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Marshall JL, Satti I, Surakhy M, Harris SA, Morrison H, Wittenberg RE, Peralta Alvarez MP, Li S, Lopez Ramon R, Hoogkamer E, Salguero FJ, Ramos Lopez F, Mitton C, Cabrera Puig I, Powell Doherty R, Tanner R, Hinks TSC, Bettinson H, McShane H. Early mucosal responses following a randomised controlled human inhaled infection with attenuated Mycobacterium bovis BCG. Nat Commun 2025; 16:4989. [PMID: 40442144 PMCID: PMC12122720 DOI: 10.1038/s41467-025-60285-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 05/20/2025] [Indexed: 06/02/2025] Open
Abstract
The development of an effective vaccine against Mycobacterium tuberculosis is hampered by an incomplete understanding of immunoprotective mechanisms. We utilise an aerosol human challenge model using attenuated Mycobacterium bovis BCG, in BCG-naïve UK adults. The primary endpoint of this study (NCT03912207) was to characterise the early immune responses induced by aerosol BCG infection, the secondary endpoint was to identify immune markers associated with in-vitro protection. Blinded volunteers were randomised to inhale 1 × 107 CFU aerosolised BCG or 0.9% saline (20:6); and sequentially allocated to bronchoscopy at day 2 or 7 post-inhalation (10 BCG, 3 saline each timepoint). In the bronchoalveolar lavage post-aerosol BCG infection, there was an increase in frequency of eosinophils, neutrophils, NK cells and Donor-Unrestricted T cells at day 7, and the frequency of antigen presenting cells decreased at day 7 compared with day 2. The frequency of interferon-gamma+ BCG-specific CD4+ T cells increased in the BAL and peaked in the blood at day 7 post-BCG infection compared to day 2. BAL cells at day 2 and day 7 upregulated gene pathways related to phagocytosis, MHC-II antigen loading, T cell activation and proliferation. BCG's lack of key virulence factors and its failure to induce granulomas, may mean the observed immune responses do not fully recapitulate Mycobacterium tuberculosis infection. However, human infection models can provide unique insights into early immune mechanisms, informing vaccine design for complex pathogens.
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Affiliation(s)
- Julia L Marshall
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
- The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia
| | - Iman Satti
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Mirvat Surakhy
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Stephanie A Harris
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Hazel Morrison
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Rachel E Wittenberg
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Marco Polo Peralta Alvarez
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Shuailin Li
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Raquel Lopez Ramon
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Emily Hoogkamer
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | | | - Fernando Ramos Lopez
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Celia Mitton
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Ingrid Cabrera Puig
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Rebecca Powell Doherty
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Rachel Tanner
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Timothy S C Hinks
- Oxford Centre for Respiratory Medicine, Nuffield Department of Clinical Medicine, The University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Henry Bettinson
- Oxford Centre for Respiratory Medicine, Nuffield Department of Clinical Medicine, The University of Oxford, Oxford, OX3 7DQ, United Kingdom
| | - Helen McShane
- The Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
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Viswanathan G, Hughes EJ, Gan M, Xet-Mull AM, Alexander G, Swain-Lenz D, Liu Q, Tobin DM. Granuloma Dual RNA-Seq Reveals Composite Transcriptional Programs Driven by Neutrophils and Necrosis within Tuberculous Granulomas. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.26.650783. [PMID: 40391323 PMCID: PMC12087985 DOI: 10.1101/2025.04.26.650783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2025]
Abstract
Mycobacterial granulomas lie at the center of tuberculosis (TB) pathogenesis and represent a unique niche where infecting bacteria survive in nutrient-restricted conditions and in the face of a host immune response. The granuloma's necrotic core, where bacteria reside extracellularly in humans, is difficult to assess in many experimentally tractable models. Here, using necrotic mycobacterial granulomas in adult zebrafish, we develop dual RNA-seq across different host genotypes to identify the transcriptional alterations that enable bacteria to survive within this key microenvironment. Through pharmacological and genetic interventions, we find that neutrophils within mature, necrotic granulomas promote bacterial growth, in part through upregulation of the bacterial devR regulon. We identify conserved suites of bacterial transcriptional programs induced only in the context of this unique necrotic extracellular niche, including bacterial modules related to K + transport and rpf genes. Analysis of Mycobacterium tuberculosis strains across diverse lineages and human populations suggests that granuloma-specific transcriptional modules are targets for bacterial genetic adaptation in the context of human infection. Summary sentence Dual host-pathogen transcriptional profiling defines granuloma-specific programs during mycobacterial infection.
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Thong PM, Wong YH, Kornfeld H, Goletti D, Ong CWM. Immune dysregulation of diabetes in tuberculosis. Semin Immunol 2025; 78:101959. [PMID: 40267700 DOI: 10.1016/j.smim.2025.101959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 04/04/2025] [Accepted: 04/16/2025] [Indexed: 04/25/2025]
Abstract
The rising prevalence of diabetes mellitus (DM) is undermining global efforts to eliminate tuberculosis (TB). Most studies found that patients with pulmonary TB and DM have more cavitary lung lesions, higher mycobacterial burden on the lungs, longer periods of infectiousness, and worse outcomes. Both human and animal studies indicate that TB-DM is associated with impaired innate and adaptive immune responses, resulting in delayed bacterial clearance. Similar observations have been noted in other infections, such as those caused by Klebsiella pneumoniae, where DM contributes to increased susceptibility and worse outcomes due to compromised immune functions including defective phagocytosis and impaired early immune cell recruitment. This review delves into the mechanisms of immune dysfunction in TB-DM, exploring how DM increases TB susceptibility and severity. By elucidating these complex interactions, this review aims to offer insights into more effective strategies for managing and improving outcomes for patients with this challenging comorbidity.
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Affiliation(s)
- Pei Min Thong
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yi Hao Wong
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Hardy Kornfeld
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Delia Goletti
- Translational Research Unit, Department of Epidemiology, National Institute for infectious diseases-IRCCS L. Spallanzani, Rome, Italy.
| | - Catherine W M Ong
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Infectious Diseases, Department of Medicine, National University Hospital, Singapore; Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore.
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Xu X, Liu X, Yang C, Cai L, Liu L, Chen T, Zhu H, Wei H. Diagnosis of Tuberculous Pericarditis in Zhejiang, China: A Diagnostic Prediction Model Based on LASSO Logistic Regression. J Inflamm Res 2025; 18:4681-4693. [PMID: 40195957 PMCID: PMC11975061 DOI: 10.2147/jir.s504183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 02/28/2025] [Indexed: 04/09/2025] Open
Abstract
Background and Aims Tuberculous pericarditis (TBP) is a severe, life-threatening complication, yet its diagnosis is highly challenging due to the lack of sufficient diagnostic tools. The aim of this study was to develop and validate a diagnostic prediction model suitable for primary healthcare institutions to predict the risk of TBP. Methods We collected detailed medical histories, imaging examination results, laboratory test data, and clinical characteristics of patients and used the Least Absolute Shrinkage and Selection Operator (LASSO) technique combined with logistic regression analysis to construct a predictive model. The diagnostic efficacy of the model was assessed using the Receiver Operating Characteristic (ROC) curve, calibration curve, and Decision Curve Analysis (DCA). Results A total of 304 patients were included in the study, with a median age of 64 years, of which 144 were diagnosed with tuberculous pericarditis. Patients were randomly assigned to the training and validation sets in a 7:3 ratio. LASSO logistic regression analysis revealed that weight loss (P=0.011), body mass index (BMI) (P=0.061), history of tuberculosis (P=0.022), history of dust exposure (P=0.03), moderate to severe kidney disease (P=0.005), erythrocyte sedimentation rate (ESR) (P=0.084), and B-type natriuretic peptide (BNP) (P<0.001) are independent risk factors for TBP. Based on these factors, we constructed a nomogram with an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.757 in both the training and validation sets, indicating high discriminative ability of the model. Calibration curve analysis showed good consistency of the model. DCA results indicated that the model has significant clinical application value when the threshold probability is set between 1-100% (training set) and 30-100% (validation set). Conclusion We successfully developed a nomogram model for predicting tuberculous pericarditis, which can assist clinicians in improving diagnostic accuracy and reducing misdiagnoses and missed diagnoses in primary healthcare settings.
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Affiliation(s)
- Xiaoqun Xu
- Centre of Laboratory Medicine, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Xiao Liu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Chao Yang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Long Cai
- Centre of Laboratory Medicine, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Libin Liu
- Centre of Laboratory Medicine, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Tielong Chen
- Department of Cardiology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Houyong Zhu
- Department of Cardiology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Hui Wei
- Centre of Laboratory Medicine, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, People’s Republic of China
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Santos AP, Rodrigues LS, Rother N, Mello FCDQ, Magis-Escurra C. The role of neutrophil response in lung damage and post-tuberculosis lung disease: a translational narrative review. Front Immunol 2025; 16:1528074. [PMID: 40124364 PMCID: PMC11925771 DOI: 10.3389/fimmu.2025.1528074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
It is estimated that more than 150 million individuals alive in 2020 had survived tuberculosis (TB). A portion of this large population continues to experience chronic respiratory abnormalities, with or without symptoms, due to previous active pulmonary TB. This condition known as Post-TB Lung Disease (PTLD), involves a complex interaction between pathogen, host and environmental factors. These interactions are believed to drive a hyperinflammatory process in the lungs during active TB, resulting in tissue damage, which may lead to radiological sequelae, impaired pulmonary function, clinical symptoms, such as cough, dyspnea, hemoptysis, and respiratory infections. Such complications impose significant health, financial, and social burdens, which remain poorly understood and inadequately addressed by health care systems. Given the heterogeneity of immune cells and their products infiltrating the airways and the lung parenchyma during acute and chronic inflammation caused by Mycobacterium tuberculosis infection, it is evident that TB immunopathology is multifactorial. Among the various components involved, neutrophils have recently emerged as critical contributors to the deleterious immune response against TB, leading to severe pulmonary damage. In this translational narrative review, we aim to summarize the role of neutrophils and their primary products - proteases (such as elastase), matrix metalloproteinases and neutrophils extracellular traps (NETs) - in pulmonary TB. We highlight new concepts and emerging evidence of neutrophil involvement during the active disease, translating these insights from "bench to bedside" to facilitate dialogue between fundamental researchers and clinical practitioners. Additionally, we present potential targets for future treatment strategies that could mitigate or even prevent PTLD.
