environmental factors, dietary habits, and host intrinsic factors. The tumor microenvironment in GC appears to be chronically inflamed which promotes tumor progression and reduces the therapeutic opportunities. It has been suggested that inflammation assessment needs to be measured qualitatively and quantitatively, considering cell-infiltration types, availability of receptors to detect damage and pathogens, and presence or absence of aggressive H. pylori strains. Gastrointestinal epithelial cells express several Toll-like receptors and determine the first defensive line against pathogens, and have been also described as mediators of tumorigenesis. However, other molecules, such as cytokines related to inflammation and innate immunity, including immune checkpoint molecules, interferon-gamma pathway and NETosis have been associated with an increased risk of GC. Therefore, this review will explore innate immune activation in the context of premalignant lesions of the gastric epithelium and established gastric tumors.
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Affiliation(s)
- Franz Villarroel-Espindola
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Troy Ejsmentewicz
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Roxana Gonzalez-Stegmaier
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Roddy A Jorquera
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Esteban Salinas
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
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36
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Malfertheiner P, Camargo MC, El-Omar E, Liou JM, Peek R, Schulz C, Smith SI, Suerbaum S. Helicobacter pylori infection. Nat Rev Dis Primers 2023; 9:19. [PMID: 37081005 PMCID: PMC11558793 DOI: 10.1038/s41572-023-00431-8] [Citation(s) in RCA: 349] [Impact Index Per Article: 174.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2023] [Indexed: 04/22/2023]
Abstract
Helicobacter pylori infection causes chronic gastritis, which can progress to severe gastroduodenal pathologies, including peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori is usually transmitted in childhood and persists for life if untreated. The infection affects around half of the population in the world but prevalence varies according to location and sanitation standards. H. pylori has unique properties to colonize gastric epithelium in an acidic environment. The pathophysiology of H. pylori infection is dependent on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors, resulting in distinct gastritis phenotypes that determine possible progression to different gastroduodenal pathologies. The causative role of H. pylori infection in gastric cancer development presents the opportunity for preventive screen-and-treat strategies. Invasive, endoscopy-based and non-invasive methods, including breath, stool and serological tests, are used in the diagnosis of H. pylori infection. Their use depends on the specific individual patient history and local availability. H. pylori treatment consists of a strong acid suppressant in various combinations with antibiotics and/or bismuth. The dramatic increase in resistance to key antibiotics used in H. pylori eradication demands antibiotic susceptibility testing, surveillance of resistance and antibiotic stewardship.
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Affiliation(s)
- Peter Malfertheiner
- Medical Department II, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
- Medical Department Klinik of Gastroenterology, Hepatology and Infectiology, Otto-von-Guericke Universität, Magdeburg, Germany.
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Emad El-Omar
- Microbiome Research Centre, St George & Sutherland Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
| | - Jyh-Ming Liou
- Department of Internal Medicine, National Taiwan University Cancer Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Richard Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Christian Schulz
- Medical Department II, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
- DZIF Deutsches Zentrum für Infektionsforschung, Partner Site Munich, Munich, Germany
| | - Stella I Smith
- Department of Molecular Biology and Biotechnology, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria
| | - Sebastian Suerbaum
- DZIF Deutsches Zentrum für Infektionsforschung, Partner Site Munich, Munich, Germany
- Max von Pettenkofer Institute, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany
- National Reference Center for Helicobacter pylori, Munich, Germany
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37
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Innate immune activation and modulatory factors of Helicobacter pylori towards phagocytic and nonphagocytic cells. Curr Opin Immunol 2023; 82:102301. [PMID: 36933362 DOI: 10.1016/j.coi.2023.102301] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/17/2023] [Indexed: 03/18/2023]
Abstract
Helicobacter pylori is an intriguing obligate host-associated human pathogen with a specific host interaction biology, which has been shaped by thousands of years of host-pathogen coevolution. Molecular mechanisms of interaction of H. pylori with the local immune cells in the human system are less well defined than epithelial cell interactions, although various myeloid cells, including neutrophils and other phagocytes, are locally present or attracted to the sites of infection and interact with H. pylori. We have recently addressed the question of novel bacterial innate immune stimuli, including bacterial cell envelope metabolites, that can activate and modulate cell responses via the H. pylori Cag type IV secretion system. This review article gives an overview of what is currently known about the interaction modes and mechanisms of H. pylori with diverse human cell types, with a focus on bacterial metabolites and cells of the myeloid lineage including phagocytic and antigen-presenting cells.
