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Cardones AR, Emiola A, Hall RP, Sung AD, Zhang J, Petty AJ, Puza C, Bohannon LM, Bush AT, Lew MV, Fleming E, Jin YJ, Nichols KR, Jain V, Gregory SG, Sullivan KM, Chao NJ, Oh J. Cutaneous dysbiosis characterizes the post-allogeneic hematopoietic stem cell transplantation period. Blood Adv 2025; 9:2173-2182. [PMID: 39853270 DOI: 10.1182/bloodadvances.2021004792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 01/26/2025] Open
Abstract
ABSTRACT Gut dysbiosis is linked to mortality and the development of graft-versus-host disease after hematopoietic stem cell transplantation (HSCT), but the impact of cutaneous dysbiosis remains unexplored. We performed a pilot observational study, obtained retroauricular and forearm skin swabs from 12 adult patients before conditioning chemotherapy/radiation and at 1 week, 1 month, and 3 months after allogeneic HSCT, and performed shotgun metagenomic sequencing. The cutaneous microbiome among HSCT patients was enriched for gram-negative bacteria such as Escherichia coli and Pseudomonas, fungi, and viruses. Enrichment with bacteriophages and Polyomavirus species was observed among patients who died within 1 year. We observed longitudinal stability of the cutaneous microbiome at the 3-month time point among those who survived beyond 1 year after HSCT, although these may simply be a reflection of the overall medical status of the patients. There was no association with fungal abundance and any of the outcomes observed. The cutaneous microbiome may be a reservoir of pathobionts among allogeneic HSCT patients. Our findings suggest that cutaneous dysbiosis exists after HSCT, but the ultimate implication of this to patient outcomes remains to be seen through larger studies.
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Affiliation(s)
- Adela R Cardones
- Division of Dermatology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS
| | - Akintunde Emiola
- Microbial Therapeutics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Russell P Hall
- Department of Dermatology, Duke University Medical Center, Durham, NC
| | - Anthony D Sung
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
- Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Jennifer Zhang
- Department of Dermatology, Duke University Medical Center, Durham, NC
| | - Amy J Petty
- Department of Dermatology, Duke University Medical Center, Durham, NC
| | | | - Lauren M Bohannon
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Amy T Bush
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Meagan V Lew
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Elizabeth Fleming
- Microbial Therapeutics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Yingai J Jin
- Department of Dermatology, Duke University Medical Center, Durham, NC
| | - Krista Rowe Nichols
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | | | - Simon G Gregory
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC
- Department of Neurology, Duke University School of Medicine, Durham, NC
| | - Keith M Sullivan
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
- Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Nelson J Chao
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
- Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Julia Oh
- Department of Dermatology, Duke University Medical Center, Durham, NC
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC
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2
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Arekar T, Katikaneni D, Kasem S, Desai D, Acharya T, Cole A, Khodayari N, Vaulont S, Hube B, Nemeth E, Drakesmith A, Lionakis MS, Mehrad B, Scindia Y. Essential role of hepcidin in host resistance to disseminated candidiasis. Cell Rep 2025; 44:115649. [PMID: 40333187 DOI: 10.1016/j.celrep.2025.115649] [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: 10/14/2024] [Revised: 02/20/2025] [Accepted: 04/11/2025] [Indexed: 05/09/2025] Open
Abstract
Candida albicans is a leading cause of life-threatening invasive infection despite antifungal therapy. Patients with chronic liver disease are at increased risk of candidemia, but the mechanisms underlying this susceptibility are incompletely defined. One consequence of chronic liver disease is an attenuated ability to produce hepcidin and maintain organismal control of iron homeostasis. To address the biology underlying this critical clinical problem, we demonstrate the mechanistic link between hepcidin insufficiency and candida infection using genetic and inducible hepcidin knockout mice. Hepcidin deficiency led to unrestrained fungal growth and increased transition to the invasive hypha morphology with exposed 1,3-β-glucan, which exacerbated kidney injury, independent of the fungal pore-forming toxin candidalysin in immunocompetent mice. Of translational relevance, the therapeutic administration of PR-73, a hepcidin mimetic, improved the outcome of infection. Thus, we identify hepcidin deficiency as a host susceptibility factor against C. albicans and hepcidin mimetics as a potential intervention.
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Affiliation(s)
- Tanmay Arekar
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Divya Katikaneni
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Sadat Kasem
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Dhruv Desai
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Thrisha Acharya
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Augustina Cole
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Nazli Khodayari
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Sophie Vaulont
- Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France
| | - Bernhard Hube
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany
| | - Elizabeta Nemeth
- Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Alexander Drakesmith
- MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA
| | - Borna Mehrad
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Yogesh Scindia
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA; Center for Integrated Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA.
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3
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Özdemir Ö. Relation between dysbiosis and inborn errors of immunity. World J Methodol 2024; 14:96380. [PMID: 39712559 PMCID: PMC11287548 DOI: 10.5662/wjm.v14.i4.96380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 05/27/2024] [Accepted: 06/14/2024] [Indexed: 07/26/2024] Open
Abstract
Inborn errors of immunity (IEI) disorders, formerly primary immune deficiency diseases, are a heterogeneous group of disorders with variable hereditary transitions, clinical manifestations, complications and varying disease severity. Many of the clinical symptoms, signs and complications in IEI patients can be attributed to inflammatory and immune dysregulatory processes due to loss of microbial diversity (dysbiosis). For example, in common variable immunodeficiency patients, the diversity of bacteria, but not fungi, in the gut microbiota has been found to be reduced and significantly altered. Again, this was associated with a more severe disease phenotype. Compromise of the STAT3/Th17 pathway in hyper-IgE syndrome may lead to dysbiosis of the oral microbiota in these patients, causing Candida albicans to switch from commensal to pathogenic. Modification of the microbiota can be used as a therapeutic approach in patients with IEI. Prebiotics, probiotics, postbiotics and fecal microbiota transplantation can be used to restore the balance of the gut microbiota and reduce pathogenicity in IEI patients. Clinical trials are currently underway to understand the impact of this dysbiosis on the phenotype of IEI diseases and its role in their treatment.
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Affiliation(s)
- Öner Özdemir
- Department of Pediatric Allergy and Immunology, Sakarya University, Medical Faculty, Adapazarı 54100, Sakarya, Türkiye
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Wang Y, Li J, Chen R, Xu Q, Wang D, Mao C, Xiang Z, Wu G, Yu Y, Li J, Zheng Y, Chen K. Emerging concepts in mucosal immunity and oral microecological control of respiratory virus infection-related inflammatory diseases. Microbiol Res 2024; 289:127930. [PMID: 39427450 DOI: 10.1016/j.micres.2024.127930] [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: 01/08/2024] [Revised: 09/22/2024] [Accepted: 10/06/2024] [Indexed: 10/22/2024]
Abstract
Oral microecological imbalance is closely linked to oral mucosal inflammation and is implicated in the development of both local and systemic diseases, including those caused by viral infections. This review examines the critical role of the interleukin (IL)-17/helper T cell 17 (Th17) axis in regulating immune responses within the oral mucosa, focusing on both its protective and pathogenic roles during inflammation. We specifically highlight how the IL-17/Th17 pathway contributes to dysregulated inflammation in the context of respiratory viral infections. Furthermore, this review explores the potential interactions between respiratory viruses and the oral microbiota, emphasizing how alterations in the oral microbiome and increased production of proinflammatory factors may serve as early, non-invasive biomarkers for predicting the severity of respiratory viral infections. These findings provide insights into novel diagnostic approaches and therapeutic strategies aimed at mitigating respiratory disease severity through monitoring and modulating the oral microbiome.
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Affiliation(s)
- Ying Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Jiaxuan Li
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Ruyi Chen
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Qiuyi Xu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Di Wang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Chenxi Mao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Ziyi Xiang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Guangshang Wu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Ying Yu
- School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang 310063, China
| | - Jianhua Li
- Zhejiang Key Laboratory of Public Health Detection and Pathogenesis Research, Department of Microbiology, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.
| | - Yuejuan Zheng
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Keda Chen
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China.
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5
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Ren X, Wang M, Du J, Dai Y, Dang L, Li Z, Shu J. Glycans in the oral bacteria and fungi: Shaping host-microbe interactions and human health. Int J Biol Macromol 2024; 282:136932. [PMID: 39490874 DOI: 10.1016/j.ijbiomac.2024.136932] [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: 05/16/2024] [Revised: 10/12/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
The human oral cavity serves as the natural entry port to both the gastrointestinal and respiratory tracts, and hosts a diverse microbial community essential for maintaining health. Dysbiosis of this microbiome can lead to various diseases. Glycans, as vital carriers of biological information, are indispensable structural components of living organisms and play key roles in numerous biological processes. In the oral microbiome, glycans influence microbial binding to host receptors, promote colonization, and mediate communication among microbial communities, as well as between microbes and the host immune system. Targeting glycans may provide innovative strategies for modulating the composition of the oral microbiome, with broader implications for human health. Additionally, exogenous glycans regulate the oral microbiome by serving as carbon and energy sources for microbes, while certain specific glycans can inhibit microbial growth and activity. This review summarizes glycosylation pathways in oral bacteria and fungi, explores the regulation of host-microbiota interactions by glycans, and discusses the effects of exogenous glycans on oral microbiome. The review aims to highlight the multifaceted role of glycans in shaping the oral microbiome and its impact on the host, while also indicates potential future applications.
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Affiliation(s)
- Xiameng Ren
- Laboratory for Functional Glycomics, Faculty of Life Science & Medicine, Northwest University, Xi'an, China
| | - Min Wang
- Laboratory for Functional Glycomics, Faculty of Life Science & Medicine, Northwest University, Xi'an, China
| | - Jiabao Du
- Laboratory for Functional Glycomics, Faculty of Life Science & Medicine, Northwest University, Xi'an, China
| | - Yu Dai
- School of Medicine, Faculty of Life Science & Medicine, Northwest University, Xi'an, China
| | - Liuyi Dang
- Laboratory for Functional Glycomics, Faculty of Life Science & Medicine, Northwest University, Xi'an, China
| | - Zheng Li
- Laboratory for Functional Glycomics, Faculty of Life Science & Medicine, Northwest University, Xi'an, China
| | - Jian Shu
- Laboratory for Functional Glycomics, Faculty of Life Science & Medicine, Northwest University, Xi'an, China; School of Medicine, Faculty of Life Science & Medicine, Northwest University, Xi'an, China.
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6
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Jørgensen MR. Pathophysiological microenvironments in oral candidiasis. APMIS 2024; 132:956-973. [PMID: 38571459 DOI: 10.1111/apm.13412] [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: 01/15/2024] [Accepted: 03/20/2024] [Indexed: 04/05/2024]
Abstract
Oral candidiasis (OC), a prevalent opportunistic infection of the oral mucosa, presents a considerable health challenge, particularly in individuals with compromised immune responses, advanced age, and local predisposing conditions. A considerable part of the population carries Candida in the oral cavity, but only few develop OC. Therefore, the pathogenesis of OC may depend on factors other than the attributes of the fungus, such as host factors and other predisposing factors. Mucosal trauma and inflammation compromise epithelial integrity, fostering a conducive environment for fungal invasion. Molecular insights into the immunocompromised state reveal dysregulation in innate and adaptive immunity, creating a permissive environment for Candida proliferation. Detailed examination of Candida species (spp.) and their virulence factors uncovers a nuanced understanding beyond traditional C. albicans focus, which embrace diverse Candida spp. and their strategies, influencing adhesion, invasion, immune evasion, and biofilm formation. Understanding the pathophysiological microenvironments in OC is crucial for the development of targeted therapeutic interventions. This review aims to unravel the diverse pathophysiological microenvironments influencing OC development focusing on microbial, host, and predisposing factors, and considers Candida resistance to antifungal therapy. The comprehensive approach offers a refined perspective on OC, seeking briefly to identify potential therapeutic targets for future effective management.