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Affiliation(s)
- Ana Paula Santos
- Pulmonary Diseases Department, Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil
- Thoracic Diseases Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Department of Respiratory Diseases-TB Expert Center, Radboud University Medical Center, Nijmegen, Netherlands
| | - Luciana Silva Rodrigues
- Department of Pathology and Laboratories, Medical Sciences Faculty, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Nils Rother
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | | | - Cecile Magis-Escurra
- Department of Respiratory Diseases-TB Expert Center, Radboud University Medical Center, Nijmegen, Netherlands
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Saqib M, Das S, Nafiz TN, McDonough E, Sankar P, Mishra LK, Zhang X, Cai Y, Subbian S, Mishra BB. Pathogenic role for CD101-negative neutrophils in the type I interferon-mediated immunopathogenesis of tuberculosis. Cell Rep 2025; 44:115072. [PMID: 39693225 PMCID: PMC11829800 DOI: 10.1016/j.celrep.2024.115072] [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: 05/01/2024] [Revised: 09/13/2024] [Accepted: 11/25/2024] [Indexed: 12/20/2024] Open
Abstract
Neutrophils are vital for immunity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), yet their heterogeneous nature suggests a complex role in TB pathogenesis. Here, we identify two distinct neutrophil populations based on CD101 expression, highlighting their divergent roles in TB. CD101-negative (CD101-ve) neutrophils, which resemble immature, pro-inflammatory granulocytes, exhibit reduced Mtb phagocytosis compared to their mature, CD101-positive (CD101+ve) counterparts. Our findings reveal that type I interferons (IFN-Is) suppress neutrophil Mtb uptake and drive the recruitment of CD101-ve neutrophils to the lungs. Infiltration of these cells promotes Mtb extracellular persistence, exacerbates epithelial damage, and impairs surfactant production. Furthermore, we demonstrate that granulocyte colony-stimulating factor (G-CSF) and chemokine receptor CXCR2 are essential for the pulmonary accumulation of CD101-ve neutrophils. Our study uncovers a pathogenic role for CD101-ve neutrophils in TB and highlights the IFN-I-dependent recruitment of this functionally compromised immature neutrophil as a driver of TB immunopathogenesis.
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Affiliation(s)
- Mohd Saqib
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA
| | - Shreya Das
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA
| | - Tanvir N Nafiz
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA
| | - Elizabeth McDonough
- GE Healthcare Technology and Innovation Center, GE Research, Niskayuna, NY, USA
| | - Poornima Sankar
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA
| | - Lokesh K Mishra
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA
| | - Ximeng Zhang
- Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
| | - Yi Cai
- Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
| | - Selvakumar Subbian
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ, USA
| | - Bibhuti B Mishra
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
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7
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Hu X, Li S, Huang R, Fu Z, Ma C, Cheng Z, Hu H, Zhou Q, Petersen F, Yu X, Zheng J. The autoimmune disease risk variant NCF1-His90 is associated with a reduced risk of tuberculosis in women. Front Immunol 2025; 16:1514296. [PMID: 39917298 PMCID: PMC11799249 DOI: 10.3389/fimmu.2025.1514296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 01/08/2025] [Indexed: 02/09/2025] Open
Abstract
Introduction The neutrophil cytosolic factor 1 (NCF1) rs201802880 polymorphism is a missense mutation resulting in an amino acid substitution from arginine to histidine at position 90, which impairs the function of NADPH oxidase. This casual variant confers an increased risk for multiple autoimmune disorders, including primary Sjögren's syndrome and systemic lupus erythematosus. Given the high prevalence of this autoimmune disease risk variant in East Asia, we hypothesized that it may confer an evolutionary advantage by providing protection against infectious diseases. Methods To test this hypothesis, we investigated whether the NCF1 rs201802880 variant offers a protective effect against tuberculosis (TB), a historically significant and deadly infectious disease. Our study included 490 healthy controls and 492 TB patients who were genotyped for the NCF1 rs201802880 polymorphism. Results Our results showed that the NCF1 rs201802880 AA genotype was associated with a reduced risk of TB in women (OR= 0.25, 95% CI: 0.09-0.68, p=0.0023). Additionally, healthy individuals with the NCF1 rs201802880 AA genotype had significantly lower circulating white blood cell (5.56 ± 1.78 vs 6.43 ± 1.59, p=0.003) and neutrophil (3.23 ± 1.20 vs 3.74 ± 1.23, p = 0.02) counts compared to those with the GG or GA genotypes, with this difference being more pronounced in women than in men. Conclusion This study demonstrates that the autoimmune disease-causal NCF1 variant is associated with a protective effect against TB infection.
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Affiliation(s)
- Xinjun Hu
- Department of Infectious Diseases, The First Affiliated Hospital of Henan University of Science and Technology, Henan Medical Key Laboratory of Gastrointestinal Microecology and Hepatology, Luoyang, China
| | - Shasha Li
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Renliang Huang
- Department of Genetics and Prenatal Diagnosis, Hainan Women and Children’s Medical Center, Haikou, Hainan, China
| | - Ziwei Fu
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Chenyu Ma
- Department of Infectious Diseases, The First Affiliated Hospital of Henan University of Science and Technology, Henan Medical Key Laboratory of Gastrointestinal Microecology and Hepatology, Luoyang, China
| | - Zheng Cheng
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Hongjun Hu
- Department of Surgical Oncology, Xinxiang Central Hospital, The Fourth Clinical of Xinxiang Medical University, Xinxiang, China
| | - Qiaomiao Zhou
- Department of Genetics and Prenatal Diagnosis, Hainan Women and Children’s Medical Center, Haikou, Hainan, China
| | - Frank Petersen
- Priority Area Chronic Lung Diseases, Research Center Borstel - Leibniz Lung Center, Members of the German Center for Lung Research (DZL), Borstel, Germany
| | - Xinhua Yu
- Department of Genetics and Prenatal Diagnosis, Hainan Women and Children’s Medical Center, Haikou, Hainan, China
- Priority Area Chronic Lung Diseases, Research Center Borstel - Leibniz Lung Center, Members of the German Center for Lung Research (DZL), Borstel, Germany
| | - Junfeng Zheng
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
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Ryanto GRT, Suraya R, Nagano T. The Importance of Lung Innate Immunity During Health and Disease. Pathogens 2025; 14:91. [PMID: 39861052 PMCID: PMC11768135 DOI: 10.3390/pathogens14010091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
The lung is a vital organ for the body as the main source of oxygen input. Importantly, it is also an internal organ that has direct contact with the outside world. Innate immunity is a vital protective system in various organs, whereas, in the case of the lung, it helps maintain a healthy, functioning cellular and molecular environment and prevents any overt damage caused by pathogens or other inflammatory processes. Disturbances in lung innate immunity properties and processes, whether over-responsiveness of the process triggered by innate immunity or lack of responses due to dysfunctions in the immune cells that make up the innate immunity system of the lung, could be correlated to various pathological conditions. In this review, we discuss globally how the components of lung innate immunity are important not only for maintaining lung homeostasis but also during the pathophysiology of notable lung diseases beyond acute pulmonary infections, including chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis.
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Affiliation(s)
- Gusty Rizky Teguh Ryanto
- Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, Kobe 658-8558, Japan
| | - Ratoe Suraya
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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Scriba TJ, Maseeme M, Young C, Taylor L, Leslie AJ. Immunopathology in human tuberculosis. Sci Immunol 2024; 9:eado5951. [PMID: 39671470 DOI: 10.1126/sciimmunol.ado5951] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 11/15/2024] [Indexed: 12/15/2024]
Abstract
Mycobacterium tuberculosis (M.tb) is a bacterial pathogen that has evolved in humans, and its interactions with the host are complex and best studied in humans. Myriad immune pathways are involved in infection control, granuloma formation, and progression to tuberculosis (TB) disease. Inflammatory cells, such as macrophages, neutrophils, conventional and unconventional T cells, B cells, NK cells, and innate lymphoid cells, interact via cytokines, cell-cell communication, and eicosanoid signaling to contain or eliminate infection but can alternatively mediate pathological changes required for pathogen transmission. Clinical manifestations include pulmonary and extrapulmonary TB, as well as post-TB lung disease. Risk factors for TB progression, in turn, largely relate to immune status and, apart from traditional chemotherapy, interventions primarily target immune mechanisms, highlighting the critical role of immunopathology in TB. Maintaining a balance between effector mechanisms to achieve protective immunity and avoid detrimental inflammation is central to the immunopathogenesis of TB. Many research gaps remain and deserve prioritization to improve our understanding of human TB immunopathogenesis.
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Affiliation(s)
- Thomas J Scriba
- South African Tuberculosis Vaccine Initiative, Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Mahlatse Maseeme
- Africa Health Research Institute, Durban, South Africa
- College of Heath Sciences, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Carly Young
- South African Tuberculosis Vaccine Initiative, Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Laura Taylor
- Forensic Pathology Services, Western Cape Government/University of Cape Town, Cape Town, South Africa
| | - Alasdair J Leslie
- Africa Health Research Institute, Durban, South Africa
- University College London, London, UK
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10
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Chowdhury CS, Kinsella RL, McNehlan ME, Naik SK, Lane DS, Talukdar P, Smirnov A, Dubey N, Rankin AN, McKee SR, Woodson R, Hii A, Chavez SM, Kreamalmeyer D, Beatty W, Mattila JT, Stallings CL. Type I IFN-mediated NET release promotes Mycobacterium tuberculosis replication and is associated with granuloma caseation. Cell Host Microbe 2024; 32:2092-2111.e7. [PMID: 39637864 PMCID: PMC11637906 DOI: 10.1016/j.chom.2024.11.008] [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: 12/13/2022] [Revised: 10/16/2024] [Accepted: 11/11/2024] [Indexed: 12/07/2024]
Abstract
Neutrophils are the most abundant cell type in the airways of tuberculosis patients. Mycobacterium tuberculosis (Mtb) infection induces the release of neutrophil extracellular traps (NETs); however, the molecular regulation and impact of NET release on Mtb pathogenesis are unknown. We find that during Mtb infection in neutrophils, PAD4 citrullinates histones to decondense chromatin that gets released as NETs in a manner that can maintain neutrophil viability and promote Mtb replication. Type I interferon promotes the formation of chromatin-containing vesicles that allow NET release without compromising plasma membrane integrity. Analysis of nonhuman primate granulomas supports a model where neutrophils are exposed to type I interferon from macrophages as they migrate into the granuloma, thereby enabling the release of NETs associated with necrosis and caseation. Our data reveal NET release as a promising target to inhibit Mtb pathogenesis.
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Affiliation(s)
- Chanchal Sur Chowdhury
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Rachel L Kinsella
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Michael E McNehlan
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Sumanta K Naik
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Daniel S Lane
- Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261, USA
| | - Priyanka Talukdar
- Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261, USA
| | - Asya Smirnov
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Neha Dubey
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ananda N Rankin
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Samuel R McKee
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Reilly Woodson
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Abigail Hii
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA; UCD School of Medicine, University College Dublin, Belfield, Dublin, Ireland
| | - Sthefany M Chavez
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Darren Kreamalmeyer
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Wandy Beatty
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Joshua T Mattila
- Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261, USA
| | - Christina L Stallings
- Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
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11
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Hazrati A, Mirarefin SMJ, Malekpour K, Rahimi A, Khosrojerdi A, Rasouli A, Akrami S, Soudi S. Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells. Front Immunol 2024; 15:1469696. [PMID: 39582867 PMCID: PMC11581898 DOI: 10.3389/fimmu.2024.1469696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/01/2024] [Indexed: 11/26/2024] Open
Abstract
Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Arezou Rahimi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Ashkan Rasouli
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Akrami
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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12
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Sankar P, Ramos RB, Corro J, Mishra LK, Nafiz TN, Bhargavi G, Saqib M, Poswayo SKL, Parihar SP, Cai Y, Subbian S, Ojha AK, Mishra BB. Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis. PLoS Pathog 2024; 20:e1012188. [PMID: 39365825 PMCID: PMC11482725 DOI: 10.1371/journal.ppat.1012188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 10/16/2024] [Accepted: 09/24/2024] [Indexed: 10/06/2024] Open
Abstract
Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial β-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions.