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Recombinant Domain of Flagellin Promotes In Vitro a Chemotactic Inflammatory Profile in Human Immune Cells Independently of a Dendritic Cell Phenotype. Molecules 2023; 28:molecules28052394. [PMID: 36903639 PMCID: PMC10005431 DOI: 10.3390/molecules28052394] [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: 01/25/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Flagellin is the major component of the flagellum in gram-positive and -negative bacteria and is also the ligand for the Toll-like receptor 5 (TLR5). The activation of TLR5 promotes the expression of proinflammatory cytokines and chemokines and the subsequent activation of T cells. This study evaluated a recombinant domain from the amino-terminus D1 domain (rND1) of flagellin from Vibrio anguillarum, a fish pathogen, as an immunomodulator in human peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MoDCs). We demonstrated that rND1 induced an upregulation of proinflammatory cytokines in PBMCs, characterized at the transcriptional level by an expression peak of 220-fold for IL-1β, 20-fold for IL-8, and 65-fold for TNF-α. In addition, at the protein level, 29 cytokines and chemokines were evaluated in the supernatant and were correlated with a chemotactic signature. MoDCs treated with rND1 showed low levels of co-stimulatory and HLA-DR molecules and kept an immature phenotype with a decreased phagocytosis of dextran. We probed that rND1 from a non-human pathogen promotes modulation in human cells, and it may be considered for further studies in adjuvant therapies based on pathogen-associated patterns (PAMPs).
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Marzhoseyni Z, Mousavi MJ, Saffari M, Ghotloo S. Immune escape strategies of Pseudomonas aeruginosa to establish chronic infection. Cytokine 2023; 163:156135. [PMID: 36724716 DOI: 10.1016/j.cyto.2023.156135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 01/08/2023] [Accepted: 01/12/2023] [Indexed: 02/02/2023]
Abstract
The infection caused by P. aeruginosa still is dangerous throughout the world. This is partly due to its immune escape mechanisms considerably increasing the bacterial survival in the host. By escape from recognition by TLRs, interference with complement system activation, phagocytosis inhibition, production of ROS, inhibition of NET production, interference with the generation of cytokines, inflammasome inhibition, reduced antigen presentation, interference with cellular and humoral immunity, and induction of apoptotic cell death and MDSc, P. aeruginosa breaks down the barriers of the immune system and causes lethal infections in the host. Recognition of other immune escape mechanisms of P. aeruginosa may provide a basis for the future treatment of the infection. This manuscript may provide new insights and information for the development of new strategies to combat P. aeruginosa infection. In the present manuscript, the escape mechanisms of P. aeruginosa against immune response would be reviewed.
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Affiliation(s)
- Zeynab Marzhoseyni
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Javad Mousavi
- Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mahmood Saffari
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Somayeh Ghotloo
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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40
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'Silent' flagellin drives immunotolerance to commensal bacteria. Trends Immunol 2023; 44:150-152. [PMID: 36739206 DOI: 10.1016/j.it.2023.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/05/2023]
Abstract
Distinguishing between commensal and pathogenic bacteria to generate appropriate responses (tolerance vs. immunogenicity) is a key decision that the human immune system must make to maintain homeostasis. Recently, Clasen and colleagues reported a distinct allosteric interaction between bacterial flagellin and host Toll-like receptor 5 (TLR5), which may shed light on these differences.
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41
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Selenomonas sputigena Interactions with Gingival Epithelial Cells That Promote Inflammation. Infect Immun 2023; 91:e0031922. [PMID: 36648232 PMCID: PMC9933688 DOI: 10.1128/iai.00319-22] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Increased prevalence and abundance of Selenomonas sputigena have been associated with periodontitis, a chronic inflammatory disease of tooth-supporting tissues, for more than 50 years. Over the past decade, molecular surveys of periodontal disease using 16S and shotgun metagenomic sequencing approaches have confirmed the disease association of classically recognized periodontal pathogens such as Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia while highlighting previously underappreciated organisms such as Filifactor alocis and S. sputigena. Despite abundant clinical association between S. sputigena and periodontal disease, we have little to no understanding of its pathogenic potential, and virulence mechanisms have not been studied. In this study, we sought to characterize the response of gingival epithelial cells to infection with S. sputigena. Here, we show that S. sputigena attaches to gingival keratinocytes and induces expression and secretion of cytokines and chemokines associated with inflammation and leukocyte recruitment. We demonstrate that S. sputigena induces signaling through Toll-like receptor 2 (TLR2) and TLR4 but evades activation of TLR5. Cytokines released from S. sputigena-infected keratinocytes induced monocyte and neutrophil chemotaxis. These results show that S. sputigena-host interactions have the potential to contribute to bacterially driven inflammation and tissue destruction, the hallmark of periodontitis. Characterization of previously unstudied pathogens may provide novel approaches to develop therapeutics to treat or prevent periodontal disease.