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Affiliation(s)
- Mette Rose Jørgensen
- Section of Oral Pathology and Oral Medicine, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Liu X, Ling Z, Cheng Y, Wu L, Shao L, Gao J, Lei W, Zhu Z, Ding W, Song Q, Zhao L, Jin G. Oral fungal dysbiosis and systemic immune dysfunction in Chinese patients with schizophrenia. Transl Psychiatry 2024; 14:475. [PMID: 39572530 PMCID: PMC11582559 DOI: 10.1038/s41398-024-03183-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 11/24/2024] Open
Abstract
Oral microbial dysbiosis contributes to the development of schizophrenia (SZ). While numerous studies have investigated alterations in the oral bacterial microbiota among SZ patients, investigations into the fungal microbiota, another integral component of the oral microbiota, are scarce. In this cross-sectional study, we enrolled 118 Chinese patients with SZ and 97 age-matched healthy controls (HCs) to evaluate the oral fungal microbiota from tongue coating samples using internal transcribed spacer 1 amplicon sequencing and assess host immunity via multiplex immunoassays. Our findings revealed that SZ patients exhibited reduced fungal richness and significant differences in β-diversity compared to HCs. Within the oral fungal communities, we identified two distinct fungal clusters (mycotypes): Candida and Malassezia, with SZ patients showing increased Malassezia and decreased Candida levels. These key functional oral fungi may serve as potential diagnostic biomarkers for SZ. Furthermore, SZ patients displayed signs of immunological dysfunction, characterized by elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α, and chemokines including MIP-1α and MCP-1. Importantly, Malassezia mycotype correlated positively with peripheral pro-inflammatory cytokines, while Candida mycotype exhibited a negative correlation with these cytokines. In conclusion, we have demonstrated, for the first time, the presence of altered oral fungal communities and systemic immune dysfunction in Chinese SZ patients compared to HCs, providing novel insights into the potential role of oral fungi as biomarkers and the broader implications for understanding SZ pathogenesis.
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Affiliation(s)
- Xia Liu
- Department of Intensive Care Unit, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China
| | - Zongxin Ling
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
| | - Yiwen Cheng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China
| | - Lingbin Wu
- Department of Psychiatry, Lishui Second People's Hospital, Lishui, Zhejiang, 323000, China
| | - Li Shao
- School of Clinical Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, 310015, China
| | - Jie Gao
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China
| | - Wenhui Lei
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, 250000, China
| | - Zhangcheng Zhu
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Wenwen Ding
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Qinghai Song
- Department of Psychiatry, Lishui Second People's Hospital, Lishui, Zhejiang, 323000, China
| | - Longyou Zhao
- Department of Psychiatry, Lishui Second People's Hospital, Lishui, Zhejiang, 323000, China.
| | - Guolin Jin
- Department of Psychiatry, Lishui Second People's Hospital, Lishui, Zhejiang, 323000, China.
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Wang C, Freeman AF. Infections in Inborn Errors of STATs. Pathogens 2024; 13:955. [PMID: 39599507 PMCID: PMC11597637 DOI: 10.3390/pathogens13110955] [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: 09/27/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is highly conserved and essential for numerous biological functions triggered by extracellular signals, including cell proliferation, metabolism, immune response, and inflammation. Defects in STATs, either loss-of-function or gain-of-function defects, lead to a broad spectrum of clinical phenotypes in humans, including a wide range of infectious complications. The susceptibility to pathogens can stem from defects in immune cells within the hematopoietic compartment, impaired barrier functions of non-hematopoietic compartment, or a combination of both, depending on the specific STAT defect as well as the pathogen exposure history. Effective management involves antimicrobial prophylaxis tailored to the patient's infection risk and improving disease control with targeted therapies and/or hematopoietic cell transplantation.
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Affiliation(s)
| | - Alexandra F. Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;
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Arekar T, Katikaneni D, Kasem S, Desai D, Acharya T, Cole A, Khodayari N, Vaulont S, Hube B, Nemeth E, Drakesmith A, Lionakis MS, Mehrad B, Scindia Y. Essential role of Hepcidin in host resistance to disseminated candidiasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.29.620511. [PMID: 39553949 PMCID: PMC11565830 DOI: 10.1101/2024.10.29.620511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Candida albicans is a leading cause of life-threatening invasive infections with up to 40% mortality rates in hospitalized individuals despite antifungal therapy. Patients with chronic liver disease are at an increased risk of candidemia, but the mechanisms underlying this susceptibility are incompletely defined. One consequence of chronic liver disease is attenuated ability to produce hepcidin and maintain organismal control of iron homeostasis. To address the biology underlying this critical clinical problem, we demonstrate the mechanistic link between hepcidin insufficiency and candida infection using genetic and inducible hepcidin knockout mice. Hepcidin deficiency led to unrestrained fungal growth and increased transition to the invasive hypha morphology with exposed 1,3, β-glucan that exacerbated kidney injury, independent of the fungal pore-forming toxin candidalysin in immunocompetent mice. Of translational relevance, the therapeutic administration of PR-73, a hepcidin mimetic, improved the outcomes of infection. Thus, we identify hepcidin deficiency as a novel host susceptibility factor against C. albicans and hepcidin mimetics as a potential intervention.
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10
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Vazquez-Munoz R, Thompson A, Sobue T, Dongari-Bagtzoglou A. Lactobacillus johnsonii is a dominant Lactobacillus in the murine oral mucosa and has chitinase activity that compromises fungal cell wall integrity. mBio 2024; 15:e0241624. [PMID: 39287438 PMCID: PMC11481578 DOI: 10.1128/mbio.02416-24] [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: 08/07/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
The oral microbiome is a critical determinant of health and disease, as interactions between oral microorganisms can influence their physiology and the development or severity of oral infections. Lactobacilli have a widely recognized antagonistic relationship with Candida albicans and may exhibit probiotic properties that limit oral fungal infection. We previously reported that Lactobacillus johnsonii strain MT4, an oral strain isolated from C57BL/6 mice, can induce global changes in the murine oral microbiome and has anti-Candida activity in vitro. To build on this information, we analyzed its abundance on the mouse oral mucosa, tested its impact on the severity and progression of oropharyngeal candidiasis (OPC) in a mouse model, and further explored the mechanism of antifungal activity in vitro. Our findings reveal that L. johnsonii MT4 is a dominant cultivable Lactobacillus in the oral mucosa of C57BL/6 mice. Strain MT4 has chitinase activity against C. albicans, which damages the cell wall and compromises fungal metabolic activity. Oral inoculation with strain MT4 causes a reduction in the Candida-induced rise in the abundance of oral enterococci and oral mucosal damage. This research underscores the potential of L. johnsonii strain MT4 as a novel probiotic agent in the prevention or management of OPC, and it contributes to a better understanding of the role of oral bacterial microbiota role in the pathogenesis of fungal infections. IMPORTANCE The interactions between the opportunistic pathogen Candida albicans and resident oral bacteria are particularly crucial in maintaining oral health. Emerging antifungal drug-resistant strains, slow-paced drug discovery, and the risk of side effects can compromise the effectiveness of current treatments available for oropharyngeal candidiasis. This study advances the search for alternative microbiome-targeted therapies in oral fungal infections. We report that Lactobacillus johnsonii strain MT4 prevents the Candida-induced bloom of dysbiotic oral enterococci and reduces oral mucosal lesions in an oropharyngeal candidiasis murine model. We also show that this strain directly compromises the cell wall and reduces fungal metabolic activity, partly due to its chitinase activity.
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Affiliation(s)
- Roberto Vazquez-Munoz
- Department of General Dentistry, the University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Angela Thompson
- Department of General Dentistry, the University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Takanori Sobue
- Department of General Dentistry, the University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Anna Dongari-Bagtzoglou
- Department of General Dentistry, the University of Connecticut Health Center, Farmington, Connecticut, USA
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11
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Belibasakis GN, Seneviratne CJ, Jayasinghe RD, Vo PT, Bostanci N, Choi Y. Bacteriome and mycobiome dysbiosis in oral mucosal dysplasia and oral cancer. Periodontol 2000 2024; 96:95-111. [PMID: 38501658 PMCID: PMC11579824 DOI: 10.1111/prd.12558] [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: 12/12/2023] [Revised: 02/13/2024] [Accepted: 02/17/2024] [Indexed: 03/20/2024]
Abstract
It has long been considered that the oral microbiome is tightly connected to oral health and that dysbiotic changes can be detrimental to the occurrence and progression of dysplastic oral mucosal lesions or oral cancer. Improved understanding of the concepts of microbial dysbiosis together with advances in high-throughput molecular sequencing of these pathologies have charted in greater microbiological detail the nature of their clinical state. This review discusses the bacteriome and mycobiome associated with oral mucosal lesions, oral candidiasis, and oral squamous cell carcinoma, aiming to delineate the information available to date in pursuit of advancing diagnostic and prognostic utilities for oral medicine.
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Affiliation(s)
- Georgios N. Belibasakis
- Division of Oral Diseases, Department of Dental MedicineKarolinska InstitutetStockholmSweden
| | | | - Ruwan Duminda Jayasinghe
- Department of Oral Medicine and Periodontology, Faculty of Dental SciencesUniversity of PeradeniyaPeradeniyaSri Lanka
| | - Phuc Thi‐Duy Vo
- Department of Immunology and Molecular Microbiology, School of DentistrySeoulKorea
| | - Nagihan Bostanci
- Division of Oral Diseases, Department of Dental MedicineKarolinska InstitutetStockholmSweden
| | - Youngnim Choi
- Department of Immunology and Molecular Microbiology, School of DentistrySeoulKorea
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Nenciarini S, Renzi S, di Paola M, Meriggi N, Cavalieri D. Ascomycetes yeasts: The hidden part of human microbiome. WIREs Mech Dis 2024; 16:e1641. [PMID: 38228159 DOI: 10.1002/wsbm.1641] [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: 05/17/2023] [Revised: 12/17/2023] [Accepted: 12/19/2023] [Indexed: 01/18/2024]
Abstract
The fungal component of the microbiota, the mycobiota, has been neglected for a long time due to its poor richness compared to bacteria. Limitations in fungal detection and taxonomic identification arise from using metagenomic approaches, often borrowed from bacteriome analyses. However, the relatively recent discoveries of the ability of fungi to modulate the host immune response and their involvement in human diseases have made mycobiota a fundamental component of the microbial communities inhabiting the human host, deserving some consideration in host-microbe interaction studies and in metagenomics. Here, we reviewed recent data on the identification of yeasts of the Ascomycota phylum across human body districts, focusing on the most representative genera, that is, Saccharomyces and Candida. Then, we explored the key factors involved in shaping the human mycobiota across the lifespan, ranging from host genetics to environment, diet, and lifestyle habits. Finally, we discussed the strengths and weaknesses of culture-dependent and independent methods for mycobiota characterization. Overall, there is still room for some improvements, especially regarding fungal-specific methodological approaches and bioinformatics challenges, which are still critical steps in mycobiota analysis, and to advance our knowledge on the role of the gut mycobiota in human health and disease. This article is categorized under: Immune System Diseases > Genetics/Genomics/Epigenetics Immune System Diseases > Environmental Factors Infectious Diseases > Environmental Factors.
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Affiliation(s)
| | - Sonia Renzi
- Department of Biology, University of Florence, Florence, Italy
| | - Monica di Paola
- Department of Biology, University of Florence, Florence, Italy
| | - Niccolò Meriggi
- Department of Biology, University of Florence, Florence, Italy
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Arce M, Rodriguez-Peña M, Espinoza-Arrue J, Godoy R, Reyes M, Kajikawa T, Greenwell-Wild T, Hajishengallis G, Abusleme L, Moutsopoulos N, Dutzan N. Increased STAT3 Activation in Periodontitis Drives Inflammatory Bone Loss. J Dent Res 2023; 102:1366-1375. [PMID: 37697911 PMCID: PMC10714379 DOI: 10.1177/00220345231192381] [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] [Indexed: 09/13/2023] Open
Abstract
Periodontitis is one of the most prevalent human inflammatory diseases. It is characterized by periodontal tissue destruction, progressively driven by the host response. In this regard, cytokines associated with tissue destruction, such as interleukin (IL)-6 and IL-23, use a common signaling pathway mediated by STAT3. This transcription factor is also needed for IL-17A production, a key mediator in periodontitis pathogenesis. Although several studies have reported increased activation of STAT3 in experimental periodontitis, a detailed characterization of STAT3 activation in human gingival tissues and its involvement in alveolar bone loss has yet to be explored. Using a cross-sectional study design, we detected increased proportions of pSTAT3-positive cells during periodontitis compared with health, particularly in epithelial cells and T cells. Other cell types of hematopoietic and nonhematopoietic origin also display STAT3 activation in gingival tissues. We detected increased STAT3 phosphorylation and expression of STAT3-related genes during experimental periodontitis. Next, we evaluated the role of STAT3 in alveolar bone destruction using a mouse model of STAT3 loss of function (mut-Stat3 mice). Compared with controls, mut-Stat3 mice had reduced alveolar bone loss following ligature-induced periodontitis. We also evaluated pharmacologic inhibition of STAT3 in ligature-induced periodontitis. Like mut-Stat3 mice, mice treated with STAT3 small-molecule inhibitor had reduced bone loss compared with controls. Our results demonstrate that STAT3 activation is increased in epithelial and T cells during periodontitis and indicate a pathogenic role of STAT3 in inflammatory alveolar bone loss.