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Affiliation(s)
- Poornima Sankar
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America
| | - Ramon Bossardi Ramos
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, United States of America
| | - Jamie Corro
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America
| | - Lokesh K. Mishra
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America
| | - Tanvir Noor Nafiz
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America
| | - Gunapati Bhargavi
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America
| | - Mohd Saqib
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America
| | - Sibongiseni K. L. Poswayo
- Center for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Medical Microbiology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Suraj P. Parihar
- Center for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Medical Microbiology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Yi Cai
- Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
| | - Selvakumar Subbian
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America
| | - Anil K. Ojha
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America
| | - Bibhuti B. Mishra
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America
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13
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Zhou Y, Zhang Y, Li L. Identification of immune subtypes associated with neutrophils in tuberculosis infection based on weighted gene co-expression network analysis. Diagn Microbiol Infect Dis 2024; 109:116322. [PMID: 38677053 DOI: 10.1016/j.diagmicrobio.2024.116322] [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: 02/06/2024] [Revised: 04/01/2024] [Accepted: 04/19/2024] [Indexed: 04/29/2024]
Abstract
Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is a major global health concern. Neutrophils play a significant role in TB infection and patient outcomes. This study aimed to identify gene modules associated with neutrophil infiltration in TB samples using WGCNA. Gene ontology and enrichment analyses were performed, and a random forest model was constructed to identify differentially expressed genes. K-means clustering was used to classify samples into subtypes, and immune-related scores, PD-L1 expression, HLA expression, and gene enrichment analysis were evaluated. The blue module showed significant correlation with neutrophils and enrichment in immune-related processes. The model exhibited good classification performance, and subtype 1 demonstrated higher immune-related scores, PD-L1 expression, HLA class I molecule expression, and immune-related pathway enrichment. These findings enhance our understanding of TB pathogenesis and provide potential targets for diagnosis and treatment strategies.
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Affiliation(s)
- Yingying Zhou
- Respiratory Medicine, Daqing Oilfield General Hospital, Daqing City, 163000, PR China
| | - Yanli Zhang
- General Practice, Da Qing Long Nan Hospital, Daqing City, 163000, PR China
| | - Li Li
- Respiratory Medicine, Daqing Oilfield General Hospital, Daqing City, 163000, PR China.
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14
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Nhamoyebonde S, Chambers M, Ndlovu L, Karim F, Mazibuko M, Mhlane Z, Madziwa L, Moosa Y, Moodley S, Hoque M, Leslie A. Detailed phenotyping reveals diverse and highly skewed neutrophil subsets in both the blood and airways during active tuberculosis infection. Front Immunol 2024; 15:1422836. [PMID: 38947330 PMCID: PMC11212598 DOI: 10.3389/fimmu.2024.1422836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 05/21/2024] [Indexed: 07/02/2024] Open
Abstract
Introduction Neutrophils play a complex and important role in the immunopathology of TB. Data suggest they are protective during early infection but become a main driver of immunopathology if infection progresses to active disease. Neutrophils are now recognized to exist in functionally diverse states, but little work has been done on how neutrophil states or subsets are skewed in TB disease. Methods To address this, we carried out comprehensive phenotyping by flow cytometry of neutrophils in the blood and airways of individuals with active pulmonary TB with and without HIV co-infection recruited in Durban, South Africa. Results Active TB was associated with a profound skewing of neutrophils in the blood toward phenotypes associated with activation and apoptosis, reduced phagocytosis, reverse transmigration, and immune regulation. This skewing was also apparently in airway neutrophils, particularly the regulatory subsets expressing PDL-1 and LOX-1. HIV co-infection did not impact neutrophil subsets in the blood but was associated with a phenotypic change in the airways and a reduction in key neutrophil functional proteins cathelicidin and arginase 1. Discussion Active TB is associated with profound skewing of blood and airway neutrophils and suggests multiple mechanisms by which neutrophils may exacerbate the immunopathology of TB. These data indicate potential avenues for reducing neutrophil-mediated lung pathology at the point of diagnosis.
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Affiliation(s)
| | - Mark Chambers
- Africa Health Research Institute, Durban, South Africa
| | - Lerato Ndlovu
- Africa Health Research Institute, Durban, South Africa
| | - Farina Karim
- Africa Health Research Institute, Durban, South Africa
| | | | - Zoey Mhlane
- Africa Health Research Institute, Durban, South Africa
| | | | - Yunus Moosa
- Department of Infectious Diseases, Nelson R. Mandela School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa
| | | | - Monjurul Hoque
- Department of Infectious Diseases, Nelson R. Mandela School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Alasdair Leslie
- Africa Health Research Institute, Durban, South Africa
- Department of Infectious Diseases, Nelson R. Mandela School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa
- Department of Infection and Immunity, University College London, London, United Kingdom
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15
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Tyagi S, Sadhu S, Sharma T, Paul A, Pandey M, Nain VK, Rathore DK, Chatterjee S, Awasthi A, Pandey AK. VapC12 ribonuclease toxin modulates host immune response during Mycobacterium tuberculosis infection. Front Immunol 2024; 15:1302163. [PMID: 38515752 PMCID: PMC10955575 DOI: 10.3389/fimmu.2024.1302163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 02/01/2024] [Indexed: 03/23/2024] Open
Abstract
Mechanistic understanding of antibiotic persistence is a prerequisite in controlling the emergence of MDR cases in Tuberculosis (TB). We have reported that the cholesterol-induced activation of VapC12 ribonuclease is critical for disease persistence in TB. In this study, we observed that relative to the wild type, mice infected with ΔvapC12 induced a pro-inflammatory response, had a higher pathogen load, and responded better to the anti-TB treatment. In a high-dose infection model, all the mice infected with ΔvapC12 succumbed early to the disease. Finally, we reported that the above phenotype of ΔvapC12 was dependent on the presence of the TLR4 receptor. Overall, the data suggests that failure of a timely resolution of the early inflammation by the ΔvapC12 infected mice led to hyperinflammation, altered T-cell response and high bacterial load. In conclusion, our findings suggest the role of the VapC12 toxin in modulating the innate immune response of the host in ways that favor the long-term survival of the pathogen inside the host.
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Affiliation(s)
- Shaifali Tyagi
- Mycobacterial Pathogenesis Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India
| | - Srikanth Sadhu
- Immunobiology Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Taruna Sharma
- Mycobacterial Pathogenesis Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India
| | - Abhijit Paul
- Complex Analysis Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Manitosh Pandey
- Mycobacterial Pathogenesis Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Vaibhav Kumar Nain
- Mycobacterial Pathogenesis Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India
| | - Deepak Kumar Rathore
- Immunobiology Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Samrat Chatterjee
- Complex Analysis Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Amit Awasthi
- Immunobiology Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Amit Kumar Pandey
- Mycobacterial Pathogenesis Laboratory, Translational Health Science and Technology Institute, Faridabad, Haryana, India
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16
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Murphy DM, Walsh A, Stein L, Petrasca A, Cox DJ, Brown K, Duffin E, Jameson G, Connolly SA, O'Connell F, O'Sullivan J, Basdeo SA, Keane J, Phelan JJ. Human Macrophages Activate Bystander Neutrophils' Metabolism and Effector Functions When Challenged with Mycobacterium tuberculosis. Int J Mol Sci 2024; 25:2898. [PMID: 38474145 DOI: 10.3390/ijms25052898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 02/20/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Neutrophils are dynamic cells, playing a critical role in pathogen clearance; however, neutrophil infiltration into the tissue can act as a double-edged sword. They are one of the primary sources of excessive inflammation during infection, which has been observed in many infectious diseases including pneumonia and active tuberculosis (TB). Neutrophil function is influenced by interactions with other immune cells within the inflammatory lung milieu; however, how these interactions affect neutrophil function is unclear. Our study examined the macrophage-neutrophil axis by assessing the effects of conditioned medium (MΦ-CM) from primary human monocyte-derived macrophages (hMDMs) stimulated with LPS or a whole bacterium (Mycobacterium tuberculosis) on neutrophil function. Stimulated hMDM-derived MΦ-CM boosts neutrophil activation, heightening oxidative and glycolytic metabolism, but diminishes migratory potential. These neutrophils exhibit increased ROS production, elevated NET formation, and heightened CXCL8, IL-13, and IL-6 compared to untreated or unstimulated hMDM-treated neutrophils. Collectively, these data show that MΦ-CM from stimulated hMDMs activates neutrophils, bolsters their energetic profile, increase effector and inflammatory functions, and sequester them at sites of infection by decreasing their migratory capacity. These data may aid in the design of novel immunotherapies for severe pneumonia, active tuberculosis and other diseases driven by pathological inflammation mediated by the macrophage-neutrophil axis.
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Affiliation(s)
- Dearbhla M Murphy
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - Anastasija Walsh
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - Laura Stein
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - Andreea Petrasca
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, D02 R590 Dublin, Ireland
| | - Donal J Cox
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - Kevin Brown
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - Emily Duffin
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - Gráinne Jameson
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - Sarah A Connolly
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - Fiona O'Connell
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute (TTMI), St. James's Hospital, Dublin 8, D08 W9RT Dublin, Ireland
| | - Jacintha O'Sullivan
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute (TTMI), St. James's Hospital, Dublin 8, D08 W9RT Dublin, Ireland
| | - Sharee A Basdeo
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - Joseph Keane
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
| | - James J Phelan
- Department of Clinical Medicine, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity Centre for Health Sciences, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, D08 W9RT Dublin, Ireland
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17
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Ghoshal A, Verma A, Bhaskar A, Dwivedi VP. The uncharted territory of host-pathogen interaction in tuberculosis. Front Immunol 2024; 15:1339467. [PMID: 38312835 PMCID: PMC10834760 DOI: 10.3389/fimmu.2024.1339467] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/03/2024] [Indexed: 02/06/2024] Open
Abstract
Mycobacterium tuberculosis (M.tb) effectively manipulates the host processes to establish the deadly respiratory disease, Tuberculosis (TB). M.tb has developed key mechanisms to disrupt the host cell health to combat immune responses and replicate efficaciously. M.tb antigens such as ESAT-6, 19kDa lipoprotein, Hip1, and Hsp70 destroy the integrity of cell organelles (Mitochondria, Endoplasmic Reticulum, Nucleus, Phagosomes) or delay innate/adaptive cell responses. This is followed by the induction of cellular stress responses in the host. Such cells can either undergo various cell death processes such as apoptosis or necrosis, or mount effective immune responses to clear the invading pathogen. Further, to combat the infection progression, the host secretes extracellular vesicles such as exosomes to initiate immune signaling. The exosomes can contain M.tb as well as host cell-derived peptides that can act as a double-edged sword in the immune signaling event. The host-symbiont microbiota produces various metabolites that are beneficial for maintaining healthy tissue microenvironment. In juxtaposition to the above-mentioned mechanisms, M.tb dysregulates the gut and respiratory microbiome to support its replication and dissemination process. The above-mentioned interconnected host cellular processes of Immunometabolism, Cellular stress, Host Microbiome, and Extracellular vesicles are less explored in the realm of exploration of novel Host-directed therapies for TB. Therefore, this review highlights the intertwined host cellular processes to control M.tb survival and showcases the important factors that can be targeted for designing efficacious therapy.