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Clasen SJ, Bell MEW, Borbón A, Lee DH, Henseler ZM, de la Cuesta-Zuluaga J, Parys K, Zou J, Wang Y, Altmannova V, Youngblut ND, Weir JR, Gewirtz AT, Belkhadir Y, Ley RE. Silent recognition of flagellins from human gut commensal bacteria by Toll-like receptor 5. Sci Immunol 2023; 8:eabq7001. [PMID: 36608151 DOI: 10.1126/sciimmunol.abq7001] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Flagellin, the protein subunit of the bacterial flagellum, stimulates the innate immune receptor Toll-like receptor 5 (TLR5) after pattern recognition or evades TLR5 through lack of recognition. This binary response fails to explain the weak agonism of flagellins from commensal bacteria, raising the question of how TLR5 response is tuned. Here, we screened abundant flagellins present in metagenomes from human gut for both TLR5 recognition and activation and uncovered a class of flagellin-TLR5 interaction termed silent recognition. Silent flagellins were weak TLR5 agonists despite pattern recognition. Receptor activity was tuned by a TLR5-flagellin interaction distal to the site of pattern recognition that was present in Salmonella flagellin but absent in silent flagellins. This interaction enabled flagellin binding to preformed TLR5 dimers and increased TLR5 signaling by several orders of magnitude. Silent recognition by TLR5 occurred in human organoids and mice, and silent flagellin proteins were present in human stool. These flagellins were produced primarily by the abundant gut bacteria Lachnospiraceae and were enriched in nonindustrialized populations. Our findings provide a mechanism for the innate immune system to tolerate commensal-derived flagellins while remaining vigilant to the presence of flagellins produced by pathogens.
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Affiliation(s)
- Sara J Clasen
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen 72076, Germany
| | - Michael E W Bell
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen 72076, Germany
| | - Andrea Borbón
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen 72076, Germany
| | - Du-Hwa Lee
- Gregor Mendel Institute (GMI), Austrian Academy of Sciences, Vienna BioCenter (VBC), Dr. Bohr-Gasse 3, Vienna, Austria
| | - Zachariah M Henseler
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen 72076, Germany
| | | | - Katarzyna Parys
- Gregor Mendel Institute (GMI), Austrian Academy of Sciences, Vienna BioCenter (VBC), Dr. Bohr-Gasse 3, Vienna, Austria
| | - Jun Zou
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Yanling Wang
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Veronika Altmannova
- Friedrich Miescher Laboratory of the Max Planck Society, Max-Planck-Ring 9, Tübingen 72076, Germany
| | - Nicholas D Youngblut
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen 72076, Germany
| | - John R Weir
- Friedrich Miescher Laboratory of the Max Planck Society, Max-Planck-Ring 9, Tübingen 72076, Germany
| | - Andrew T Gewirtz
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Youssef Belkhadir
- Gregor Mendel Institute (GMI), Austrian Academy of Sciences, Vienna BioCenter (VBC), Dr. Bohr-Gasse 3, Vienna, Austria
| | - Ruth E Ley
- Department of Microbiome Science, Max Planck Institute for Biology, Tübingen 72076, Germany.,Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany
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Baer HM, Sandilya S, Steiner TS. Evading the Toll booth: How "silent" flagellins may bind yet fail to activate TLR5. Sci Immunol 2023; 8:eadf0244. [PMID: 36608148 DOI: 10.1126/sciimmunol.adf0244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The nature of flagellin-Toll-like receptor 5 (TLR5) interactions, depending on binding to and activation of TLR5, may hold a key to the distinct differences in gut microbiome and intestinal immune function in different populations around the world (see related Research Article by Clasen et al.).