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Affiliation(s)
- M. Arce
- Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago, Chile
- Laboratory of Oral Microbiology and Immunology, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - M. Rodriguez-Peña
- Laboratory of Oral Microbiology and Immunology, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - J. Espinoza-Arrue
- Laboratory of Oral Microbiology and Immunology, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - R.A. Godoy
- Laboratory of Oral Microbiology and Immunology, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - M. Reyes
- Department of Pathology and Oral Medicine, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - T. Kajikawa
- Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - T. Greenwell-Wild
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - G. Hajishengallis
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - L. Abusleme
- Laboratory of Oral Microbiology and Immunology, Faculty of Dentistry, University of Chile, Santiago, Chile
- Department of Pathology and Oral Medicine, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - N. Moutsopoulos
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - N. Dutzan
- Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago, Chile
- Laboratory of Oral Microbiology and Immunology, Faculty of Dentistry, University of Chile, Santiago, Chile
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14
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Revianti S, Andriani D, Pargaputri AF, Hartono MR. Acanthus ilicifolius Methanolic Extract for Oral Candidiasis Treatment through Tongue Epithelial STAT3 and Cell Death Evaluation. Eur J Dent 2023; 17:1201-1206. [PMID: 36764307 PMCID: PMC10756784 DOI: 10.1055/s-0042-1760298] [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: 02/12/2023] Open
Abstract
OBJECTIVES This study aimed to evaluate the effects of topical application of Acanthus ilicifolius methanolic extract on signal transducer and activator of transcription 3 (STAT3) expression and tongue epithelial cell death caused by oral candidiasis under immunosuppressive conditions. MATERIALS AND METHODS To obtain the oral candidiasis model, 20 healthy male Rattus norvegicus (Wistar) rats were administered oral dexamethasone and tetracycline for 14 days and oral candidiasis was induced with Candida albicans (ATCC-10231) 1 McFarland. They were then randomized into four groups-immunosuppression (K-), oral candidiasis (K + ), nystatin treatment (P1), and 20% A. ilicifolius methanolic extract treatment (P2) and were treated for 14 days. Histological analyses of cell death and candida invasion and immunohistochemical analysis of STAT3 in epithelial cells were performed. STATISTICAL ANALYSIS Epithelial cell death data were analyzed using one-way analysis of variance (ANOVA) and the post hoc Games-Howell test (p < 0.05) and STAT3 expression with one-way ANOVA and the post hoc least significant difference test (p < 0.05). RESULTS Cell death was significantly different between K- and K+ and between K+ and P1 and P2 (p < 0.05); there were no significant differences between K- and P1 and P2 and between P1 and P2 (p > 0.05). STAT3 expression was significantly different between K- and P1 and P2 and between K+ and P1 and P2 (p < 0.05), but there were no significant differences between K+ and K- and between P1 and P2 (p > 0.05). CONCLUSION Topical administration of A. ilicifolius methanol extract increased STAT3 expression and decreased tongue epithelial cell death caused by oral candidiasis.
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Affiliation(s)
- Syamsulina Revianti
- Department of Oral Biology, Faculty of Dentistry, Universitas Hang Tuah, Surabaya, Surabaya, Indonesia
| | - Dwi Andriani
- Department of Oral Biology, Faculty of Dentistry, Universitas Hang Tuah, Surabaya, Surabaya, Indonesia
| | - Agni Febrina Pargaputri
- Department of Oral Biology, Faculty of Dentistry, Universitas Hang Tuah, Surabaya, Surabaya, Indonesia
| | - Mardiyanto Riski Hartono
- Department of Oral Biology, Faculty of Dentistry, Universitas Hang Tuah, Surabaya, Surabaya, Indonesia
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15
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Vazquez-Munoz R, Thompson A, Sobue T, Dongari-Bagtzoglou A. A prebiotic diet modulates the oral microbiome composition and results in the attenuation of oropharyngeal candidiasis in mice. Microbiol Spectr 2023; 11:e0173423. [PMID: 37671879 PMCID: PMC10580959 DOI: 10.1128/spectrum.01734-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/06/2023] [Indexed: 09/07/2023] Open
Abstract
Oral bacteria can influence the ability of Candida albicans to cause oropharyngeal candidiasis (OPC). We recently reported that a Lactobacillus johnsonii-enriched oral microbiota reduced C. albicans virulence in an immunosuppressed OPC mouse model. As a follow-up, in this work, we aimed to enrich the resident oral Lactobacillus communities with a prebiotic diet to further assess their effect on the severity of OPC. We tested the effect of a prebiotic xylo-oligosaccharides (XOS)-enriched diet in the oral global bacterial composition and severity of OPC. We assessed changes in the oral microbiome composition via 16S-rRNA gene high-throughput sequencing, validated by qPCR. The impact of the prebiotic diet on Candida infection was assessed by quantifying changes in oral fungal and bacterial biomass and scoring tongue lesions. Contrary to expectations, oral Lactobacillus communities were not enriched by the XOS-supplemented diet. Yet, XOS modulated the oral microbiome composition, increasing Bifidobacterium abundance and reducing enterococci and staphylococci. In the OPC model, the XOS diet attenuated Candida virulence and bacterial dysbiosis, increasing lactobacilli and reducing enterococci on the oral mucosa. We conclude that XOS attenuates Candida virulence by promoting a bacterial microbiome structure more resilient to Candida infection. IMPORTANCE This is the first study on the effects of a prebiotic diet on the oral mucosal bacterial microbiome and an oropharyngeal candidiasis (OPC) mouse model. We found that xylo-oligosaccharides change the oral bacterial community composition and attenuate OPC. Our results contribute to the understanding of the impact of the oral bacterial communities on Candida virulence.
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Affiliation(s)
- Roberto Vazquez-Munoz
- Department of General Dentistry, The University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Angela Thompson
- Department of General Dentistry, The University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Takanori Sobue
- Department of General Dentistry, The University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Anna Dongari-Bagtzoglou
- Department of General Dentistry, The University of Connecticut Health Center, Farmington, Connecticut, USA
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16
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Yang L, Cheng T, Shao J. Perspective on receptor-associated immune response to Candida albicans single and mixed infections: Implications for therapeutics in oropharyngeal candidiasis. Med Mycol 2023; 61:myad077. [PMID: 37533203 DOI: 10.1093/mmy/myad077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/11/2023] [Accepted: 07/25/2023] [Indexed: 08/04/2023] Open
Abstract
Oropharyngeal candidiasis (OPC), commonly known as 'thrush', is an oral infection that usually dismantles oral mucosal integrity and malfunctions local innate and adaptive immunities in compromised individuals. The major pathogen responsible for the occurrence and progression of OPC is the dimorphic opportunistic commensal Candida albicans. However, the incidence induced by non-albicans Candida species including C. glabrata, C. tropicalis, C. dubliniensis, C. parapsilosis, and C. krusei are increasing in company with several oral bacteria, such as Streptococcus mutans, S. gordonii, S. epidermidis, and S. aureus. In this review, the microbiological and infection features of C. albicans and its co-contributors in the pathogenesis of OPC are outlined. Since the invasion and concomitant immune response lie firstly on the recognition of oral pathogens through diverse cellular surface receptors, we subsequently emphasize the roles of epidermal growth factor receptor, ephrin-type receptor 2, human epidermal growth factor receptor 2, and aryl hydrocarbon receptor located on oral epithelial cells to delineate the underlying mechanism by which host immune recognition to oral pathogens is mediated. Based on these observations, the therapeutic approaches to OPC comprising conventional and non-conventional antifungal agents, fungal vaccines, cytokine and antibody therapies, and antimicrobial peptide therapy are finally overviewed. In the face of newly emerging life-threatening microbes (C. auris and SARS-CoV-2), risks (biofilm formation and interconnected translocation among diverse organs), and complicated clinical settings (HIV and oropharyngeal cancer), the research on OPC is still a challenging task.
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Affiliation(s)
- Liu Yang
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, P. R. China
| | - Ting Cheng
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, P. R. China
| | - Jing Shao
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, P. R. China
- Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, P. R. China
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17
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Peng Y, Chen Y, Wang Y, Wang W, Qiao S, Lan J, Wang M. Dysbiosis and primary B-cell immunodeficiencies: current knowledge and future perspective. Immunol Res 2023; 71:528-536. [PMID: 36933165 DOI: 10.1007/s12026-023-09365-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 01/27/2023] [Indexed: 03/19/2023]
Abstract
According to Elie Metchnikoff, an originator of modern immunology, several pivotal functions for disease and health are provided by indigenous microbiota. Nonetheless, important mechanistic insights have been elucidated more recently, owing to the growing availability of DNA sequencing technology. There are 10 to 100 trillion symbiotic microbes (such as viruses, bacteria, and yeast) in each human gut microbiota. Both locally and systemically, the gut microbiota has been demonstrated to impact immune homeostasis. Primary B-cell immunodeficiencies (PBIDs) are a group of primary immunodeficiency diseases (PIDs) referring to the dysregulated antibody production due to either intrinsic genetic defects or failures in functions of B cells. Recent studies have found that PBIDs cause disruptions in the gut's typical homeostatic systems, resulting in inadequate immune surveillance in the gastrointestinal (GI) tract, which is linked to increased dysbiosis, which is characterized by a disruption in the microbial homeostasis. This study aimed to review the published articles in this field to provide a comprehensive view of the existing knowledge about the crosstalk between the gut microbiome and PBID, the factors shaping the gut microbiota in PBID, as well as the potential clinical approaches for restoring a normal microbial community.
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Affiliation(s)
- Ye Peng
- Cancer Center, Department of Hematology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 58 Shangtang Road, Zhejiang, 310014, Hangzhou, China
| | - Yirui Chen
- Cancer Center, Department of Hematology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 58 Shangtang Road, Zhejiang, 310014, Hangzhou, China
| | - Yanzhong Wang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Zhejiang, Hangzhou, China
| | - Wensong Wang
- Cancer Center, Department of Hematology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 58 Shangtang Road, Zhejiang, 310014, Hangzhou, China
| | - Sai Qiao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Zhejiang, Hangzhou, China
| | - Jianping Lan
- Cancer Center, Department of Hematology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 58 Shangtang Road, Zhejiang, 310014, Hangzhou, China.
| | - Manling Wang
- Cancer Center, Department of Hematology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 58 Shangtang Road, Zhejiang, 310014, Hangzhou, China.
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18
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Archambault L, Koshy-Chenthittayil S, Thompson A, Dongari-Bagtzoglou A, Laubenbacher R, Mendes P. Corrected and Republished from: "Understanding Lactobacillus paracasei and Streptococcus oralis Biofilm Interactions through Agent-Based Modeling". mSphere 2023; 8:e0065622. [PMID: 36942961 PMCID: PMC10187049 DOI: 10.1128/msphere.00656-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 12/22/2022] [Indexed: 03/23/2023] Open
Abstract
As common commensals residing on mucosal tissues, Lactobacillus species are known to promote health, while some Streptococcus species act to enhance the pathogenicity of other organisms in those environments. In this study we used a combination of in vitro imaging of live biofilms and computational modeling to explore biofilm interactions between Streptococcus oralis, an accessory pathogen in oral candidiasis, and Lactobacillus paracasei, an organism with known probiotic properties. A computational agent-based model was created where the two species interact only by competing for space, oxygen, and glucose. Quantification of bacterial growth in live biofilms indicated that S. oralis biomass and cell numbers were much lower than predicted by the model. Two subsequent models were then created to examine more complex interactions between these species, one where L. paracasei secretes a surfactant and another where L. paracasei secretes an inhibitor of S. oralis growth. We observed that the growth of S. oralis could be affected by both mechanisms. Further biofilm experiments support the hypothesis that L. paracasei may secrete an inhibitor of S. oralis growth, although they do not exclude that a surfactant could also be involved. This contribution shows how agent-based modeling and experiments can be used in synergy to address multiple-species biofilm interactions, with important roles in mucosal health and disease. IMPORTANCE We previously discovered a role of the oral commensal Streptococcus oralis as an accessory pathogen. S. oralis increases the virulence of Candida albicans infections in murine oral candidiasis and epithelial cell models through mechanisms which promote the formation of tissue-damaging biofilms. Lactobacillus species have known inhibitory effects on biofilm formation of many microbes, including Streptococcus species. Agent-based modeling has great advantages as a means of exploring multifaceted relationships between organisms in complex environments such as biofilms. Here, we used an iterative collaborative process between experimentation and modeling to reveal aspects of the mostly unexplored relationship between S. oralis and L. paracasei in biofilm growth. The inhibitory nature of L. paracasei on S. oralis in biofilms may be exploited as a means of preventing or alleviating mucosal fungal infections.