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Affiliation(s)
| | | | | | - Ved Prakash Dwivedi
- Immunobiology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
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18
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Kazemi S, Mirzaei R, Karampoor S, Hosseini-Fard SR, Ahmadyousefi Y, Soltanian AR, Keramat F, Saidijam M, Alikhani MY. Circular RNAs in tuberculosis: From mechanism of action to potential diagnostic biomarker. Microb Pathog 2023; 185:106459. [PMID: 37995882 DOI: 10.1016/j.micpath.2023.106459] [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: 05/25/2023] [Revised: 10/01/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023]
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), continues to be a major global health concern. Understanding the molecular intricacies of TB pathogenesis is crucial for developing effective diagnostic and therapeutic approaches. Circular RNAs (circRNAs), a class of single-stranded RNA molecules characterized by covalently closed loops, have recently emerged as potential diagnostic biomarkers in various diseases. CircRNAs have been demonstrated to modulate the host's immunological responses against TB, specifically by reducing monocyte apoptosis, augmenting autophagy, and facilitating macrophage polarization. This review comprehensively explores the roles and mechanisms of circRNAs in TB pathogenesis. We also discuss the growing body of evidence supporting their utility as promising diagnostic biomarkers for TB. By bridging the gap between fundamental circRNA biology and TB diagnostics, this review offers insights into the exciting potential of circRNAs in combatting this infectious disease.
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Affiliation(s)
- Sima Kazemi
- Infectious Disease Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Hosseini-Fard
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yaghoub Ahmadyousefi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran; Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Reza Soltanian
- Department of Biostatistics and Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Iran
| | - Fariba Keramat
- Infectious Disease Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Yousef Alikhani
- Infectious Disease Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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19
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Cheng M, Zheng Y, Fan Y, Yan P, Zhao W. The contribution of IL-17A-dependent low LCN2 levels to Helicobacter pylori infection: Insights from clinical and experimental studies. Int Immunopharmacol 2023; 124:110960. [PMID: 37722259 DOI: 10.1016/j.intimp.2023.110960] [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: 07/13/2023] [Revised: 09/04/2023] [Accepted: 09/14/2023] [Indexed: 09/20/2023]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection is a common bacterial infection that is widespread globally. It is crucial to comprehend the molecular mechanisms that underlie the infection caused by H. pylori in order to devise successful therapeutic approaches. The objective of this study was to examine the involvement of Lipocalin-2 (LCN2) in the development of H. pylori infection. METHODS LCN2 expression levels in human gastric mucosa and H. pylori-infected mouse models were analyzed using quantitative PCR and immunohistochemistry methods. The effects of LCN2 on the attachment of H. pylori to gastric mucosa cells were assessed using bacterial culture and fluorescence intensity tests. To investigate the correlation between LCN2, CCL20, and IL-17A, we performed gene expression analysis and measured serum levels. RESULTS The findings indicated an increase in LCN2 levels in the gastric mucosa of both patients and mice infected with H. pylori. Blocking the natural LCN2 resulted in an increased attachment of H. pylori to cells in the gastric mucosa. In addition, we noticed that reduced levels of LCN2 promoted the attachment of H. pylori to cells in the gastric mucosa. Furthermore, H. pylori-infected patients exhibited increased expression of both LCN2 and CCL20, and there was a positive correlation between serum levels of CCL20 and LCN2. LCN2 expression was found to depend on the presence of IL-17A, and inhibiting IL-17A led to a higher H. pylori colonization. CONCLUSION The persistence of H. pylori infection is facilitated by the presence of low levels of LCN2, which is dependent on IL-17A. This finding offers valuable perspectives for the development of novel therapeutic approaches for H. pylori infection.
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Affiliation(s)
- Mingjing Cheng
- Department of Clinical Laboratory, School of Clinical Medicine, Dali University, Dali, Yunnan, China
| | - Yong Zheng
- Department of Clinical Laboratory, First Affiliated Hospital of Dali University, Dali, Yunnan, China
| | - Yujuan Fan
- Department of Clinical Laboratory, School of Clinical Medicine, Dali University, Dali, Yunnan, China
| | - Ping Yan
- Department of Gastroenterology, First Affiliated Hospital of Dali University, Dali, Yunnan, China.
| | - Weidong Zhao
- Department of Clinical Laboratory, School of Clinical Medicine, Dali University, Dali, Yunnan, China; Department of Clinical Laboratory, Second Infectious Disease Hospital of Yunnan Province, Dali, Yunnan, China.
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20
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Li A, Bao J, Gao S, He Y, Nie X, Hosyanto FF, He X, Li T, Xu L. MicroRNA hsa-miR-320a-3p and Its Targeted mRNA FKBP5 Were Differentially Expressed in Patients with HIV/TB Co-Infection. ACS Infect Dis 2023; 9:1742-1753. [PMID: 37624586 DOI: 10.1021/acsinfecdis.3c00211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/26/2023]
Abstract
Among the PLWH (people living with HIV) population, the risk of developing active tuberculosis (TB) is increasing. Active TB also accelerates the deterioration of PLWH's immune function and is one of the leading causes of death in the PLWH population. So far, accurate diagnosis of active TB in the PLWH population remains challenging. Through data analysis of HIV/TB co-infection in the GEO database, the differentially expressed genes as well as their related microRNA (miRNA) were acquired and were further verified through clinical blood samples. Dual-luciferase assay was used to verify the mechanism of miRNA on mRNA. The enrichment of immune cells in database patient samples was analyzed by bioinformatics and finally verified by blood routine data. Our study found that FKBP5 (FK506 binding protein 5) was highly expressed in the HIV/TB co-infection group; hsa-miR-320a-3p was highly expressed in the HIV infection group but decreased in the HIV/TB co-infection group. Dual-luciferase assay results showed that hsa-miR-320a-3p mimics significantly reduced the relative luciferase activity of the WT-FKBP5 group; however, this phenomenon was not observed in the MUT-FKBP5 group. At the same time, as a key molecule of the immune-related pathway, FKBP5 is highly correlated with the amount of neutrophils, which provides a new suggestion for the treatment of the HIV/TB co-infection population. Our study found that hsa-miR-320a-3p can decrease FKBP5 expression, suggesting a potential regulatory role for FKBP5. The involvement of FKBP5 and its related molecule hsa-miR-320a-3p in HIV/TB co-infection proposes them as potential biomarkers for the diagnosis of active TB in the PLWH population.
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Affiliation(s)
- Anlong Li
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Jiajia Bao
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
- Hospital-Acquired Infection Control Department, First People's Hospital of Jintang County, Chengdu 610400, China
| | - Sijia Gao
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Ying He
- Central Laboratory, Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing 400036, China
| | - Xiaoping Nie
- Central Laboratory, Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing 400036, China
| | | | - Xintong He
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Tongxin Li
- Central Laboratory, Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing 400036, China
| | - Lei Xu
- Department of Pathogenic Biology, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
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21
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Kroon EE, Correa-Macedo W, Evans R, Seeger A, Engelbrecht L, Kriel JA, Loos B, Okugbeni N, Orlova M, Cassart P, Kinnear CJ, Tromp GC, Möller M, Wilkinson RJ, Coussens AK, Schurr E, Hoal EG. Neutrophil extracellular trap formation and gene programs distinguish TST/IGRA sensitization outcomes among Mycobacterium tuberculosis exposed persons living with HIV. PLoS Genet 2023; 19:e1010888. [PMID: 37616312 PMCID: PMC10470897 DOI: 10.1371/journal.pgen.1010888] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 08/31/2023] [Accepted: 07/26/2023] [Indexed: 08/26/2023] Open
Abstract
Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and show no evidence of immune sensitization to Mycobacterium tuberculosis (Mtb) as defined by persistently negative tuberculin skin tests (TST) and interferon gamma release assays (IGRA). This group has been identified and defined as HIV+ persistently TB, tuberculin and IGRA negative (HITTIN). To investigate potential innate mechanisms unique to individuals with the HITTIN phenotype we compared their neutrophil Mtb infection response to that of PLWH, with no TB history, but who test persistently IGRA positive, and tuberculin positive (HIT). Neutrophil samples from 17 HITTIN (PMNHITTIN) and 11 HIT (PMNHIT) were isolated and infected with Mtb H37Rv for 1h and 6h. RNA was extracted and used for RNAseq analysis. Since there was no significant differential transcriptional response at 1h between infected PMNHITTIN and PMNHIT, we focused on the 6h timepoint. When compared to uninfected PMN, PMNHITTIN displayed 3106 significantly upregulated and 3548 significantly downregulated differentially expressed genes (DEGs) (absolute cutoff of a log2FC of 0.2, FDR < 0.05) whereas PMNHIT demonstrated 3816 significantly upregulated and 3794 significantly downregulated DEGs following 6h Mtb infection. Contrasting the log2FC 6h infection response to Mtb from PMNHITTIN against PMNHIT, 2285 genes showed significant differential response between the two groups. Overall PMNHITTIN had a lower fold change response to Mtb infection compared to PMNHIT. According to pathway enrichment, Apoptosis and NETosis were differentially regulated between HITTIN and HIT PMN responses after 6h Mtb infection. To corroborate the blunted NETosis transcriptional response measured among HITTIN, fluorescence microscopy revealed relatively lower neutrophil extracellular trap formation and cell loss in PMNHITTIN compared to PMNHIT, showing that PMNHITTIN have a distinct response to Mtb.