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Affiliation(s)
- Hannah M Baer
- BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Shruti Sandilya
- BC Children's Hospital Research Institute, Vancouver, BC, Canada
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Fuchs S, Gong R, Gerhard M, Mejías-Luque R. Immune Biology and Persistence of Helicobacter pylori in Gastric Diseases. Curr Top Microbiol Immunol 2023; 444:83-115. [PMID: 38231216 DOI: 10.1007/978-3-031-47331-9_4] [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
Helicobacter pylori is a prevalent pathogen, which affects more than 40% of the global population. It colonizes the human stomach and persists in its host for several decades or even a lifetime, if left untreated. The persistent infection has been linked to various gastric diseases, including gastritis, peptic ulcers, and an increased risk for gastric cancer. H. pylori infection triggers a strong immune response directed against the bacterium associated with the infiltration of innate phagocytotic immune cells and the induction of a Th1/Th17 response. Even though certain immune cells seem to be capable of controlling the infection, the host is unable to eliminate the bacteria as H. pylori has developed remarkable immune evasion strategies. The bacterium avoids its killing through innate recognition mechanisms and manipulates gastric epithelial cells and immune cells to support its persistence. This chapter focuses on the innate and adaptive immune response induced by H. pylori infection, and immune evasion strategies employed by the bacterium to enable persistent infection.
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Affiliation(s)
- Sonja Fuchs
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich (TUM), Trogerstraße 30, 81675, Munich, Germany
| | - Ruolan Gong
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich (TUM), Trogerstraße 30, 81675, Munich, Germany
| | - Markus Gerhard
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich (TUM), Trogerstraße 30, 81675, Munich, Germany
| | - Raquel Mejías-Luque
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich (TUM), Trogerstraße 30, 81675, Munich, Germany.
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Tan A, Alsenani Q, Lanz M, Birchall C, Drage LKL, Picton D, Mowbray C, Ali A, Harding C, Pickard RS, Hall J, Aldridge PD. Evasion of toll-like receptor recognition by Escherichia coli is mediated via population level regulation of flagellin production. Front Microbiol 2023; 14:1093922. [PMID: 37032848 PMCID: PMC10078357 DOI: 10.3389/fmicb.2023.1093922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 03/03/2023] [Indexed: 04/11/2023] Open
Abstract
Uropathogenic Escherichia coli is a major cause of urinary tract infections. Analysis of the innate immune response in immortalized urothelial cells suggests that the bacterial flagellar subunit, flagellin, is key in inducing host defenses. A panel of 48 clinical uro-associated E. coli isolates recovered from either cystitis, pyelonephritis asymptomatic bacteriuria (ABU) or UTI-associated bacteraemia infections were characterized for motility and their ability to induce an innate response in urothelial cells stably transfected with a NF-κB luciferase reporter. Thirty-two isolates (67%) were identified as motile with strains recovered from cystitis patients exhibiting an uneven motility distribution pattern; seven of the cystitis isolates were associated with a > 5-fold increase in NF-κB signaling. To explore whether the NF-κB signaling response reflected antigenic variation, flagellin was purified from 14 different isolates. Purified flagellin filaments generated comparable NF-κB signaling responses, irrespective of either the source of the isolate or H-serotype. These data argued against any variability between isolates being related to flagellin itself. Investigations also argued that neither TLR4 dependent recognition of bacterial lipopolysaccharide nor growth fitness of the isolates played key roles in leading to the variable host response. To determine the roles, if any, of flagellar abundance in inducing these variable responses, flagellar hook numbers of a range of cystitis and ABU isolates were quantified. Images suggested that up to 60% of the isolate population exhibited flagella with the numbers averaging between 1 and 2 flagella per bacterial cell. These data suggest that selective pressures exist in the urinary tract that allow uro-associated E. coli strains to maintain motility, but exploit population heterogeneity, which together function to prevent host TLR5 recognition and bacterial killing.