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Affiliation(s)
- Linda Archambault
- Center for Quantitative Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
| | - Sherli Koshy-Chenthittayil
- Center for Quantitative Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
| | - Angela Thompson
- Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA
| | - Anna Dongari-Bagtzoglou
- Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA
| | | | - Pedro Mendes
- Center for Quantitative Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Center for Cell Analysis and Modeling, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
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19
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Karajacob AS, Azizan NB, Al-Maleki ARM, Goh JPE, Loke MF, Khor HM, Ho GF, Ponnampalavanar S, Tay ST. Candida species and oral mycobiota of patients clinically diagnosed with oral thrush. PLoS One 2023; 18:e0284043. [PMID: 37068057 PMCID: PMC10109505 DOI: 10.1371/journal.pone.0284043] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/22/2023] [Indexed: 04/18/2023] Open
Abstract
Overgrowth of Candida yeasts in the oral cavity may result in the development of oral thrush in immunocompromised individuals. This study analyzed the diversity and richness of the oral mycobiota of patients clinically diagnosed with oral thrush (OT), follow-up of oral thrush patients after antifungal therapy (AT), and healthy controls (HC). Oral rinse and oral swab samples were collected from 38 OT patients, 21 AT patients, and 41 healthy individuals (HC). Pellet from the oral rinse and oral swab were used for the isolation of oral Candida yeasts on Brilliance Candida Agar followed by molecular speciation. ITS1 amplicon sequencing using Illumina MiSeq was performed on DNA extracted from the oral rinse pellet of 16 OT, 7 AT, and 7 HC oral rinse samples. Trimmed sequence data were taxonomically grouped and analyzed using the CLC Microbial Genomics Module workflow. Candida yeasts were isolated at significantly higher rates from oral rinse and swab samples of OT (68.4%, p < 0.001) and AT (61.9%, p = 0.012) patients, as compared to HC (26.8%). Predominance of Candida albicans specifically, was noted in OT (60.5%, p < 0.001) and AT (42.9%, p = 0.006) vs. HC (9.8%), while non-albicans Candida species was dominant in HC. Analysis of oral mycobiota from OT patients showed the presence of 8 phyla, 222 genera, and 309 fungal species. Low alpha diversity (Shannon index, p = 0.006; Chao-1 biased corrected index, p = 0.01), varied beta diversity (Bray-Curtis, p = 0.01986; Jaccard, p = 0.02766; Weighted UniFrac, p = 0.00528), and increased relative abundance of C. albicans (p = 3.18E-02) was significantly associated with the oral mycobiota of OT vs. HC. This study supported that C. albicans is the main etiological agent in oral thrush and highlights the association of fungal biodiversity with the pathophysiology of oral thrush.
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Affiliation(s)
| | - Nuramirah Binti Azizan
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | | | - Joanne Pei En Goh
- Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Mun Fai Loke
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Hui Min Khor
- Department of Medicine, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Gwo Fuang Ho
- Department of Clinical Oncology, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Sasheela Ponnampalavanar
- Department of Medicine, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Sun Tee Tay
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
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20
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Du Q, Ren B, Zhou X, Zhang L, Xu X. Cross-kingdom interaction between Candida albicans and oral bacteria. Front Microbiol 2022; 13:911623. [PMID: 36406433 PMCID: PMC9668886 DOI: 10.3389/fmicb.2022.911623] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 09/28/2022] [Indexed: 08/27/2023] Open
Abstract
Candida albicans is a symbiotic fungus that commonly colonizes on oral mucosal surfaces and mainly affects immuno-compromised individuals. Polymicrobial interactions between C. albicans and oral microbes influence the cellular and biochemical composition of the biofilm, contributing to change clinically relevant outcomes of biofilm-related oral diseases, such as pathogenesis, virulence, and drug-resistance. Notably, the symbiotic relationships between C. albicans and oral bacteria have been well-documented in dental caries, oral mucositis, endodontic and periodontal diseases, implant-related infections, and oral cancer. C. albicans interacts with co-existing oral bacteria through physical attachment, extracellular signals, and metabolic cross-feeding. This review discusses the bacterial-fungal interactions between C. albicans and different oral bacteria, with a particular focus on the underlying mechanism and its relevance to the development and clinical management of oral diseases.
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Affiliation(s)
- Qian Du
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Biao Ren
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ling Zhang
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xin Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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21
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Hazime R, Eddehbi FE, El Mojadili S, Lakhouaja N, Souli I, Salami A, M’Raouni B, Brahim I, Oujidi M, Guennouni M, Bousfiha AA, Admou B. Inborn errors of immunity and related microbiome. Front Immunol 2022; 13:982772. [PMID: 36177048 PMCID: PMC9513548 DOI: 10.3389/fimmu.2022.982772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/19/2022] [Indexed: 11/15/2022] Open
Abstract
Inborn errors of immunity (IEI) are characterized by diverse clinical manifestations that are dominated by atypical, recurrent, chronic, or severe infectious or non-infectious features, including autoimmunity, lymphoproliferative disease, granulomas, and/or malignancy, which contribute substantially to morbidity and mortality. Some data suggest a correlation between clinical manifestations of IEI and altered gut microbiota. Many IEI display microbial dysbiosis resulting from the proliferation of pro-inflammatory bacteria or a decrease in anti-inflammatory bacteria with variations in the composition and function of numerous microbiota. Dysbiosis is considered more established, mainly within common variable immunodeficiency, selective immunoglobulin A deficiency, severe combined immunodeficiency diseases, Wiskott–Aldrich syndrome, Hyper-IgE syndrome, autoimmune polyendocrinopathy–candidiasis–ectodermal-dystrophy (APECED), immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, IL-10 receptor deficiency, chronic granulomatous disease, and Kostmann disease. For certain IEIs, the specific predominance of gastrointestinal, respiratory, and cutaneous involvement, which is frequently associated with dysbiosis, justifies the interest for microbiome identification. With the better understanding of the relationship between gut microbiota, host immunity, and infectious diseases, the integration of microbiota modulation as a therapeutic approach or a preventive measure of infection becomes increasingly relevant. Thus, a promising strategy is to develop optimized prebiotics, probiotics, postbiotics, and fecal microbial transplantation to rebalance the intestinal microbiota and thereby attenuate the disease activity of many IEIs.
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Affiliation(s)
- Raja Hazime
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech, Morocco
| | - Fatima-Ezzohra Eddehbi
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
| | - Saad El Mojadili
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
| | - Nadia Lakhouaja
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
| | - Ikram Souli
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
| | - Abdelmouïne Salami
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
| | - Bouchra M’Raouni
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
| | - Imane Brahim
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
| | - Mohamed Oujidi
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
| | - Morad Guennouni
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
| | - Ahmed Aziz Bousfiha
- Pediatric infectious and Immunology Department, Ibn Rochd University Hospital, Casablanca, Morocco
- Laboratory of Clinical Immunology inflammation and Allergy, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Brahim Admou
- Laboratory of Immunology, Center of Clinical Research, Mohammed VI University Hospital, Marrakech, Morocco
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech, Morocco
- *Correspondence: Brahim Admou,
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22
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Ch'ng ACW, Schepergerdes L, Choong YS, Hust M, Lim TS. Antimicrobial antibodies by phage display: Identification of antibody-based inhibitor against mycobacterium tuberculosis isocitrate lyase. Mol Immunol 2022; 150:47-57. [PMID: 35987135 DOI: 10.1016/j.molimm.2022.08.005] [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: 05/13/2022] [Revised: 07/23/2022] [Accepted: 08/09/2022] [Indexed: 10/15/2022]
Abstract
The increasing incidence reports of antibiotic resistance highlights the need for alternative approaches to deal with bacterial infections. This brought about the idea of utilizing monoclonal antibodies as an alternative antibacterial treatment. Majority of the studies are focused on developing antibodies to bacterial surface antigens, with little emphasis on antibodies that inhibit the growth mechanisms of a bacteria host. Isocitrate lyase (ICL) is an important enzyme for the growth and survival of Mycobacterium tuberculosis (MTB) during latent infection as a result of its involvement in the mycobacterial glyoxylate and methylisocitrate cycles. It is postulated that the inhibition of ICL can disrupt the life cycle of MTB. To this extent, we utilized antibody phage display to identify a single chain fragment variable (scFv) antibody against the recombinant ICL protein from MTB. The soluble a-ICL-C6 scFv clone exhibited good binding characteristics with high specificity against ICL. More importantly, the clone exhibited in vitro inhibitory effect with an enzymatic assay resulting in a decrease of ICL enzymatic activity. In silico analysis showed that the scFv-ICL interactions are driven by 23 hydrogen bonds and 13 salt bridges that might disrupt the formation of ICL subunits for the tertiary structure or the formation of active site β domain. However, further validation is necessary to confirm if the isolated clone is indeed a good inhibitor against ICL for application against MTB.
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Affiliation(s)
- Angela Chiew Wen Ch'ng
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Penang, Malaysia
| | - Lena Schepergerdes
- Institut für Biochemie, Biotechnologie und Bioinformatik, Technische Universität Braunschweig, 38106 Braunschweig
| | - Yee Siew Choong
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Penang, Malaysia
| | - Michael Hust
- Institut für Biochemie, Biotechnologie und Bioinformatik, Technische Universität Braunschweig, 38106 Braunschweig
| | - Theam Soon Lim
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Penang, Malaysia; Analytical Biochemistry Research Centre, Universiti Sains Malaysia, 11800 Penang, Malaysia.
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23
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Archambault LS, Dongari-Bagtzoglou A. Probiotics for Oral Candidiasis: Critical Appraisal of the Evidence and a Path Forward. FRONTIERS IN ORAL HEALTH 2022; 3:880746. [PMID: 35495563 PMCID: PMC9046664 DOI: 10.3389/froh.2022.880746] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 03/23/2022] [Indexed: 11/29/2022] Open
Abstract
Oropharyngeal Candidiasis (OPC) is a mucosal fungal infection that is prevalent among patients with compromised immunity. The success of probiotics in treating chronic diseases with a microbial etiology component at other mucosal sites (i.e., gastro-intestinal, genitourinary and alveolar mucosae) has inspired research into the use of probiotics in the treatment of OPC. A growing body of research in vitro and in animal models indicates that some probiotic species and strains have inhibitory activities against Candida albicans growth, morphological switching, and biofilm formation. However, recent review and meta-analysis studies reveal a dearth of human randomized, controlled clinical trials on the efficacy of probiotics to treat or prevent OPC, while the majority of these have not based their selection of probiotic strains or the type of administration on sound pre-clinical evidence. In this mini-review, we assess the state of the field, outline some of the difficulties in translating lab results to clinical efficacy, and make recommendations for future research needed in order to move the field forward.