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Affiliation(s)
- Elouise E. Kroon
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Wilian Correa-Macedo
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada
- McGill International TB Centre, McGill University, Montréal, Canada
- Department of Biochemistry, McGill University, Montréal, Canada
| | - Rachel Evans
- Infectious Diseases and Immune Defence Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department Medical Biology (WEHI), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
| | - Allison Seeger
- Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Observatory, South Africa
| | - Lize Engelbrecht
- Central Analytical Facilities, Microscopy Unit, Stellenbosch University, Cape Town, South Africa
| | - Jurgen A. Kriel
- Central Analytical Facilities, Microscopy Unit, Stellenbosch University, Cape Town, South Africa
| | - Ben Loos
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Naomi Okugbeni
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- South African Medical Research Council Genomics Platform, Tygerberg, South Africa
| | - Marianna Orlova
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada
- McGill International TB Centre, McGill University, Montréal, Canada
- Department of Biochemistry, McGill University, Montréal, Canada
| | - Pauline Cassart
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada
- McGill International TB Centre, McGill University, Montréal, Canada
| | - Craig J. Kinnear
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- South African Medical Research Council Genomics Platform, Tygerberg, South Africa
| | - Gerard C. Tromp
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Centre for Bioinformatics and Computational Biology, University of Stellenbosch, Cape Town, South Africa
- SAMRC-SHIP South African Tuberculosis Bioinformatics Initiative (SATBBI), Center for Bioinformatics and Computational Biology, Cape Town, South Africa
| | - Marlo Möller
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Centre for Bioinformatics and Computational Biology, University of Stellenbosch, Cape Town, South Africa
| | - Robert J. Wilkinson
- Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Observatory, South Africa
- Department of Infectious Diseases, Imperial College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
| | - Anna K. Coussens
- Infectious Diseases and Immune Defence Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department Medical Biology (WEHI), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
- Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Observatory, South Africa
| | - Erwin Schurr
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada
- McGill International TB Centre, McGill University, Montréal, Canada
- Department of Biochemistry, McGill University, Montréal, Canada
| | - Eileen G. Hoal
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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22
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Wang PH, Lin SY, Liou HH, Chen CC, Shu CC, Lee CY, Tsai MK, Yu CJ. Protective Effect of BCG and Neutrophil-to-Lymphocyte Ratio on Latent Tuberculosis in End Stage Renal Disease. Infect Dis Ther 2023:10.1007/s40121-023-00839-5. [PMID: 37410344 PMCID: PMC10390420 DOI: 10.1007/s40121-023-00839-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 06/21/2023] [Indexed: 07/07/2023] Open
Abstract
INTRODUCTION Bacillus Calmette-Guérin (BCG) vaccination has been reported to be protective against latent tuberculosis infection (LTBI) in the general population. The aim of this study was to investigate the protective effect of BCG vaccination against LTBI in adult patients with end-stage renal disease (ESRD) and renal transplants. METHODS Patients aged ≥ 20 years with ESRD who received hemodialysis (HD), peritoneal dialysis (PD) or kidney transplant were enrolled from January 2012 to December 2019 at a medical center and a regional hemodialysis center. Patients with active tuberculosis (TB), previously treated TB, active immunosuppressant therapy or human immunodeficiency virus infection were excluded. LTBI status was determined by QuantiFERON-TB Gold In-tube (QFT-GIT). RESULTS After the exclusion of indeterminate results of QFT-GIT, 517 participants were enrolled and 97 (18.8%) were identified as having LTBI. Participants with LTBI were older (55.1 ± 11.4 vs. 48.5 ± 14.6 years, p < 0.001) and had a significantly higher proportion receiving HD than those without LTBI (70.1% vs. 56.7%, p = 0.001). The percentage with BCG scars was higher in the non-LTBI group than in the LTBI group (94.8% vs. 81.4%, p < 0.001), whereas the neutrophil-to-lymphocyte ratio (NLR) (≥ 2.68) was significantly higher in the LTBI group (62.8% vs. 45.5%, p = 0.02). By multivariate logistic regression analysis, presence of BCG scar and high NLR were independent protective factors against LTBI [adjusted OR: 0.19 (0.063-0.58, p = 0.001) and 0.50 (0.28-0.89, p = 0.02)]. CONCLUSION The prevalence of LTBI was as high as 18.8% in patients with end-stage kidney disease or kidney transplant. BCG vaccination and high NLR might have protective effects against LTBI in patients with renal failure or transplant.
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Affiliation(s)
- Ping-Huai Wang
- Division of Thoracic Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shu-Yung Lin
- Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung Shan South Road, Taipei, Taiwan
- College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hung-Hsiang Liou
- Division of Nephrology, Department of Internal Medicine, Hsin-Jen Hospital, New Taipei City, Taiwan
| | - Chien-Chia Chen
- College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital, No 7, Chung Shan South Road, Taipei, Taiwan
| | - Chin-Chung Shu
- Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung Shan South Road, Taipei, Taiwan.
- College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - Chih-Yuan Lee
- College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Surgery, National Taiwan University Hospital, No 7, Chung Shan South Road, Taipei, Taiwan.
| | - Meng-Kun Tsai
- College of Medicine, National Taiwan University, Taipei, Taiwan
- National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Chong-Jen Yu
- College of Medicine, National Taiwan University, Taipei, Taiwan
- National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan
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23
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Arora A, Singh A. Exploring the role of neutrophils in infectious and noninfectious pulmonary disorders. Int Rev Immunol 2023; 43:41-61. [PMID: 37353973 DOI: 10.1080/08830185.2023.2222769] [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: 03/25/2022] [Accepted: 05/31/2023] [Indexed: 06/25/2023]
Abstract
With the change in global environment, respiratory disorders are becoming more threatening to the health of people all over the world. These diseases are closely linked to performance of immune system. Within the innate arm of immune system, Neutrophils are an important moiety to serve as an immune defense barrier. They are one of the first cells recruited to the site of infection and plays a critical role in pathogenesis of various pulmonary diseases. It is established that the migration and activation of neutrophils can lead to inflammation either directly or indirectly and this inflammation caused is very crucial for the clearance of pathogens and resolution of infection. However, the immunopathological mechanisms involved to carry out the same is very complex and not well understood. Despite there being studies concentrating on the role of neutrophils in multiple respiratory diseases, there is still a long way to go in order to completely understand the complexity of the participation of neutrophils and mechanisms involved in the development of these respiratory diseases. In the present article, we have reviewed the literature to comprehensively provide an insight in the current development and advancements about the role of neutrophils in infectious respiratory disorders including viral respiratory disorders such as Coronavirus disease (COVID-19) and bacterial pulmonary disorders with a focused review on pulmonary tuberculosis as well as in noninfectious disorders like Chronic obstructive pulmonary disease (COPD) and asthma. Also, future directions into research and therapeutic targets have been discussed for further exploration.
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Affiliation(s)
- Alisha Arora
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Archana Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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24
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Acen EL, Worodria W, Kateete DP, Olum R, Joloba ML, Akintola A, Bbuye M, Andia IB. Association of circulating serum free bioavailable and total vitamin D with cathelicidin levels among active TB patients and household contacts. Sci Rep 2023; 13:5365. [PMID: 37005478 PMCID: PMC10067953 DOI: 10.1038/s41598-023-32543-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 03/29/2023] [Indexed: 04/04/2023] Open
Abstract
The free hormone hypothesis postulates that the estimation of free circulating 25 (OH)D may be a better marker of vitamin D status and is of clinical importance compared to total vitamin D fraction. The unbound fraction is involved in biological activities since it is able to penetrate into the cell. Studies have shown that cathelicidin/LL-37 inhibits the growth of Mycobacterium tuberculosis in a vitamin D-dependent manner and therefore adequate vitamin D is required for its expression. The study aimed to determine the association between serum bioavailable and total vitamin D with LL-37 levels in ATB patients, LTBI, and individuals with no TB infection. This was a cross-sectional study in which bioavailable vitamin D and LL-37 levels were measured using competitive ELISA kits and total vitamin D was measured using electrochemilumiscence and consequently determined their association. The mean (SD) bioavailable vitamin D levels of the study participants were 3.8 ng/mL (2.6) and the median (IQR) of LL-37 levels were 320 ng/mL (160, 550 ng/mL). The mean (SD) of total vitamin D levels was 19.0 ng/mL (8.3) ng/mL. Similar weak correlations were observed between the bioavailable and total vitamin D with LL-37 levels, therefore, deviating from our hypothesis.
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Affiliation(s)
- Ester Lilian Acen
- Department of Physiology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda.
| | - William Worodria
- Pulmonary Division, Department of Internal Medicine, Mulago National Referral Hospital, Kampala, Uganda
| | - David Patrick Kateete
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Ronald Olum
- Department of Internal Medicine, School of Medicine, College of Health Sciences Unit, Makerere University, Kampala, Uganda
| | - Moses L Joloba
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Ashraf Akintola
- Department of Biomedical Convergence Science and Technology, School of Industrial Technology Advances, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Mudarshiru Bbuye
- Makerere Lung Institute College of Health Sciences, Makerere University, Kampala, Uganda
| | - Irene Biraro Andia
- Department of Internal Medicine, School of Medicine, College of Health Sciences Unit, Makerere University, Kampala, Uganda
- Medical Research Council, Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
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25
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Anwar MC, Budiono I, Putriningtyas ND, Nisa AA, Santjaka A, Suswandany DL. The efficacy of Bloso fish (Glossogobius giuris sp.) in improving hemoglobin, hematocrit, platelet, and albumin levels of Wistar rats with hypoalbuminemia. POTRAVINARSTVO 2023. [DOI: 10.5219/1847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023] Open
Abstract
Tuberculosis (TB) is an infectious disease worldwide that causes death. Common clinical manifestations of patients with TB include anemia, hypoalbuminemia, and malnutrition. Most patients with TB are infected with coccus bacteria, such as Staphylococcus aureus, that commonly attack the respiratory tract. However, the consumption of heme protein sources could improve the nutritional status of patients with TB. Fish comprise one of the most widely consumed sources of heme. The bloso fish (Glossogobius giuris sp.), considered a fish without economic value is a new alternative source of heme protein. This study aimed to develop supplements using bloso fish (Glossogobius giuris sp.). This study used an experimental pretest-post-test control group design. Seven male Wistar rats were used as the negative control group. Twenty- eight male Wistar rats were administered S. aureus, fed a protein-deficient diet, and divided into the positive control group, the K1 group, which received up to 675 mg/200 g of bloso fish flour, the K2 group, which received up to 67.5 mg/200 g of bloso fish oil, and the K3 group, which received up to 675 mg/200 g of bloso fish fluor from oil extraction dregs. Treatment was administered for 28 days. The hemoglobin (Hb), hematocrit (Ht), platelet, and albumin levels in blood serum from the retroorbital vein were measured. Data were processed using a paired t-test and one-way analysis of variance. The results showed differences in Hb, Ht, platelet, and albumin levels were observed before and after treatment. Additionally, differences in Hb, Ht, platelet, and albumin levels were observed in the groups that received bloso fish flour and bloso fish oil. Bloso fish flour and bloso fish oil increased the Hb, Ht, platelet, and albumin levels of rats with hypoalbuminemia.
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26
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Alkarni M, Lipman M, Lowe DM. The roles of neutrophils in non-tuberculous mycobacterial pulmonary disease. Ann Clin Microbiol Antimicrob 2023; 22:14. [PMID: 36800956 PMCID: PMC9938600 DOI: 10.1186/s12941-023-00562-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 01/30/2023] [Indexed: 02/19/2023] Open
Abstract
Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) is an increasingly recognised global health issue. Studies have suggested that neutrophils may play an important role in controlling NTM infection and contribute to protective immune responses within the early phase of infection. However, these cells are also adversely associated with disease progression and exacerbation and can contribute to pathology, for example in the development of bronchiectasis. In this review, we discuss the key findings and latest evidence regarding the diverse functions of neutrophils in NTM infection. First, we focus on studies that implicate neutrophils in the early response to NTM infection and the evidence reporting neutrophils' capability to kill NTM. Next, we present an overview of the positive and negative effects that characterise the bidirectional relationship between neutrophils and adaptive immunity. We consider the pathological role of neutrophils in driving the clinical phenotype of NTM-PD including bronchiectasis. Finally, we highlight the current promising treatments in development targeting neutrophils in airways diseases. Clearly, more insights on the roles of neutrophils in NTM-PD are needed in order to inform both preventative strategies and host-directed therapy for these important infections.