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Affiliation(s)
- Aaron Tan
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Qusai Alsenani
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Marcello Lanz
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Christopher Birchall
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Lauren K. L. Drage
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - David Picton
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Catherine Mowbray
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Ased Ali
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Christopher Harding
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Urology Department, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Robert S. Pickard
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Urology Department, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Judith Hall
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- *Correspondence: Judith Hall,
| | - Phillip D. Aldridge
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Phillip D. Aldridge,
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Lin YJ, Jamin A, Wolfheimer S, Fiedler A, Junker AC, Goretzki A, Scheurer S, Schülke S. A flagellin-conjugate protein induces dual NLRC4- and NLRP3-inflammasome activation which modulates inflammatory cytokine secretion from macrophages. Front Immunol 2023; 14:1136669. [PMID: 37026001 PMCID: PMC10070734 DOI: 10.3389/fimmu.2023.1136669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 02/20/2023] [Indexed: 04/08/2023] Open
Abstract
Background A recombinant fusion protein combining the adjuvant and TLR5-ligand flagellin with the major birch pollen allergen Bet v 1 (rFlaA:Betv1) has been suggested to prevent the manifestation of birch allergy. Noteworthy, rFlaA:Betv1 induced both pro- and anti-inflammatory responses which were differentially regulated. However, the mechanism by which flagellin fusion proteins modulate allergen-specific immune responses, especially the mechanisms underlying IL-1β secretion and their contribution to the overall immune responses remains elusive. Objective To investigate the mechanisms underlying the production of IL-1β from rFlaA:Betv1 stimulated macrophages. Methods Macrophages were derived from mouse peritoneal-, human buffy-coat-, and PMA-differentiated THP-1 (wild type or lacking either ASC, NLRP3, or NLRC4) cells. Macrophages were stimulated with non-modified rFlaA:Betv1, mutant variants lacking either the flagellin DC0 domain or a sequence motif formerly described to mediate TLR5-activation, and respective controls in the presence or absence of inhibitors interfering with MAPK- and NFκB-signaling. Cytokine secretion was analyzed by ELISA and intracellular signaling by Western Blot. To study the contribution of IL-1β to the overall immune responses, IL1R-deficient mouse peritoneal macrophages were used. Results rFlaA:Betv1 consistently activated all types of investigated macrophages, inducing higher IL-1β secretion compared with the equimolar mixture of both proteins. rFlaA:Betv1-induced activation of THP-1 macrophages was shown to be independent of either the TLR5-activating sequence motif or the flagellin DC0 domain but depended on both NLRP3- and NLRC4-inflammasomes. In addition, NFκB and SAP/JNK MAP kinases regulated rFlaA:Betv1-induced inflammasome activation and cytokine secretion by modulating pro-Caspase-1- and pro-IL-1β-expression in THP-1 macrophages. Finally, lack of IL-1β positive feedback via the IL1R strongly diminished the rFlaA:Betv1-induced secretion of IL-1β, IL-6, and TNF-α from peritoneal macrophages. Conclusion The mechanisms contributing to rFlaA:Betv1-induced IL-1β secretion from macrophages were shown to be complex, involving both NLRC4- and NLRP3-inflammsomes, as well as NFκB- and SAP/JNK MAP kinase-signaling. Better understanding the mechanisms regulating the activation of immune cells by novel therapeutic candidates like the rFlaA:Betv1 fusion protein will allow us to further improve and develop new treatment strategies when using flagellin as an adjuvant.
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Woo CW, Tso P, Yiu JHC. Commensal gut microbiota-based strategies for oral delivery of therapeutic proteins. Trends Pharmacol Sci 2022; 43:1004-1013. [PMID: 36057462 PMCID: PMC9669164 DOI: 10.1016/j.tips.2022.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 01/13/2023]
Abstract
Therapeutic proteins are rarely available in oral dosage form because the hostile environment of the human gastrointestinal (GI) tract and their large size make this delivery method difficult. Commensal bacteria in the gut face the same situation; however, they not only survive but low levels of their structural components such as lipopolysaccharide (LPS), peptidoglycan, and flagellin are also consistently detectable in the circulatory systems of healthy individuals. This opinion article discusses how gut bacteria survive in the gut, how their components penetrate the body from the perspective of the bacteria's and the host's proactivity, and how orally administered therapeutic proteins may be developed that exploit similar mechanisms to enter the body.
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Affiliation(s)
- Connie W Woo
- Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, OH, USA
| | - Jensen H C Yiu
- Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Reyes VE. Helicobacter pylori Immune Response in Children Versus Adults. MEDICAL RESEARCH ARCHIVES 2022; 10:3370. [PMID: 37936946 PMCID: PMC10629867 DOI: 10.18103/mra.v10i12.3370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
H. pylori is perhaps the most prevalent human pathogen worldwide and infects almost half of the world's population. Despite the decreasing prevalence of infection overall, it is significant in developing countries. Most infections are acquired in childhood and persist for a lifetime unless treated. Children are often asymptomatic and often develop a tolerogenic immune response that includes T regulatory cells and their products, immunosuppressive cytokines, such as interleukin (IL)-10, and transforming growth factor-β (TGF-β). This contrasts to the gastric immune response seen in H. pylori-infected adults, where the response is mainly inflammatory, with predominant Th1 and Th17 cells, as well as, inflammatory cytokines, such as TNF-α, IFN-γ, IL-1, IL-6, IL-8, and IL-17. Therefore, compared to adults, infected children generally have limited gastric inflammation and peptic ulcer disease. H. pylori surreptitiously subverts immune defenses to persist in the human gastric mucosa for decades. The chronic infection might result in clinically significant diseases in adults, such as peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This review compares the infection in children and adults and highlights the H. pylori virulence mechanisms responsible for the pathogenesis and immune evasion.