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Affiliation(s)
- Linda S. Archambault
- Department of Craniofacial Sciences, University of Connecticut Health Center, Farmington, CT, United States
- Center for Quantitative Medicine, University of Connecticut Health Center, Farmington, CT, United States
| | - Anna Dongari-Bagtzoglou
- Department of Craniofacial Sciences, University of Connecticut Health Center, Farmington, CT, United States
- *Correspondence: Anna Dongari-Bagtzoglou
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24
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Archambault L, Koshy-Chenthittayil S, Thompson A, Dongari-Bagtzoglou A, Laubenbacher R, Mendes P. Understanding Lactobacillus paracasei and Streptococcus oralis Biofilm Interactions through Agent-Based Modeling. mSphere 2021; 6:e0087521. [PMID: 34908459 PMCID: PMC8673396 DOI: 10.1128/msphere.00875-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/22/2021] [Indexed: 11/20/2022] Open
Abstract
As common commensals residing on mucosal tissues, Lactobacillus species are known to promote health, while some Streptococcus species act to enhance the pathogenicity of other organisms in those environments. In this study, we used a combination of in vitro imaging of live biofilms and computational modeling to explore biofilm interactions between Streptococcus oralis, an accessory pathogen in oral candidiasis, and Lactobacillus paracasei, an organism with known probiotic properties. A computational agent-based model was created where the two species interact only by competing for space, oxygen and glucose. Quantification of bacterial growth in live biofilms indicated that S. oralis biomass and cell numbers were much lower than predicted by the model. Two subsequent models were then created to examine more complex interactions between these species, one where L. paracasei secretes a surfactant, and another where L. paracasei secretes an inhibitor of S. oralis growth. We observed that the growth of S. oralis could be affected by both mechanisms. Further biofilm experiments support the hypothesis that L. paracasei may secrete an inhibitor of S. oralis growth, although they do not exclude that a surfactant could also be involved. This contribution shows how agent-based modeling and experiments can be used in synergy to address multiple species biofilm interactions, with important roles in mucosal health and disease. IMPORTANCE We previously discovered a role of the oral commensal Streptococcus oralis as an accessory pathogen. S. oralis increases the virulence of Candida albicans infections in murine oral candidiasis and epithelial cell models through mechanisms which promote the formation of tissue-damaging biofilms. Lactobacillus species have known inhibitory effects on biofilm formation of many microbes, including Streptococcus species. Agent-based modeling has great advantages as a means of exploring multifaceted relationships between organisms in complex environments such as biofilms. Here, we used an iterative collaborative process between experimentation and modeling to reveal aspects of the mostly unexplored relationship between S. oralis and L. paracasei in biofilm growth. The inhibitory nature of L. paracasei on S. oralis in biofilms may be exploited as a means of preventing or alleviating mucosal fungal infections.
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Affiliation(s)
- Linda Archambault
- Center for Quantitative Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA
| | - Sherli Koshy-Chenthittayil
- Center for Quantitative Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
| | - Angela Thompson
- Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA
| | - Anna Dongari-Bagtzoglou
- Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA
| | | | - Pedro Mendes
- Center for Quantitative Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Center for Cell Analysis and Modeling, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Department of Cell Biology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
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25
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Villar CC, Dongari-Bagtzoglou A. Fungal diseases: Oral dysbiosis in susceptible hosts. Periodontol 2000 2021; 87:166-180. [PMID: 34463992 DOI: 10.1111/prd.12378] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The oral cavity is colonized by a large number of microorganisms that are referred to collectively as the oral microbiota. These indigenous microorganisms have evolved in symbiotic relationships with the oral mucosal immune system and are involved in maintaining homeostasis in the oral cavity. Although Candida species are commonly found in the healthy oral cavity without causing infection, these fungi can become pathogenic. Recents advances indicate that the development of oral candidiasis is driven both by Candida albicans overgrowth in a dysbiotic microbiome and by disturbances in the host's immune system. Perturbation of the oral microbiota triggered by host-extrinsic (ie, medications), host-intrinsic (ie, host genetics), and microbiome-intrinsic (ie, microbial interactions) factors may increase the risk of oral candidiasis. In this review, we provide an overview of the oral mycobiome, with a particular focus on the interactions of Candida albicans with some of the most common oral bacteria and the oral mucosal immune system. Also, we present a summary of our current knowledge of the host-intrinsic and host-extrinsic factors that can predispose to oral candidiasis.
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Affiliation(s)
- Cristina Cunha Villar
- Division of Periodontics, Department of Stomatology, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Anna Dongari-Bagtzoglou
- Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, CT, USA
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26
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Bertolini M, Vazquez Munoz R, Archambault L, Shah S, Souza JGS, Costa RC, Thompson A, Zhou Y, Sobue T, Dongari-Bagtzoglou A. Mucosal Bacteria Modulate Candida albicans Virulence in Oropharyngeal Candidiasis. mBio 2021; 12:e0193721. [PMID: 34399623 PMCID: PMC8406182 DOI: 10.1128/mbio.01937-21] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/09/2021] [Indexed: 01/12/2023] Open
Abstract
Oropharyngeal candidiasis (OPC) is the most prevalent oral infection in immunocompromised patients, primarily associated with Candida albicans. Increasing evidence points to a significant role of mucosal bacteria on the transition of C. albicans from commensal to pathogenic. In this work, we hypothesized that changes in the abundance or composition of the mucosal bacterial microbiota induced by dietary sucrose during the development of OPC can modulate C. albicans virulence. C. albicans burdens and mucosal lesions were evaluated in a mouse cortisone immunosuppression model amended with sucrose. We also analyzed the mucosal bacterial composition using 16S rRNA gene sequencing and culture methods. In immunocompetent mice, sucrose significantly increased total bacterial burdens and reduced alpha diversity, by increasing the relative abundance of mitis group streptococci. In immunocompromised mice, C. albicans infection was associated with a significantly reduced bacterial alpha diversity due to an increase in the relative abundance of enterococci. When exposed to dietary sucrose, these mice had reduced C. albicans burdens and reduced bacterial alpha diversity, associated with an increase in the relative abundance of Lactobacillus. SparCC correlation networks showed a significant negative correlation between Lactobacillus and Enterococcus in all Candida-infected mice. Depletion of lactobacilli with antibiotic treatment partially restored C. albicans burdens in mice receiving sucrose. In coculture in vitro experiments, mouse oral Lactobacillus johnsonii isolates inhibited growth of Enterococcus faecalis isolates and C. albicans. These results support the hypothesis that the sucrose-induced attenuation of C. albicans virulence was a result of changes in the mucosal bacterial microbiome characterized by a reduction in enterococci and an increase in lactobacilli. IMPORTANCE By comparing Candida albicans virulence and the mucosal bacterial composition in a mouse oral infection model, we were able to dissect the effects of the host environment (immunosuppression), infection with C. albicans, and local modulating factors (availability of sucrose as a carbon source) on the mucosal bacterial microbiome and its role on fungal virulence. We showed that changes in endogenous microbial communities in response to sucrose can lead to attenuation of fungal disease. We also showed that Lactobacillus johnsonii may curtail Candida virulence both by inhibiting its growth and by inhibiting the growth of potentially synergistic bacteria such as enterococci. Our results support the concept that Candida pathogenesis should be viewed in the contexts of both a susceptible host and a mucosal bacterial microbiota conducive to virulence.
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Affiliation(s)
- M. Bertolini
- Department of Oral Health and Diagnostic Sciences, UConn Health, Farmington, Connecticut, USA
| | - R. Vazquez Munoz
- Department of Oral Health and Diagnostic Sciences, UConn Health, Farmington, Connecticut, USA
| | - L. Archambault
- Department of Oral Health and Diagnostic Sciences, UConn Health, Farmington, Connecticut, USA
| | - S. Shah
- Department of Computer Science and Engineering, University of Connecticut, Storrs, Connecticut, USA
| | - J. G. S. Souza
- Dental Research Division, Guarulhos University, Guarulhos, SP, Brazil
- Dental Science School (Faculdade de Ciências Odontológicas [FCO]), Montes Claros, MG, Brazil
| | - R. C. Costa
- Department of Prosthodontics and Periodontology, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, SP, Brazil
| | - A. Thompson
- Department of Oral Health and Diagnostic Sciences, UConn Health, Farmington, Connecticut, USA
| | - Y. Zhou
- Department of Medicine, UConn Health, Connecticut, Farmington, Connecticut, USA
| | - T. Sobue
- Department of Oral Health and Diagnostic Sciences, UConn Health, Farmington, Connecticut, USA
| | - A. Dongari-Bagtzoglou
- Department of Oral Health and Diagnostic Sciences, UConn Health, Farmington, Connecticut, USA
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27
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The Role of IL-17-Producing Cells in Cutaneous Fungal Infections. Int J Mol Sci 2021; 22:ijms22115794. [PMID: 34071562 PMCID: PMC8198319 DOI: 10.3390/ijms22115794] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/15/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
The skin is the outermost layer of the body and is exposed to many environmental stimuli, which cause various inflammatory immune responses in the skin. Among them, fungi are common microorganisms that colonize the skin and cause cutaneous fungal diseases such as candidiasis and dermatophytosis. The skin exerts inflammatory responses to eliminate these fungi through the cooperation of skin-component immune cells. IL-17 producing cells are representative immune cells that play a vital role in anti-fungal action in the skin by producing antimicrobial peptides and facilitating neutrophil infiltration. However, the actual impact of IL-17-producing cells in cutaneous fungal infections remains unclear. In this review, we focused on the role of IL-17-producing cells in a series of cutaneous fungal infections, the characteristics of skin infectious fungi, and the recognition of cell components that drive cutaneous immune cells.
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28
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Desamero MJM, Chung SH, Kakuta S. Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models. Int J Mol Sci 2021; 22:4778. [PMID: 33946381 PMCID: PMC8125483 DOI: 10.3390/ijms22094778] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/21/2021] [Accepted: 04/27/2021] [Indexed: 12/18/2022] Open
Abstract
Understanding the host anti-fungal immunity induced by beta-glucan has been one of the most challenging conundrums in the field of biomedical research. During the last couple of decades, insights on the role of beta-glucan in fungal disease progression, susceptibility, and resistance have been greatly augmented through the utility of various beta-glucan cognate receptor-deficient mouse models. Analysis of dectin-1 knockout mice has clarified the downstream signaling pathways and adaptive effector responses triggered by beta-glucan in anti-fungal immunity. On the other hand, assessment of CR3-deficient mice has elucidated the compelling action of beta-glucans in neutrophil-mediated fungal clearance, and the investigation of EphA2-deficient mice has highlighted its novel involvement in host sensing and defense to oral mucosal fungal infection. Based on these accounts, this review focuses on the recent discoveries made by these gene-targeted mice in beta-glucan research with particular emphasis on the multifaceted aspects of fungal immunity.
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Affiliation(s)
- Mark Joseph Maranan Desamero
- Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan;
- Department of Basic Veterinary Sciences, College of Veterinary Medicine, University of the Philippines Los Baños, Laguna 4031, Philippines
| | - Soo-Hyun Chung
- Division of Experimental Animal Immunology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan;
| | - Shigeru Kakuta
- Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan;
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29
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Teles F, Wang Y, Hajishengallis G, Hasturk H, Marchesan JT. Impact of systemic factors in shaping the periodontal microbiome. Periodontol 2000 2021; 85:126-160. [PMID: 33226693 DOI: 10.1111/prd.12356] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Since 2010, next-generation sequencing platforms have laid the foundation to an exciting phase of discovery in oral microbiology as it relates to oral and systemic health and disease. Next-generation sequencing has allowed large-scale oral microbial surveys, based on informative marker genes, such as 16S ribosomal RNA, community gene inventories (metagenomics), and functional analyses (metatranscriptomics), to be undertaken. More specifically, the availability of next-generation sequencing has also paved the way for studying, in greater depth and breadth, the effect of systemic factors on the periodontal microbiome. It was natural to investigate systemic diseases, such as diabetes, in such studies, along with systemic conditions or states, , pregnancy, menopause, stress, rheumatoid arthritis, and systemic lupus erythematosus. In addition, in recent years, the relevance of systemic "variables" (ie, factors that are not necessarily diseases or conditions, but may modulate the periodontal microbiome) has been explored in detail. These include ethnicity and genetics. In the present manuscript, we describe and elaborate on the new and confirmatory findings unveiled by next-generation sequencing as it pertains to systemic factors that may shape the periodontal microbiome. We also explore the systemic and mechanistic basis for such modulation and highlight the importance of those relationships in the management and treatment of patients.