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Affiliation(s)
- Meyad Alkarni
- grid.83440.3b0000000121901201Institute of Immunity and Transplantation, University College London, Pears Building, Rowland Hill Street, London, NW3 2PP UK
| | - Marc Lipman
- grid.83440.3b0000000121901201UCL Respiratory, University College London, London, UK
| | - David M. Lowe
- grid.83440.3b0000000121901201Institute of Immunity and Transplantation, University College London, Pears Building, Rowland Hill Street, London, NW3 2PP UK
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27
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Flores-Villalva S, Remot A, Carreras F, Winter N, Gordon SV, Meade KG. Vitamin D induced microbicidal activity against Mycobacterium bovis BCG is dependent on the synergistic activity of bovine peripheral blood cell populations. Vet Immunol Immunopathol 2023; 256:110536. [PMID: 36586390 DOI: 10.1016/j.vetimm.2022.110536] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/17/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
A growing appreciation is emerging of the beneficial role of vitamin D for health and resistance against infectious diseases, including tuberculosis. However, research has predominantly focused on murine and human species and functional data in bovines is limited. Therefore, the objective of this study was to assess the microbicidal activity and immunoregulatory effect of the vitamin D metabolite 1,25(OH)2D3 on bovine peripheral blood leukocytes (PBL) in response to Mycobacterium bovis BCG (BCG) infection using a combination of functional assays and gene expression profiling. Blood from Holstein-Friesian bull calves with low circulating levels of 25(OH)D was stimulated with 1,25(OH)2D3 for 2 h, and then infected with M. bovis BCG. Results showed that 1,25(OH)2D3 supplementation significantly increased BCG killing by on average 16 %, although responses varied between 1 % and 38 % killing. Serial cell subset depletion was then performed on PBL prior to 1,25(OH)2D3 incubation and BCG infected as before to analyse the contribution of major cell types to mycobacterial growth control. Specific antibodies and either magnetic cell separation or density gradient centrifugation of monocytes, granulocytes, CD3+, CD4+, and CD8+ T lymphocytes were used to capture each cell subset. Results showed that depletion of granulocytes had the greatest impact on BCG growth, leading to a significant enhancement of bacterial colonies. In contrast, depletion of CD4+ or CD8+ T cells individually, or in combination (CD3+), had no impact on mycobacterial growth control. In agreement with our previous data, 1,25(OH)2D3 significantly increased bacterial killing in PBL, in monocyte depleted samples, and a similar trend was observed in the granulocyte depleted subset. In addition, specific analysis of sorted neutrophils treated with 1,25(OH)2D3 showed an enhanced microbicidal activity against both BCG and a virulent strain of M. bovis. Lastly, data showed that 1,25(OH)2D3 stimulation increased reactive oxygen species (ROS) production and the expression of genes encoding host defence peptides (HDP) and pathogen recognition receptors (PRRs), factors that play an important role in the microbicidal activity against mycobacteria. In conclusion, the vitamin D metabolite 1,25(OH)2D3 improves antimycobacterial killing in bovine PBLs via the synergistic activity of monocytes and granulocytes and enhanced activation of innate immunity.
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Affiliation(s)
- Susana Flores-Villalva
- School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland; CENID Fisiología, INIFAP, Querétaro, Mexico
| | - Aude Remot
- INRAE, Université de Tours, ISP, F-37380 Nouzilly, France
| | | | | | - Stephen V Gordon
- UCD School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland
| | - Kieran G Meade
- School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; Institute of Food and Health, University College Dublin, Belfield, Dublin 4, Ireland.
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28
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Peruhype-Magalhães V, de Araújo FF, de Morais Papini TF, Wendling APB, Campi-Azevedo AC, Coelho-Dos-Reis JG, de Almeida IN, do Valle Antonnelli LR, Amaral LR, de Souza Gomes M, Brito-de-Sousa JP, Elói-Santos SM, Augusto VM, Pretti Dalcolmo MM, Carneiro CM, Teixeira-Carvalho A, Martins-Filho OA. Serum biomarkers in patients with unilateral or bilateral active pulmonary tuberculosis: Immunological networks and promising diagnostic applications. Cytokine 2023; 162:156076. [PMID: 36417816 DOI: 10.1016/j.cyto.2022.156076] [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: 04/05/2022] [Revised: 10/08/2022] [Accepted: 10/14/2022] [Indexed: 11/21/2022]
Abstract
The present observational study was designed to characterize the integrative profile of serum soluble mediators to describe the immunological networks associated with clinical findings and identify putative biomarkers for diagnosis and prognosis of active tuberculosis. The study population comprises 163 volunteers, including 84 patients with active pulmonary tuberculosis/(TB), and 79 controls/(C). Soluble mediators were measured by multiplexed assay. Data analysis demonstrated that the levels of CCL3, CCL5, CXCL10, IL-1β, IL-6, IFN-γ, IL-1Ra, IL-4, IL-10, PDGF, VEGF, G-CSF, IL-7 were increased in TB as compared to C. Patients with bilateral pulmonary involvement/(TB-BI) exhibited higher levels of CXCL8, IL-6 and TNF with distinct biomarker signatures (CCL11, CCL2, TNF and IL-10) as compared to patients with unilateral infiltrates/(TB-UNI). Analysis of biomarker networks based in correlation power graph demonstrated small number of strong connections in TB and TB-BI. The search for biomarkers with relevant implications to understand the pathogenetic mechanisms and useful as complementary diagnosis tool of active TB pointed out the excellent performance of single analysis of IL-6 or CXCL10 and the stepwise combination of IL-6 → CXCL10 (Accuracy = 84 %; 80 % and 88 %, respectively). Together, our finding demonstrated that immunological networks of serum soluble biomarkers in TB patients differ according to the unilateral or bilateral pulmonary involvement and may have relevant implications to understand the pathogenetic mechanisms involved in the clinical outcome of Mtb infection.
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Affiliation(s)
- Vanessa Peruhype-Magalhães
- Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais, Brazil
| | - Fernanda Fortes de Araújo
- Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais, Brazil
| | - Tatiane Figueiredo de Morais Papini
- Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais, Brazil; Pós-graduação em Ciências Farmacêuticas (CIPHARMA), Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Ana Paula Barbosa Wendling
- Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais, Brazil
| | - Ana Carolina Campi-Azevedo
- Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais, Brazil
| | - Jordana Grazziela Coelho-Dos-Reis
- Laboratório de Virologia Básica e Aplicada, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Isabela Neves de Almeida
- Departamento de Análises Clínicas, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Lis Ribeiro do Valle Antonnelli
- Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias, Instituto René Rachou - FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil
| | - Laurence Rodrigues Amaral
- Rede Multidisciplinar de Pesquisa, Ciência e Tecnologia, Laboratório de Bioinformática e Análises Moleculares, Universidade Federal de Uberlândia, Campus Patos de Minas, Patos de Minas, MG, Brazil
| | - Matheus de Souza Gomes
- Rede Multidisciplinar de Pesquisa, Ciência e Tecnologia, Laboratório de Bioinformática e Análises Moleculares, Universidade Federal de Uberlândia, Campus Patos de Minas, Patos de Minas, MG, Brazil
| | - Joaquim Pedro Brito-de-Sousa
- Pós-graduação em Imunologia e Parasitologia Aplicadas (PPIPA), Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, Brazil
| | - Silvana Maria Elói-Santos
- Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais, Brazil; Departamento de Propedêutica Complementar, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Valéria Maria Augusto
- Departamento de Propedêutica Complementar, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Margareth Maria Pretti Dalcolmo
- Escola Nacional de Saúde Pública, Centro de Referência Professor Hélio Fraga, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Cláudia Martins Carneiro
- Pós-graduação em Ciências Farmacêuticas (CIPHARMA), Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil; Departamento de Análises Clínicas, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Andréa Teixeira-Carvalho
- Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais, Brazil.
| | - Olindo Assis Martins-Filho
- Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais, Brazil.
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Udinia S, Suar M, Kumar D. Host-directed therapy against tuberculosis: Concept and recent developments. J Biosci 2023; 48:54. [PMID: 38088376 DOI: 10.1007/s12038-023-00374-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 02/28/2023] [Indexed: 01/04/2025]
Abstract
Tuberculosis (TB) continues to remain at the forefront of the infectious disease burden globally, albeit with some aberrations during the COVID-19 pandemic. Among many factors, the emergence of drug resistance or antimicrobial resistance (AMR) has necessitated a renewed focus on developing novel and repurposed drugs against TB. Host-directed therapy (HDT) has emerged as an attractive alternative and a complementary strategy to the conventional antibiotic-based therapy of tuberculosis since HDT enjoys the advantage of disarming the pathogen of its ability to develop drug resistance. Considering the imminent threat of AMR across the spectrum of bacterial pathogens, HDT promises to overcome the drug shortage against superbugs. While all these make HDT a very attractive strategy, identifying the right set of host targets to develop HDT remains a challenge, despite remarkable development in the field over the past decade. In this review, we examine the host mechanisms, that either inadvertently or through targeted perturbation by the pathogen, help TB pathogenesis, and we discuss the latest developments in the targeting of some of the key pathways to achieve newer TB therapeutics.
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Affiliation(s)
- Sonakshi Udinia
- Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
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Gaffney E, Murphy D, Walsh A, Connolly S, Basdeo SA, Keane J, Phelan JJ. Defining the role of neutrophils in the lung during infection: Implications for tuberculosis disease. Front Immunol 2022; 13:984293. [PMID: 36203565 PMCID: PMC9531133 DOI: 10.3389/fimmu.2022.984293] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/30/2022] [Indexed: 11/25/2022] Open
Abstract
Neutrophils are implicated in the pathogenesis of many diseases involving inflammation. Neutrophils are also critical to host defence and have a key role in the innate immune response to infection. Despite their efficiencies against a wide range of pathogens however, their ability to contain and combat Mycobacterium tuberculosis (Mtb) in the lung remains uncertain and contentious. The host response to Mtb infection is very complex, involving the secretion of various cytokines and chemokines from a wide variety of immune cells, including neutrophils, macrophages, monocytes, T cells, B cells, NK cells and dendritic cells. Considering the contributing role neutrophils play in the advancement of many diseases, understanding how an inflammatory microenvironment affects neutrophils, and how neutrophils interact with other immune cells, particularly in the context of the infected lung, may aid the design of immunomodulatory therapies. In the current review, we provide a brief overview of the mechanisms that underpin pathogen clearance by neutrophils and discuss their role in the context of Mtb and non-Mtb infection. Next, we examine the current evidence demonstrating how neutrophils interact with a range of human and non-human immune cells and how these interactions can differentially prime, activate and alter a repertoire of neutrophil effector functions. Furthermore, we discuss the metabolic pathways employed by neutrophils in modulating their response to activation, pathogen stimulation and infection. To conclude, we highlight knowledge gaps in the field and discuss plausible novel drug treatments that target host neutrophil metabolism and function which could hold therapeutic potential for people suffering from respiratory infections.