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Affiliation(s)
- Victor E. Reyes
- Department of Pediatrics, Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd. Galveston, TX 77555-0372 USA
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49
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Zhang Y, Li X, Shan B, Zhang H, Zhao L. Perspectives from recent advances of Helicobacter pylori vaccines research. Helicobacter 2022; 27:e12926. [PMID: 36134470 DOI: 10.1111/hel.12926] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/25/2022] [Accepted: 08/17/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection is the main factor leading to some gastric diseases. Currently, H. pylori infection is primarily treated with antibiotics. However, with the widespread application of antibiotics, H. pylori resistance to antibiotics has also gradually increased year by year. Vaccines may be an alternative solution to clear H. pylori. AIMS By reviewing the recent progress on H. pylori vaccines, we expected it to lead to more research efforts to accelerate breakthroughs in this field. MATERIALS & METHODS We searched the research on H. pylori vaccine in recent years through PubMed®, and then classified and summarized these studies. RESULTS The study of the pathogenic mechanism of H. pylori has led to the development of vaccines using some antigens, such as urease, catalase, and heat shock protein (Hsp). Based on these antigens, whole-cell, subunit, nucleic acid, vector, and H. pylori exosome vaccines have been tested. DISCUSSION At present, researchers have developed many types of vaccines, such as whole cell vaccines, subunit vaccines, vector vaccines, etc. However, although some of these vaccines induced protective immunity in mouse models, only a few were able to move into human trials. We propose that mRNA vaccine may play an important role in preventing or treating H. pylori infection. The current study shows that we have developed various types of vaccines based on the virulence factors of H. pylori. However, only a few vaccines have entered human clinical trials. In order to improve the efficacy of vaccines, it is necessary to enhance T-cell immunity. CONCLUSION We should fully understand the pathogenic mechanism of H. pylori and find its core antigen as a vaccine target.
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Affiliation(s)
- Ying Zhang
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoya Li
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Baoen Shan
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hongtao Zhang
- University of Pennsylvania School of Medicine Philadelphia, Philadelphia, Pennsylvania, USA
| | - Lianmei Zhao
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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50
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Immunogenic Modification of Ligilactobacillus agilis by Specific Amino Acid Substitution of Flagellin. Appl Environ Microbiol 2022; 88:e0127722. [PMID: 36173204 PMCID: PMC9599256 DOI: 10.1128/aem.01277-22] [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: 12/01/2022] Open
Abstract
Ligilactobacillus agilis is a flagellated motile commensal microbe that resides in the gastrointestinal tract of mammals and birds. Flagellin, the major subunit protein of flagellar filament, from pathogenic bacteria is generally a proinflammatory molecule that stimulates immune cells via Toll-like receptor 5 (TLR5). Interestingly, the flagellins of L. agilis are known to be immunologically attenuated despite the fact that the structure of the proteins, including the TLR5 recognition site, is highly conserved among bacteria. The results of our previous study suggested that this is attributed to the differences in three specific amino acids within the conserved TLR5 recognition site; however, this hypothesis remains to be confirmed. In this study, a series of recombinant L. agilis flagellins, with amino acid substitutions at the TLR5 recognition site, were constructed, and their immunogenic activity was evaluated in vitro. Then, an L. agilis strain with an active immunogenic TLR5 recognition site was generated. In vitro and in vivo immunological studies revealed that the mutant L. agilis strain with the modified flagellin was more immunogenic than the wild-type strain. In conclusion, the specific amino acid residues in L. agilis flagellins likely contribute to the discrimination between pathogens and commensals by the host defense system. Additionally, the immunogenically potent L. agilis mutants may serve as a useful platform for oral vaccine delivery. IMPORTANCE The interactions between gut microbes and immune cells play an important role in the health and disease of hosts. Ligilactobacillus agilis is a flagellated commensal bacterium found in the gut of mammals and birds. However, the flagellin proteins of L. agilis are immunologically attenuated and barely induce TLR5-dependent inflammation, unlike the flagellins of several pathogenic bacteria. This study demonstrated that three specific amino acids in the flagellin protein are responsible for this low immunogenicity in L. agilis. The results obtained herein improve our understanding of the symbiosis between gut microbes and their hosts.
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