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Affiliation(s)
- Flavia Teles
- Department of Basic and Translational Sciences, Center for Innovation & Precision Dentistry, School of Dental Medicine & School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Yu Wang
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - George Hajishengallis
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hatice Hasturk
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, USA
| | - Julie T Marchesan
- Department of Comprehensive Oral Health, Periodontology, Adams School of Dentistry, University of North Carolina, Chapel Hill, NC, USA
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30
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Abstract
The microbial communities that inhabit the gingival crevice are responsible for the pathological processes that affect the periodontium. The changes in composition and function of subgingival bacteria as disease develops have been extensively studied. Subgingival communities, however, also contain fungi, Archaea, and viruses, which could contribute to the dysbiotic processes associated with periodontal diseases. High-throughput DNA sequencing has facilitated a better understanding of the mycobiome, archaeome, and virome. However, the number of studies available on the nonbacterial components of the subgingival microbiome remains limited in comparison with publications focusing on bacteria. Difficulties in characterizing fungal, archaeal, and viral populations arise from the small portion of the total metagenome mass they occupy and lack of comprehensive reference genome databases. In addition, specialized approaches potentially introducing bias are required to enrich for viral particles, while harsh methods of cell lysis are needed to recover nuclei acids from certain fungi. While the characterization of the subgingival diversity of fungi, Archaea and viruses is incomplete, emerging evidence suggests that they could contribute in different ways to subgingival dysbiosis. Certain fungi, such as Candida albicans are suggested to facilitate colonization of bacterial pathogens. Methanogenic Archaea are associated with periodontitis severity and are thought to partner synergistically with bacterial fermenters, while viruses may affect immune responses or shape microbial communities in ways incompletely understood. This review describes the manner in which omics approaches have improved our understanding of the diversity of fungi, Archaea, and viruses within subgingival communities. Further characterization of these understudied components of the subgingival microbiome is required, together with mechanistic studies to unravel their ecological role and potential contributions to dysbiosis.
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Affiliation(s)
- Patricia I Diaz
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY
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31
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Borst J, Ma L. Oral ulcerations in a patient with autosomal dominant hyper-IgE syndrome (AD-HIES). BMJ Case Rep 2020; 13:13/11/e236705. [PMID: 33139362 DOI: 10.1136/bcr-2020-236705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
A 23-year-old woman with autosomal dominant hyper-IgE syndrome complicated by recurrent pneumonia and sinusitis presented with 1 week of multiple painful oral ulcers unresponsive to empiric antiviral and antifungal treatment. Her ulcers progressively worsened and she required hospitalisation for intravenous hydration and pain control. PCR swab of an ulcer was positive for varicella-zoster virus. Her symptoms never fully resolved despite antiviral therapy, and within 2 weeks, she relapsed with new and worsening ulcers. Biopsy revealed chronic active inflammation with no evidence of viral inclusion bodies or fungal hyphae. She was diagnosed with recurrent aphthous stomatitis and referred to a local dentist for CO2 laser treatments with rapid resolution of her symptoms. This case highlights the broad differential for recurrent oral ulcers in people with a primary immunodeficiency. It also raises awareness of the benefits of laser therapy for aphthous stomatitis treatment and the importance of partnering with our colleagues in dentistry.
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Affiliation(s)
- Johanna Borst
- School of Medicine, University of California San Diego, La Jolla, California, USA
| | - Lawrence Ma
- Department of Internal Medicine and Pediatrics, University of California San Diego, La Jolla, California, USA
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32
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Diaz PI, Dongari-Bagtzoglou A. Critically Appraising the Significance of the Oral Mycobiome. J Dent Res 2020; 100:133-140. [PMID: 32924741 DOI: 10.1177/0022034520956975] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Recent efforts to understand the oral microbiome have focused on its fungal component. Since fungi occupy a low proportion of the oral microbiome biomass, mycobiome studies rely on sequencing of internal transcribed spacer (ITS) amplicons. ITS-based studies usually detect hundreds of fungi in oral samples. Here, we review the oral mycobiome, critically appraising the significance of such large fungal diversity. When harsh lysis methods are used to extract DNA, 2 oral mycobiome community types (mycotypes) are evident, each dominated by only 1 genus, either Candida or Malassezia. The rest of the diversity in ITS surveys represents low-abundance fungi possibly acquired from the environment and ingested food. So far, Candida is the only genus demonstrated to reach a significant biomass in the oral cavity and clearly shown to be associated with a distinct oral ecology. Candida thrives in the presence of lower oral pH and is enriched in caries, with mechanistic studies in animal models suggesting it participates in the disease process by synergistically interacting with acidogenic bacteria. Candida serves as the main etiological agent of oral mucosal candidiasis, in which a Candida-bacteriome partnership plays a key role. The function of other potential oral colonizers, such as lipid-dependent Malassezia, is still unclear, with further studies needed to establish whether Malassezia are metabolically active oral commensals. Low-abundance oral mycobiome members acquired from the environment may be viable in the oral cavity, and although they may not play a significant role in microbiome communities, they could serve as opportunistic pathogens in immunocompromised hosts. We suggest that further work is needed to ascertain the significance of oral mycobiome members beyond Candida. ITS-based surveys should be complemented with other methods to determine the in situ biomass and metabolic state of fungi thought to play a role in the oral environment.
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Affiliation(s)
- P I Diaz
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, NY, USA.,UB Microbiome Center, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - A Dongari-Bagtzoglou
- Division of Periodontology, Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT, USA
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33
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Martinez O, Jarrah J, Revankar SG. Invasive Phaeohyphomycosis in Immunocompetent Hosts. CURRENT FUNGAL INFECTION REPORTS 2020. [DOI: 10.1007/s12281-020-00398-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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34
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Oral microbiome: possible harbinger for children's health. Int J Oral Sci 2020; 12:12. [PMID: 32350240 PMCID: PMC7190716 DOI: 10.1038/s41368-020-0082-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 04/01/2020] [Accepted: 04/01/2020] [Indexed: 12/12/2022] Open
Abstract
The human microbiome functions as an intricate and coordinated microbial network, residing throughout the mucosal surfaces of the skin, oral cavity, gastrointestinal tract, respiratory tract, and reproductive system. The oral microbiome encompasses a highly diverse microbiota, consisting of over 700 microorganisms, including bacteria, fungi, and viruses. As our understanding of the relationship between the oral microbiome and human health has evolved, we have identified a diverse array of oral and systemic diseases associated with this microbial community, including but not limited to caries, periodontal diseases, oral cancer, colorectal cancer, pancreatic cancer, and inflammatory bowel syndrome. The potential predictive relationship between the oral microbiota and these human diseases suggests that the oral cavity is an ideal site for disease diagnosis and development of rapid point-of-care tests. The oral cavity is easily accessible with a non-invasive collection of biological samples. We can envision a future where early life salivary diagnostic tools will be used to predict and prevent future disease via analyzing and shaping the infant’s oral microbiome. In this review, we present evidence for the establishment of the oral microbiome during early childhood, the capability of using childhood oral microbiome to predict future oral and systemic diseases, and the limitations of the current evidence.
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35
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Hong BY, Hoare A, Cardenas A, Dupuy AK, Choquette L, Salner AL, Schauer PK, Hegde U, Peterson DE, Dongari-Bagtzoglou A, Strausbaugh LD, Diaz PI. The Salivary Mycobiome Contains 2 Ecologically Distinct Mycotypes. J Dent Res 2020; 99:730-738. [PMID: 32315566 DOI: 10.1177/0022034520915879] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
A broad range of fungi has been detected in molecular surveys of the oral mycobiome. However, knowledge is still lacking on interindividual variability of these communities and the ecologic and clinical significance of oral fungal commensals. In this cross-sectional study, we use internal transcribed spacer 1 amplicon sequencing to evaluate the salivary mycobiome in 59 subjects, 36 of whom were scheduled to receive cancer chemotherapy. Analysis of the broad population structure of fungal communities in the whole cohort identified 2 well-demarcated genus-level community types (mycotypes), with Candida and Malassezia as the main taxa driving cluster partitioning. The Candida mycotype had lower diversity than the Malassezia mycotype and was positively correlated with cancer and steroid use in these subjects, smoking, caries, utilizing a removable prosthesis, and plaque index. Mycotypes were also associated with metabolically distinct bacteria indicative of divergent oral environments, with aciduric species enriched in the Candida mycotype and inflammophilic bacteria increased in the Malassezia mycotype. Similar to their fungal counterparts, coexisting bacterial communities associated with the Candida mycotype showed lower diversity than those associated with the Malassezia mycotype, suggesting that common environmental pressures affected bacteria and fungi. Mycotypes were also seen in an independent cohort of 24 subjects, in which cultivation revealed Malassezia as viable oral mycobiome members, although the low-abundance Malassezia sympodialis was the only Malassezia species recovered. There was a high degree of concordance between the molecular detection and cultivability of Candida, while cultivation showed low sensitivity for detection of the Malassezia mycotype. Overall, our work provides insights into the oral mycobiome landscape, revealing 2 community classes with apparently distinct ecologic constraints and specific associations with coexisting bacteria and clinical parameters. The utility of mycotypes as biomarkers for oral diseases warrants further study.
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Affiliation(s)
- B Y Hong
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT, USA.,The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - A Hoare
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT, USA.,Laboratorio de Microbiología Oral, Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | - A Cardenas
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT, USA
| | - A K Dupuy
- Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA
| | - L Choquette
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT, USA.,The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - A L Salner
- Hartford Healthcare Cancer Institute at Hartford Hospital, Hartford, CT, USA
| | - P K Schauer
- Hartford Healthcare Cancer Institute at Hartford Hospital, Hartford, CT, USA
| | - U Hegde
- Department of Medicine, UConn Health, Farmington, CT, USA
| | - D E Peterson
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT, USA
| | - A Dongari-Bagtzoglou
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT, USA
| | - L D Strausbaugh
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - P I Diaz
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT, USA
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36
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Kobayashi T, Nagao K. Host-microbial dialogues in atopic dermatitis. Int Immunol 2020; 31:449-456. [PMID: 30877745 DOI: 10.1093/intimm/dxz026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/15/2019] [Indexed: 12/11/2022] Open
Abstract
Recent advances in sequencing technologies have revealed the diversity of microbes that reside on the skin surface which has enhanced our understanding on skin as an ecosystem, wherein the epidermis, immune cells and the microbiota engage in active dialogues that maintain barrier integrity and functional immunity. This mutual dialogue is altered in atopic dermatitis (AD), in which an impaired epidermal barrier, the skin microbial flora and aberrant immunity can form a vicious cycle that leads to clinical manifestations as eczematous dermatitis. Microbiome studies have revealed an altered microbial landscape in AD and genetic studies have identified genes that underlie barrier impairment and immune dysregulation. Shifting from the long-standing notion that AD was mediated by conventional allergic responses, emerging data suggest that it is a disorder of an altered host-microbial relationship with sophisticated pathophysiology. In this review, we will discuss recent advancements that suggest the roles of the skin microbiota in AD pathophysiology, genetic factors that mediate barrier impairment, dysbiosis and inflammation. Studies in mice, classic AD and monogenic disorders that manifest as AD collectively facilitate our understanding of AD pathophysiology and provide a foundation for novel therapeutic strategies.
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Affiliation(s)
- Tetsuro Kobayashi
- Cutaneous Leukocyte Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Keisuke Nagao
- Cutaneous Leukocyte Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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37
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Yu N, Van Dyke TE. Periodontitis: a host mediated disruption of microbial homeostasis. CURRENT ORAL HEALTH REPORTS 2020; 7:3-11. [PMID: 34113536 PMCID: PMC8189440 DOI: 10.1007/s40496-020-00256-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW In a prolific scientific career, Dr. Robert J. Genco dedicated himself to enriching our understanding of the pathogenesis of periodontitis. During a period of time in the 1970s and 1980s, when periodontitis was considered a classic infectious disease, Bob had the foresight to investigate and characterize the immune/inflammatory response in periodontitis, particularly Juvenile Periodontitis. His leadership in this area brought to the fore our appreciation of host-microbiome interactions that many years later (2008) culminated in the realization that periodontitis is a fundamental inflammatory disease. In this review, the question of how the host regulates the inflammatory response will be addressed in the context of how more recently-discovered pathways of resolution of inflammation play a role in disease pathogenesis. RECENT FINDINGS The host inflammatory response to commensal organisms creates excess inflammation in susceptible individuals and likely drives the dysbiosis of the oral microbiome observed in people with Periodontitis. In periodontal health, the oral microbiome is in balance with the host response. It is the loss of this symbiotic relationship with excess inflammation and microbiome dysbiosis that characterizes progressive disease. In recent years, the role of mediators of resolution of inflammation in the loss of balance and their potential use as therapeutics to restore homeostasis has extended our knowledge of how the host drives immune responses to affect oral dysbiosis. SUMMARY Dr. Genco provided the foundation for our ever-emerging understanding host-microbial interactions. The discovery of inflammation resolution pathways has furthered our knowledge in periodontal homeostasis. More studies are needed to understand how the host regulates the microbiome to fulfill the ultimate goal of more efficient therapeutics for periodontitis and related inflammatory diseases.