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Wu DW, Cheng YC, Wang CW, Hung CH, Chen PS, Chu-Sung Hu S, Richard Lin CH, Chen SC, Kuo CH. Impact of the synergistic effect of pneumonia and air pollutants on newly diagnosed pulmonary tuberculosis in southern Taiwan. ENVIRONMENTAL RESEARCH 2022; 212:113215. [PMID: 35367429 DOI: 10.1016/j.envres.2022.113215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 03/10/2022] [Accepted: 03/26/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND An increased incidence of pulmonary tuberculosis (PTB) among patients with pulmonary diseases exposed to air pollution has been reported. OBJECTIVE To comprehensively investigate the association between pneumonia (PN) and air pollution with PTB through a large-scale follow-up study. METHODS We conducted a retrospective study using data from the Kaohsiung Medical University Hospital Research Database and the Taiwan Air Quality Monitoring Database. We included adult patients with PN, PTB and other comorbidities according to ICD-9 codes. Control subjects without PN were matched by age, sex and ten comorbidities to each PN patient at a ratio of 4:1. RESULTS A total of 82,590 subjects were included. The PTB incidence rate was significantly higher in the PN group (2,391/100,000) than in the control group (1,388/100,000). The crude hazard ratio (HR) of PN-associated PTB incidence decreased with time, and the overall 7 years the HR (95% confidence interval; CI) was 1.74 (1.55-1.96). The overall adjusted HR and 95% CI of PN-related PTB in the multivariate Cox regression analysis was 3.38 (2.98-3.84). In addition, there was a cumulative lag effect of all air pollutants within 30 days of exposure. The peak adjusted HRs for PTB were noted on the 3rd, 8th, 12th and 12th days of PM2.5, O3, SO2 and NO exposure, respectively. The overall peak HRs (95% CI) of PM2.5, O3, SO2 and NO were 1.145 (1.139-1.152), 1.153 (1.145-1.161), 1.909 (1.839-1.982) and 1.312 (1.259-1.367), respectively, and there was a synergistic effect with pneumonia on the risk of PTB. CONCLUSIONS A strong association was found between past episodes of PN and the future risk of PTB. In addition, air pollutants including PM2.5, SO2, O3 and NO, together with previous episodes of PN, had both long-term and short-term impact on the incidence of PTB.
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Affiliation(s)
- Da-Wei Wu
- Doctoral Degree Program, Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, 812, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Yu-Cheng Cheng
- Department of Computer Science and Engineering, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan
| | - Chih-Wen Wang
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, 812, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Chih-Hsing Hung
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Pei-Shih Chen
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Institute of Environmental Engineering, College of Engineering, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Stephen Chu-Sung Hu
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan; Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Dermatology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, 807, Taiwan
| | - Chun-Hung Richard Lin
- Department of Computer Science and Engineering, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
| | - Szu-Chia Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, 812, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
| | - Chao-Hung Kuo
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, 812, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
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Assessment of Paratuberculosis Vaccination Effect on In Vitro Formation of Neutrophil Extracellular Traps in a Sheep Model. Vaccines (Basel) 2022; 10:vaccines10091403. [PMID: 36146481 PMCID: PMC9501304 DOI: 10.3390/vaccines10091403] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Vaccination of domestic ruminants against paratuberculosis has been related to homologous and heterologous protective effects that have been attributed to the establishment of a trained immune response. Recent evidence suggests that neutrophils could play a role in its development. Therefore, we propose an in vitro model for the study of the effect of paratuberculosis vaccination on the release of neutrophil extracellular traps (NETs) in sheep. Ovine neutrophils were obtained from non-vaccinated (n = 5) and vaccinated sheep (n = 5) at different times post-vaccination and infected in vitro with Mycobacterium avium subsp. paratuberculosis (Map), Staphylococcus aureus (SA), and Escherichia coli (EC). NETs release was quantified by fluorimetry and visualized by immunofluorescence microscopy. Typical NETs components (DNA, neutrophil elastase, and myeloperoxidase) were visualized extracellularly in all infected neutrophils; however, no significant percentage of extracellular DNA was detected in Map-infected neutrophils compared with SA- and EC-infected. In addition, no significant effect was detected in relation to paratuberculosis vaccination. Further assays to study NETs release in ovine neutrophils are needed. Preliminary results suggest no implication of NETs formation in the early immune response after vaccination, although other neutrophil functions should be evaluated.
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Gupta M, Srikrishna G, Klein SL, Bishai WR. Genetic and hormonal mechanisms underlying sex-specific immune responses in tuberculosis. Trends Immunol 2022; 43:640-656. [PMID: 35842266 PMCID: PMC9344469 DOI: 10.1016/j.it.2022.06.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/06/2022] [Accepted: 06/13/2022] [Indexed: 11/24/2022]
Abstract
Tuberculosis (TB), the world's deadliest bacterial infection, afflicts more human males than females, with a male/female (M/F) ratio of 1.7. Sex disparities in TB prevalence, pathophysiology, and clinical manifestations are widely reported, but the underlying biological mechanisms remain largely undefined. This review assesses epidemiological data on sex disparity in TB, as well as possible underlying hormonal and genetic mechanisms that might differentially modulate innate and adaptive immune responses in males and females, leading to sex differences in disease susceptibility. We consider whether this sex disparity can be extended to the efficacy of vaccines and discuss novel animal models which may offer mechanistic insights. A better understanding of the biological factors underpinning sex-related immune responses in TB may enable sex-specific personalized therapies for TB.
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Rankin AN, Hendrix SV, Naik SK, Stallings CL. Exploring the Role of Low-Density Neutrophils During Mycobacterium tuberculosis Infection. Front Cell Infect Microbiol 2022; 12:901590. [PMID: 35800386 PMCID: PMC9253571 DOI: 10.3389/fcimb.2022.901590] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/23/2022] [Indexed: 12/14/2022] Open
Abstract
Tuberculosis (TB) is caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), which primarily infects the lungs but can also cause extrapulmonary disease. Both the disease outcome and the pathology of TB are driven by the immune response mounted by the host. Infection with Mtb elicits inflammatory host responses that are necessary to control infection, but can also cause extensive tissue damage when in excess, and thus must be precisely balanced. In particular, excessive recruitment of neutrophils to the site of infection has been associated with poor control of Mtb infection, prompting investigations into the roles of neutrophils in TB disease outcomes. Recent studies have revealed that neutrophils can be divided into subpopulations that are differentially abundant in TB disease states, highlighting the potential complexities in determining the roles of neutrophils in Mtb infection. Specifically, neutrophils can be separated into normal (NDN) and low-density neutrophils (LDNs) based on their separation during density gradient centrifugation and surface marker expression. LDNs are present in higher numbers during active TB disease and increase in frequency with disease progression, although their direct contribution to TB is still unknown. In addition, the abundance of LDNs has also been associated with the severity of other lung infections, including COVID-19. In this review, we discuss recent findings regarding the roles of LDNs during lung inflammation, emphasizing their association with TB disease outcomes. This review highlights the importance of future investigations into the relationship between neutrophil diversity and TB disease severity.
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Sholeye AR, Williams AA, Loots DT, Tutu van Furth AM, van der Kuip M, Mason S. Tuberculous Granuloma: Emerging Insights From Proteomics and Metabolomics. Front Neurol 2022; 13:804838. [PMID: 35386409 PMCID: PMC8978302 DOI: 10.3389/fneur.2022.804838] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 02/24/2022] [Indexed: 12/24/2022] Open
Abstract
Mycobacterium tuberculosis infection, which claims hundreds of thousands of lives each year, is typically characterized by the formation of tuberculous granulomas — the histopathological hallmark of tuberculosis (TB). Our knowledge of granulomas, which comprise a biologically diverse body of pro- and anti-inflammatory cells from the host immune responses, is based mainly upon examination of lungs, in both human and animal studies, but little on their counterparts from other organs of the TB patient such as the brain. The biological heterogeneity of TB granulomas has led to their diverse, relatively uncoordinated, categorization, which is summarized here. However, there is a pressing need to elucidate more fully the phenotype of the granulomas from infected patients. Newly emerging studies at the protein (proteomics) and metabolite (metabolomics) levels have the potential to achieve this. In this review we summarize the diverse nature of TB granulomas based upon the literature, and amplify these accounts by reporting on the relatively few, emerging proteomics and metabolomics studies on TB granulomas. Metabolites (for example, trimethylamine-oxide) and proteins (such as the peptide PKAp) associated with TB granulomas, and knowledge of their localizations, help us to understand the resultant phenotype. Nevertheless, more multidisciplinary ‘omics studies, especially in human subjects, are required to contribute toward ushering in a new era of understanding of TB granulomas – both at the site of infection, and on a systemic level.
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Affiliation(s)
- Abisola Regina Sholeye
- Department of Biochemistry, Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Aurelia A. Williams
- Department of Biochemistry, Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Du Toit Loots
- Department of Biochemistry, Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - A. Marceline Tutu van Furth
- Department of Pediatric Infectious Diseases and Immunology, Pediatric Infectious Diseases and Immunology, Amsterdam University Medical Center, Emma Children's Hospital, Amsterdam, Netherlands
| | - Martijn van der Kuip
- Department of Pediatric Infectious Diseases and Immunology, Pediatric Infectious Diseases and Immunology, Amsterdam University Medical Center, Emma Children's Hospital, Amsterdam, Netherlands
| | - Shayne Mason
- Department of Biochemistry, Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
- *Correspondence: Shayne Mason
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Larsen SE, Williams BD, Rais M, Coler RN, Baldwin SL. It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity. Front Immunol 2022; 13:840225. [PMID: 35359957 PMCID: PMC8960931 DOI: 10.3389/fimmu.2022.840225] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/08/2022] [Indexed: 11/18/2022] Open
Abstract
Despite co-evolving with humans for centuries and being intensely studied for decades, the immune correlates of protection against Mycobacterium tuberculosis (Mtb) have yet to be fully defined. This lapse in understanding is a major lag in the pipeline for evaluating and advancing efficacious vaccine candidates. While CD4+ T helper 1 (TH1) pro-inflammatory responses have a significant role in controlling Mtb infection, the historically narrow focus on this cell population may have eclipsed the characterization of other requisite arms of the immune system. Over the last decade, the tuberculosis (TB) research community has intentionally and intensely increased the breadth of investigation of other immune players. Here, we review mechanistic preclinical studies as well as clinical anecdotes that suggest the degree to which different cell types, such as NK cells, CD8+ T cells, γ δ T cells, and B cells, influence infection or disease prevention. Additionally, we categorically outline the observed role each major cell type plays in vaccine-induced immunity, including Mycobacterium bovis bacillus Calmette-Guérin (BCG). Novel vaccine candidates advancing through either the preclinical or clinical pipeline leverage different platforms (e.g., protein + adjuvant, vector-based, nucleic acid-based) to purposefully elicit complex immune responses, and we review those design rationales and results to date. The better we as a community understand the essential composition, magnitude, timing, and trafficking of immune responses against Mtb, the closer we are to reducing the severe disease burden and toll on human health inflicted by TB globally.