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Affiliation(s)
- Ning Yu
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, USA; The Forsyth Institute, 245 First Street, Cambridge, MA, 02142
| | - Thomas E. Van Dyke
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, USA
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38
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Peluso G, Tian E, Abusleme L, Munemasa T, Mukaibo T, Ten Hagen KG. Loss of the disease-associated glycosyltransferase Galnt3 alters Muc10 glycosylation and the composition of the oral microbiome. J Biol Chem 2020; 295:1411-1425. [PMID: 31882545 PMCID: PMC6996895 DOI: 10.1074/jbc.ra119.009807] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 12/20/2019] [Indexed: 12/26/2022] Open
Abstract
The importance of the microbiome in health and its disruption in disease is continuing to be elucidated. However, the multitude of host and environmental factors that influence the microbiome are still largely unknown. Here, we examined UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 3 (Galnt3)-deficient mice, which serve as a model for the disease hyperphosphatemic familial tumoral calcinosis (HFTC). In HFTC, loss of GALNT3 activity in the bone is thought to lead to altered glycosylation of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23), resulting in hyperphosphatemia and subdermal calcified tumors. However, GALNT3 is expressed in other tissues in addition to bone, suggesting that systemic loss could result in other pathologies. Using semiquantitative real-time PCR, we found that Galnt3 is the major O-glycosyltransferase expressed in the secretory cells of salivary glands. Additionally, 16S rRNA gene sequencing revealed that the loss of Galnt3 resulted in changes in the structure, composition, and stability of the oral microbiome. Moreover, we identified the major secreted salivary mucin, Muc10, as an in vivo substrate of Galnt3. Given that mucins and their O-glycans are known to interact with various microbes, our results suggest that loss of Galnt3 decreases glycosylation of Muc10, which alters the composition and stability of the oral microbiome. Considering that oral findings have been documented in HFTC patients, our study suggests that investigating GALNT3-mediated changes in the oral microbiome may be warranted.
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MESH Headings
- Animals
- Calcinosis/genetics
- Calcinosis/metabolism
- Calcinosis/microbiology
- Female
- Fibroblast Growth Factor-23
- Glycosylation
- Glycosyltransferases/metabolism
- Hyperostosis, Cortical, Congenital/genetics
- Hyperostosis, Cortical, Congenital/metabolism
- Hyperostosis, Cortical, Congenital/microbiology
- Hyperphosphatemia/genetics
- Hyperphosphatemia/metabolism
- Hyperphosphatemia/microbiology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Microbiota/genetics
- Mucins/chemistry
- Mucins/metabolism
- N-Acetylgalactosaminyltransferases/genetics
- N-Acetylgalactosaminyltransferases/metabolism
- Polysaccharides/metabolism
- RNA, Ribosomal, 16S/genetics
- Salivary Glands/metabolism
- Polypeptide N-acetylgalactosaminyltransferase
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Affiliation(s)
- Gabriella Peluso
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892
| | - E Tian
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892
| | - Loreto Abusleme
- Laboratory of Oral Microbiology, Faculty of Dentistry, University of Chile, Santiago 8380544, Chile
- Laboratory of Craniofacial Translational Research, Faculty of Dentistry, University of Chile, Santiago 8380544, Chile
| | - Takashi Munemasa
- Secretory Mechanisms and Dysfunctions Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892
- Division of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan
| | - Taro Mukaibo
- Secretory Mechanisms and Dysfunctions Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892
- Division of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan
| | - Kelly G Ten Hagen
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892
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39
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Liu X, Mao Y, Kang Y, He L, Zhu B, Zhang W, Lu Y, Wu Q, Xu D, Shi L. MicroRNA-127 Promotes Anti-microbial Host Defense through Restricting A20-Mediated De-ubiquitination of STAT3. iScience 2020; 23:100763. [PMID: 31958753 PMCID: PMC6992901 DOI: 10.1016/j.isci.2019.100763] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/29/2019] [Accepted: 12/06/2019] [Indexed: 02/07/2023] Open
Abstract
The increasing rising of multiple drug-resistant Staphylococcus aureus has become a major public health concern, underscoring a pressing need for developing therapies essentially based on the understanding of host defensive mechanism. In the present study, we showed that microRNA (miR)-127 played a key role in controlling bacterial infection and conferred a profound protection against staphylococcal pneumonia. The protective effect of miR-127 was largely dependent on its regulation of macrophage bactericidal activity and the generation of IL-22, IL-17, and anti-microbial peptides (AMPs), the pathway primarily driven by STAT3. Importantly, we revealed that the ubiquitin-editing enzyme A20, a genuine target of miR-127, specifically interacted with and repressed K63-ubiquitination of STAT3, thereby compromising its phosphorylation upon bacterial infection. Thus, our data not only identify miR-127 as a non-coding molecule with anti-bacterial activity but also delineate an unappreciated mechanism whereby A20 regulates STAT3-driven anti-microbial signaling via modulating its ubiquitination.
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Affiliation(s)
- Xiaoyi Liu
- Department of Immunology and Medical Microbiology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yun Mao
- Key Laboratory of Inflammation and Immunoregulation, Hangzhou Normal University School of Medicine, Hangzhou, China
| | - Yanhua Kang
- Department of Immunology and Medical Microbiology, Nanjing University of Chinese Medicine, Nanjing, China; Key Laboratory of Inflammation and Immunoregulation, Hangzhou Normal University School of Medicine, Hangzhou, China
| | - Long He
- Department of Immunology and Medical Microbiology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bo Zhu
- Department of Immunology and Medical Microbiology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei Zhang
- Department of Immunology and Medical Microbiology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qinan Wu
- Collaborative Innovation Centers of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China
| | - Dakang Xu
- Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC 3800, Australia
| | - Liyun Shi
- Department of Immunology and Medical Microbiology, Nanjing University of Chinese Medicine, Nanjing, China; Key Laboratory of Inflammation and Immunoregulation, Hangzhou Normal University School of Medicine, Hangzhou, China.
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40
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Gaffen SL, Moutsopoulos NM. Regulation of host-microbe interactions at oral mucosal barriers by type 17 immunity. Sci Immunol 2020; 5:eaau4594. [PMID: 31901072 PMCID: PMC7068849 DOI: 10.1126/sciimmunol.aau4594] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/06/2019] [Indexed: 12/13/2022]
Abstract
The oral mucosa is a primary barrier site and a portal for entry of microbes, food, and airborne particles into the gastrointestinal tract. Nonetheless, mucosal immunity at this barrier remains understudied compared with other anatomical barrier sites. Here, we review basic aspects of oral mucosal histology, the oral microbiome, and common and clinically significant diseases that present at oral mucosal barriers. We particularly focus on the role of interleukin-17 (IL-17)/T helper 17 (TH17) responses in protective immunity and inflammation in the oral mucosa. IL-17/TH17 responses are highly relevant to maintaining barrier integrity and preventing pathogenic infections by the oral commensal fungus Candida albicans On the other hand, aberrant IL-17/TH17 responses are implicated in driving the pathogenesis of periodontitis and consequent bone and tooth loss. We discuss distinct IL-17-secreting T cell subsets, emphasizing their regulation and function in oropharyngeal candidiasis and periodontitis.
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Affiliation(s)
- Sarah L Gaffen
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Niki M Moutsopoulos
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
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41
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Diaz P, Valm A. Microbial Interactions in Oral Communities Mediate Emergent Biofilm Properties. J Dent Res 2020; 99:18-25. [PMID: 31590609 PMCID: PMC6927214 DOI: 10.1177/0022034519880157] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Oral microbial communities are extraordinarily complex in taxonomic composition and comprise interdependent biological systems. The bacteria, archaea, fungi, and viruses that thrive within these communities engage in extensive cell-cell interactions, which are both beneficial and antagonistic. Direct physical interactions among individual cells mediate large-scale architectural biofilm arrangements and provide spatial proximity for chemical communication and metabolic cooperation. In this review, we summarize recent work in identifying specific molecular components that mediate cell-cell interactions and describe metabolic interactions, such as cross-feeding and exchange of electron acceptors and small molecules, that modify the growth and virulence of individual species. We argue, however, that although pairwise interaction models have provided useful information, complex community-like systems are needed to study the properties of oral communities. The networks of multiple synergistic and antagonistic interactions within oral biofilms give rise to the emergent properties of persistence, stability, and long-range spatial structure, with these properties mediating the dysbiotic transitions from health to oral diseases. A better understanding of the fundamental properties of interspecies networks will lead to the development of effective strategies to manipulate oral communities.
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Affiliation(s)
- P.I. Diaz
- Division of Periodontology, Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT, USA
| | - A.M. Valm
- Department of Biological Sciences, University at Albany, SUNY, Albany, NY, USA,A.M. Valm, Department of Biological Sciences, University at Albany, SUNY, 1400 Washington Ave., Albany, NY 12222, USA.
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42
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Peluso G, Tian E, Abusleme L, Munemasa T, Mukaibo T, Ten Hagen KG. Loss of the disease-associated glycosyltransferase Galnt3 alters Muc10 glycosylation and the composition of the oral microbiome. J Biol Chem 2020. [DOI: 10.1016/s0021-9258(17)49899-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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43
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Silva LM, Brenchley L, Moutsopoulos NM. Primary immunodeficiencies reveal the essential role of tissue neutrophils in periodontitis. Immunol Rev 2019; 287:226-235. [PMID: 30565245 DOI: 10.1111/imr.12724] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 10/06/2018] [Indexed: 12/14/2022]
Abstract
Periodontitis is a common human inflammatory disease. In this condition, microbiota trigger excessive inflammation in oral mucosal tissues surrounding the dentition, resulting in destruction of tooth-supporting structures (connective tissue and bone). While susceptibility factors for common forms of periodontitis are not clearly understood, studies in patients with single genetic defects reveal a critical role for tissue neutrophils in disease susceptibility. Indeed, various genetic defects in the development, egress from the bone marrow, chemotaxis, and extravasation are clearly linked to aggressive/severe periodontitis at an early age. Here, we provide an overview of genetic defects in neutrophil biology that are linked to periodontitis. In particular, we focus on the mechanisms underlying Leukocyte Adhesion Deficiency-I, the prototypic Mendelian defect of impaired neutrophil extravasation and severe periodontitis.
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Affiliation(s)
- Lakmali M Silva
- Oral Immunity and Inflammation Unit, NIDCR, NIH, Bethesda, Maryland.,Proteases and Remodeling Section, NIDCR, NIH, Bethesda, Maryland
| | - Laurie Brenchley
- Oral Immunity and Inflammation Unit, NIDCR, NIH, Bethesda, Maryland
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44
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The Dysbiosis and Inter-Kingdom Synergy Model in Oropharyngeal Candidiasis, a New Perspective in Pathogenesis. J Fungi (Basel) 2019; 5:jof5040087. [PMID: 31546600 PMCID: PMC6958497 DOI: 10.3390/jof5040087] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 09/18/2019] [Accepted: 09/19/2019] [Indexed: 12/28/2022] Open
Abstract
As more information emerges on oral microbiota using advanced sequencing methodologies, it is imperative to examine how organisms modulate the capacity of each other to colonize or trigger infection. Most mouse models of oral C. albicans infection have focused on interactions with single bacterial species. Thus, little is known about the microbiome-mediated interactions that control the switch of C. albicans from commensalism to infection. Evidence is accumulating that in immunosuppression where mucosal candidiasis is more prevalent, there is an altered oral bacterial microbiome with reduced diversity, but not an altered mycobiome. Oropharyngeal candidiasis in immunosuppressed humans and mice is associated with a further reduction in oral bacterial diversity and a dysbiotic shift with significant enrichment of streptococcal and enterococcal species. Our recent studies in a cancer chemotherapy mouse model supported the combined profound effect of immunosuppression and C. albicans in reducing oral bacterial diversity and provided the first direct evidence that these changes contribute to pathogenesis, representing dysbiosis. There is still a gap in understanding the relationship between Candida and the oral bacterial microbiome. We propose that certain oral commensal bacteria contribute to fungal pathogenesis and we identify gaps in our understanding of the mechanisms involved in this cooperative virulence.
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45
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Laurence M, Benito-León J, Calon F. Malassezia and Parkinson's Disease. Front Neurol 2019; 10:758. [PMID: 31396143 PMCID: PMC6667642 DOI: 10.3389/fneur.2019.00758] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 07/01/2019] [Indexed: 12/14/2022] Open
Abstract
Parkinson's disease (PD) is a common debilitating neurodegenerative disease caused by a loss of dopamine neurons in the substantia nigra within the central nervous system (CNS). The process leading to this neuronal loss is poorly understood. Seborrheic dermatitis (SD) is a common benign inflammatory condition of the skin which mainly affects lipid-rich regions of the head and trunk. SD is caused by over proliferation of the lipophilic fungus Malassezia. PD and SD are strongly associated. The increased PD risk following an SD diagnosis (OR = 1.69, 95% CI 1.36, 2.1; p < 0.001) reported by Tanner and colleagues remains unexplained. Malassezia were historically considered commensals confined to the skin. However, many recent studies report finding Malassezia in internal organs, including the CNS. This raises the possibility that Malassezia might be directly contributing to PD. Several lines of evidence support this hypothesis. AIDS is causally associated with both parkinsonism and SD, suggesting that weak T cell-mediated control of commensal microbes such as Malassezia might contribute to both. Genetic polymorphisms associated with PD (LRRK2, GBA, PINK1, SPG11, SNCA) increase availability of lipids within human cells, providing a suitable environment for Malassezia. Four LRRK2 polymorphisms which increase PD risk also increase Crohn's disease risk; Crohn's disease is strongly associated with an immune response against fungi, particularly Malassezia. Finally, Malassezia hypha formation and melanin synthesis are stimulated by L-DOPA, which could promote Malassezia invasiveness of dopamine neurons, and contribute to the accumulation of melanin in these neurons. Although Malassezia's presence in the substantia nigra remains to be confirmed, if Malassezia play a role in PD etiology, antifungal drugs should be tested as a possible therapeutic intervention.
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Affiliation(s)
| | - Julián Benito-León
- Department of Neurology, University Hospital "12 de Octubre", Madrid, Spain.,Department of Medicine, Faculty of Medicine, Complutense University, Madrid, Spain.,Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Madrid, Spain
| | - Frédéric Calon
- Faculty of Pharmacy, Université Laval, Quebec City, QC, Canada.,Neurosciences Unit, CHU de Québec-Université Laval Research Center, Quebec City, QC, Canada
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46
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Diaz PI, Hong BY, Dupuy AK, Choquette L, Thompson A, Salner AL, Schauer PK, Hegde U, Burleson JA, Strausbaugh LD, Peterson DE, Dongari-Bagtzoglou A. Integrated Analysis of Clinical and Microbiome Risk Factors Associated with the Development of Oral Candidiasis during Cancer Chemotherapy. J Fungi (Basel) 2019; 5:jof5020049. [PMID: 31200520 PMCID: PMC6617088 DOI: 10.3390/jof5020049] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 06/11/2019] [Accepted: 06/12/2019] [Indexed: 12/15/2022] Open
Abstract
Oral candidiasis is a common side effect of cancer chemotherapy. To better understand predisposing factors, we followed forty-five subjects who received 5-fluorouracil- or doxorubicin-based treatment, during one chemotherapy cycle. Subjects were evaluated at baseline, prior to the first infusion, and at three additional visits within a two-week window. We assessed the demographic, medical and oral health parameters, neutrophil surveillance, and characterized the salivary bacteriome and mycobiome communities through amplicon high throughput sequencing. Twenty percent of all subjects developed oral candidiasis. Using multivariate statistics, we identified smoking, amount of dental plaque, low bacteriome and mycobiome alpha-diversity, and the proportions of specific bacterial and fungal taxa as baseline predictors of oral candidiasis development during the treatment cycle. All subjects who developed oral candidiasis had baseline microbiome communities dominated by Candida and enriched in aciduric bacteria. Longitudinally, oral candidiasis was associated with a decrease in salivary flow prior to lesion development, and occurred simultaneously or before oral mucositis. Candidiasis was also longitudinally associated with a decrease in peripheral neutrophils but increased the neutrophil killing capacity of Candida albicans. Oral candidiasis was not found to be associated with mycobiome structure shifts during the cycle but was the result of an increase in Candida load, with C. albicans and Candida dubliniensis being the most abundant species comprising the salivary mycobiome of the affected subjects. In conclusion, we identified a set of clinical and microbiome baseline factors associated with susceptibility to oral candidiasis, which might be useful tools in identifying at risk individuals, prior to chemotherapy.
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Affiliation(s)
- Patricia I Diaz
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT 06030, USA.
| | - Bo-Young Hong
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT 06030, USA.
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
| | - Amanda K Dupuy
- Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA.
| | - Linda Choquette
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT 06030, USA.
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
| | - Angela Thompson
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT 06030, USA.
| | - Andrew L Salner
- Department of Medical Oncology, Hartford Healthcare, Hartford, CT 06106, USA.
| | - Peter K Schauer
- Department of Medical Oncology, Hartford Healthcare, Hartford, CT 06106, USA.
| | - Upendra Hegde
- Department of Medicine, UConn Health, Farmington, CT 06030, USA.
| | - Joseph A Burleson
- Department of Community Medicine and Health Care, UConn Health, Farmington, CT 06032, USA.
| | - Linda D Strausbaugh
- Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA.
| | - Douglas E Peterson
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT 06030, USA.
| | - Anna Dongari-Bagtzoglou
- Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT 06030, USA.
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47
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Associations Between Inflammatory Endotypes and Clinical Presentations in Chronic Rhinosinusitis. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2019; 7:2812-2820.e3. [PMID: 31128376 DOI: 10.1016/j.jaip.2019.05.009] [Citation(s) in RCA: 270] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/07/2019] [Accepted: 05/09/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by mucosal inflammation in the nose and paranasal sinuses. Inflammation in CRS is also heterogeneous and is mainly characterized by type 2 (T2) inflammation, but subsets of patients show type 1 (T1) and type 3 (T3) inflammation. Whether inflammatory endotypes are associated with clinical phenotypes has yet to be explored in detail. OBJECTIVE To identify associations between inflammatory endotypes and clinical presentations in CRS. METHODS We compared 121 patients with nonpolypoid CRS (CRSsNP) and 134 patients with polypoid CRS (CRSwNP) and identified inflammatory endotypes using markers including IFN-γ (T1), eosinophil cationic protein (T2), Charcot-Leyden crystal galectin (T2), and IL-17A (T3). We collected clinical parameters from medical and surgical records and examined whether there were any associations between endotype and clinical features. RESULTS The presence of nasal polyps, asthma comorbidity, smell loss, and allergic mucin was significantly associated with the presence of T2 endotype in all patients with CRS. The T1 endotype was significantly more common in females, and the presence of pus was significantly associated with T3 endotype in all patients with CRS. We further analyzed these associations in CRSsNP and CRSwNP separately and found that smell loss was still associated with T2 endotype and pus with the T3 endotype in both CRSsNP and CRSwNP. Importantly, patients with CRS with T2 and T3 mixed endotype tended to have clinical presentations shared by both T2 and T3 endotypes. CONCLUSIONS Clinical presentations are directly associated with inflammatory endotypes in CRS. Identification of inflammatory endotypes may allow for more precise and personalized medical treatments in CRS.
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The microbiome and immunodeficiencies: Lessons from rare diseases. J Autoimmun 2019; 98:132-148. [PMID: 30704941 DOI: 10.1016/j.jaut.2019.01.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 01/21/2019] [Accepted: 01/23/2019] [Indexed: 12/20/2022]
Abstract
Primary immunodeficiencies (PIDs) are inherited disorders of the immune system, associated with a considerable increase in susceptibility to infections. PIDs can also predispose to malignancy, inflammation and autoimmunity. There is increasing awareness that some aspects of the immune dysregulation in PIDs may be linked to intestinal microbiota. Indeed, the gut microbiota and its metabolites have been shown to influence immune functions and immune homeostasis both locally and systemically. Recent studies have indicated that genetic defects causing PIDs lead to perturbations in the conventional mechanisms underlying homeostasis in the gut, resulting in poor immune surveillance at the intestinal barrier, which associates with altered intestinal permeability and bacterial translocation. Consistently, a substantial proportion of PID patients presents with clinically challenging IBD-like pathology. Here, we describe the current body of literature reporting on dysbiosis of the gut microbiota in different PIDs and how this can be either the result or cause of immune dysregulation. Further, we report how infections in PIDs enhance pathobionts colonization and speculate how, in turn, pathobionts may be responsible for increased disease susceptibility and secondary infections in these patients. The potential relationship between the microbial composition in the intestine and other sites, such as the oral cavity and skin, is also highlighted. Finally, we provide evidence, in preclinical models of PIDs, for the efficacy of microbiota manipulation to ameliorate disease complications, and suggest that the potential use of dietary intervention to correct dysbiotic flora in PID patients may hold promise.
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Bertolini M, Dongari-Bagtzoglou A. The Relationship of Candida albicans with the Oral Bacterial Microbiome in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1197:69-78. [PMID: 31732935 DOI: 10.1007/978-3-030-28524-1_6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Candida albicans is an opportunistic pathogen colonizing the oropharyngeal, esophageal, and gastrointestinal mucosa in most healthy humans. In immunocompromised hosts, this fungal organism can cause mucosal candidiasis in these sites. C. albicans also causes fungemia, a serious consequence of cancer cytotoxic chemotherapy, which is thought to develop from fungal translocation through compromised mucosal barriers. Changes in endogenous bacterial population size or composition as well as changes in the host environment can transform fungal commensals into opportunistic pathogens in the upper and lower GI tract. Pioneering studies from our group have shown that a ubiquitous oral commensal of the mitis streptococcal group (Streptococcus oralis) has a mutualistic relationship with C. albicans, with C. albicans enabling streptococcal biofilm growth at mucosal sites, and S. oralis facilitating invasion of the oral and esophageal mucosa by C. albicans. In these studies, we used a cortisone-induced immunosuppression mouse model. More recently, the development of a novel mouse chemotherapy model has allowed us to examine the interactions of C. albicans with the endogenous bacterial microbiota in the oral and small intestinal mucosa, two sites adversely affected by cytotoxic chemotherapy. In this model, oral inoculation with C. albicans causes severe dysbiosis in the mucosal bacterial composition in both sites. We also found that antibiotic treatment ameliorates invasion of the oral mucosa but aggravates dissemination through the intestinal mucosa. In this chapter, we discuss work from our laboratory and others examining the relationships of C. albicans with oral bacteria and their role in mucosal homeostasis or disease.
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Affiliation(s)
- Martinna Bertolini
- Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center, Farmington, CT, USA
| | - Anna Dongari-Bagtzoglou
- Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center, Farmington, CT, USA.
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Dutzan N, Abusleme L. T Helper 17 Cells as Pathogenic Drivers of Periodontitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1197:107-117. [PMID: 31732938 DOI: 10.1007/978-3-030-28524-1_9] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
T helper 17 (Th17) cells were first described as a T helper subset involved in the pathogenesis of experimental autoimmune inflammation. Since then, these cells have been described as orchestrators of immunopathology in several human inflammatory conditions including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. More recently, the crucial role of Th17 cells in the regulation of immunity and protection of barrier sites has been unveiled. In the present work, we review the available evidence regarding Th17 cells in health and disease with a focus on the oral mucosa and their role in periodontitis pathogenesis. Recent mechanistic studies in animal models have demonstrated that interleukin-17A (IL-17A) and Th17 cells are critical mediators for alveolar bone destruction during periodontal inflammation. Observations in a cohort of patients with naturally occurring impaired Th17 cell differentiation supported these findings. However, interventional studies are needed to conclusively implicate Th17 cells in the immunopathogenesis of human alveolar bone and tissue destruction that characterize periodontitis.
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Affiliation(s)
- Nicolas Dutzan
- Oral Mucosal Immunology Section, Craniofacial and Translational Research Laboratory, Faculty of Dentistry, University of Chile, Santiago, Chile.
| | - Loreto Abusleme
- Laboratory of Oral Microbiology, Faculty of Dentistry, University of Chile, Santiago, Chile.,Oral Microbial Ecology Section, Craniofacial and Translational Research Laboratory, Faculty of Dentistry, University of Chile, Santiago, Chile
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