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Affiliation(s)
- Sasha E. Larsen
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States
| | - Brittany D. Williams
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States,Department of Global Health, University of Washington, Seattle, WA, United States
| | - Maham Rais
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States
| | - Rhea N. Coler
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States,Department of Global Health, University of Washington, Seattle, WA, United States,Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
| | - Susan L. Baldwin
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States,*Correspondence: Susan L. Baldwin,
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Feng H, Yan L, Zhao Y, Li Z, Kang J. Neutrophils in Bronchoalveolar Lavage Fluid Indicating the Severity and Relapse of Pulmonary Sarcoidosis. Front Med (Lausanne) 2022; 8:787681. [PMID: 35186971 PMCID: PMC8847269 DOI: 10.3389/fmed.2021.787681] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/31/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Pulmonary sarcoidosis is a highly heterogeneous granulomatous disease without any specific symptoms and manifestations. Neutrophils in bronchoalveolar lavage fluid (BALF) have been proposed to indicate the severity and prognosis of pulmonary sarcoidosis, but this needs confirmation in patients from different populations due to the heterogeneity of the disease. This study aimed to determine the characteristics of patients with pulmonary sarcoidosis in northeastern China and to explore the relationship between neutrophils in BALF and the severity of pulmonary sarcoidosis. METHODS We enrolled 432 patients who were diagnosed with pulmonary sarcoidosis in this retrospective study. The symptoms, extrapulmonary involvement, forced vital capacity percentage predicted (FVC % pred), and diffusing capacity of the lung for carbon monoxide percentage predicted (DLco % pred) were recorded. BAL was performed in 319 patients, and the results of a cellular examination of BALF were collected. A total of 123 patients who received corticosteroid treatment were followed up for at least 12 months, and the outcomes were recorded. RESULTS Cough was the most common symptom, and cutaneous involvement was the most common extrapulmonary manifestation in 304 (70.4%) and 82 (19.0%) patients, respectively. The percentages of patients with high neutrophil counts in BALF (>3%) were higher at Stages 2 and 3 compared with Stages 0 and 1 (33.2 vs. 19.4%, p = 0.007), although the percentages of neutrophils in BALF showed no difference between patients at Stages 0, 1, 2, and 3. Patients with high neutrophil counts in BALF had lower FVC % pred compared with the other patients (79.5 ± 18.2 vs. 84.9 ± 14.5%, p = 0.025) and were prone to relapse after corticosteroids were tapered. High neutrophil counts in BALF were independently associated with relapse after corticosteroids were tapered in a binary logistic regression analysis (p = 0.027). CONCLUSIONS Patients with pulmonary sarcoidosis lacked specific symptoms and manifestations. The neutrophil count in BALF could indicate the severity and outcomes of pulmonary sarcoidosis.
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Affiliation(s)
- Haoshen Feng
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lili Yan
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Yabin Zhao
- Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenhua Li
- Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jian Kang
- Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
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Santos AP, Ribeiro-Alves M, Corrêa R, Lopes I, Silva MA, Mafort TT, Leung J, Rodrigues LS, Rufino R. Hyporexia and cellular/biochemical characteristics of pleural fluid as predictive variables on a model for pleural tuberculosis diagnosis. J Bras Pneumol 2022; 48:e20210245. [PMID: 34909921 PMCID: PMC8946557 DOI: 10.36416/1806-3756/e20210245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/28/2021] [Indexed: 12/04/2022] Open
Abstract
Objectives Pleural tuberculosis (PlTB) diagnosis is a challenge due to its paucibacillary nature and to the need of invasive procedures. This study aimed to identify easily available variables and build a predictive model for PlTB diagnosis which may allow earlier and affordable alternative strategy to be used in basic health care units. Methods An observational cross-sectional study compared PlTB and non-TB patients followed at a tertiary Brazilian hospital between 2010 and 2018. Unconditional logistic regression analysis was performed and a Decision Tree Classifier (DTC) model was validated and applied in additional PlTB patients with empiric diagnosis. The accuracy (Acc), sensitivity (Se), specificity (Sp), positive and negative predictive values were calculated. Results From 1,135 TB patients, 160 were considered for analysis (111 confirmed PlTB and 49 unconfirmed PlTB). Indeed, 58 non-TB patients were enrolled as controls. Hyporexia [adjusted odds ratio (aOR) 27.39 (95% CI 6.26 – 119.89)] and cellular/biochemical characteristics on pleural fluid (PF) (polimorphonuclear in two categories: 3-14% aOR 26.22, 95% CI 7.11 – 96.68 and < 3% aOR 28.67, 95% CI 5.51 – 149.25; and protein ≥ 5g/dL aOR 7.24, 95% CI 3.07 – 17.11) were associated with higher risk for TB. The DTC constructed using these variables showed Acc=87.6%, Se=89.2%, Sp=84.5% for PlTB diagnosis and was successfully applied in unconfirmed PlTB patients. Conclusion The DTC model showed an excellent performance for PlTB diagnosis and can be considered as an alternative diagnostic strategy by using clinical patterns in association with PF cellular/biochemical characteristics, which were affordable and easily performed in basic health care units.
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Affiliation(s)
- Ana Paula Santos
- Departamento de Pneumologia, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro (RJ) Brasil
| | - Marcelo Ribeiro-Alves
- Laboratório de Pesquisa Clínica em DST/AIDS, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro (RJ) Brasil
| | - Raquel Corrêa
- Laboratório de Imunopatologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro (RJ) Brasil
| | - Isabelle Lopes
- Laboratório de Imunopatologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro (RJ) Brasil
| | - Mariana Almeida Silva
- Laboratório de Imunopatologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro (RJ) Brasil
| | - Thiago Thomaz Mafort
- Departamento de Pneumologia, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro (RJ) Brasil
| | - Janaina Leung
- Departamento de Pneumologia, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro (RJ) Brasil
| | - Luciana Silva Rodrigues
- Laboratório de Imunopatologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro (RJ) Brasil
| | - Rogério Rufino
- Departamento de Pneumologia, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro (RJ) Brasil
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Zhao J, Gao S, Chen C, Li H, Wang S, Yu Y, Ming L. Screening and identification of differentially expressed long non-coding RNAs in multidrug-resistant tuberculosis. PeerJ 2022; 10:e12776. [PMID: 35111403 PMCID: PMC8772445 DOI: 10.7717/peerj.12776] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/21/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Efforts to eradicate tuberculosis are largely threatened by drug-resistant tuberculosis, particularly, multidrug-resistant tuberculosis (MDR-TB). Screening and identification potential biomarkers for MDR-TB is crucial to diagnose early and reduce the incidence of MDR-TB. METHODS To screen the differentially expressed long non-coding RNAs in MDR-TB, the lncRNA and mRNA expression profiles in serum derived from healthy controls (HCs), individuals with MDR-TB and drug-sensitive tuberculosis (DS-TB) were analyzed by microarray assay and 10 lncRNAs were randomly selected for further validation by reverse transcription-quantitative real-time PCR(RT-qPCR). The biological functions of differentially expressed mRNAs as well as relationships between genes and signaling pathways were investigated using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), respectively. RESULTS A total of 353 differentially expressed lncRNAs (312 upregulated) and 202 mRNAs (99 upregulated) were found in the MDR-TB group compared to HCs. And compared with the DS-TB group, 442 differentially expressed lncRNAs (115 upregulated) and 190 mRNAs (87 upregulated) were found in the MDR-TB group. The expression levels of lncRNA n335659 were found to differ significantly between each group by RT-qPCR. Compared with DS-TB group, the GO analysis showed that the differential mRNAs were mainly enriched in the processes associated with the detection of the chemical stimulus, the regulation of mRNA metabolic process and neutrophil activation in the MDR-TB group; the KEGG analysis indicated that the differential mRNAs between DS-TB and MDR-TB were mainly enriched in proteasome and Notch signaling pathway, which might reveal a fraction of the mechanism of MDR-TB. The discovery of the serum lncRNA n335659 might serve as a potential biomarker for MDR-TB and Notch signaling pathway provided a new clue for the investigation of the pathological mechanism of MDR-TB.
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Affiliation(s)
- Junwei Zhao
- Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - ShuHui Gao
- Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunguang Chen
- Department of Clinical Laboratory, Henan Provincial Infectious Disease Hospital, Zhengzhou, China
| | - Hui Li
- Tuberculosis Reference Laboratory, Centers for Disease Control and Prevention of Henan Province, Zhengzhou, China
| | - Shaohua Wang
- Tuberculosis Reference Laboratory, Centers for Disease Control and Prevention of Henan Province, Zhengzhou, China
| | - Yongmin Yu
- Department of Clinical Laboratory, Henan Provincial Infectious Disease Hospital, Zhengzhou, China
| | - Liang Ming
- Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Parker HA, Forrester L, Kaldor CD, Dickerhof N, Hampton MB. Antimicrobial Activity of Neutrophils Against Mycobacteria. Front Immunol 2021; 12:782495. [PMID: 35003097 PMCID: PMC8732375 DOI: 10.3389/fimmu.2021.782495] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 12/06/2021] [Indexed: 12/21/2022] Open
Abstract
The mycobacterium genus contains a broad range of species, including the human pathogens M. tuberculosis and M. leprae. These bacteria are best known for their residence inside host cells. Neutrophils are frequently observed at sites of mycobacterial infection, but their role in clearance is not well understood. In this review, we discuss how neutrophils attempt to control mycobacterial infections, either through the ingestion of bacteria into intracellular phagosomes, or the release of neutrophil extracellular traps (NETs). Despite their powerful antimicrobial activity, including the production of reactive oxidants such as hypochlorous acid, neutrophils appear ineffective in killing pathogenic mycobacteria. We explore mycobacterial resistance mechanisms, and how thwarting neutrophil action exacerbates disease pathology. A better understanding of how mycobacteria protect themselves from neutrophils will aid the development of novel strategies that facilitate bacterial clearance and limit host tissue damage.
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Affiliation(s)
| | | | | | | | - Mark B. Hampton
- Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
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Sudadech P, Roytrakul S, Kaewprasert O, Sirichoat A, Chetchotisakd P, Kanthawong S, Faksri K. Assessment of in vitro activities of novel modified antimicrobial peptides against clarithromycin resistant Mycobacterium abscessus. PLoS One 2021; 16:e0260003. [PMID: 34780520 PMCID: PMC8592419 DOI: 10.1371/journal.pone.0260003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 11/01/2021] [Indexed: 01/21/2023] Open
Abstract
Mycobacterium abscessus (Mab) is one of the most drug resistant bacteria with a high treatment failure rate. Antimicrobial peptides (AMPs) are alternative therapeutic agents against this infection. This study was aimed to assess the in vitro activities of thirteen AMPs (S5, S52, S6, S61, S62, S63, KLK, KLK1, KLK2, Pug-1, Pug-2, Pug-3 and Pug-4) that have never been investigated against drug resistant Mab isolates. Only four novel modified AMPs (S61, S62, S63 and KLK1) provided the lowest minimum inhibitory concentration (MIC) values ranging from 200–400 μg/ml against the Mab ATCC19977 strain. These four potential AMPs were further tested with 16 clinical isolates of clarithromycin resistant Mab. The majority of the tested strains (10/16 isolates, 62.5%) showed ~99% kill by all four AMPs within 24 hours with an MIC <50 μg/ml. Only two isolates (12.5%) with acquired clarithromycin resistance, however, exhibited values <50 μg/ml of four potential AMPs, S61, S62, S63 and KLK1 after 3-days-incubation. At the MICs level, S63 showed the lowest toxicity with 1.50% hemolysis and 100% PBMC viability whereas KLK1 showed the highest hemolysis (10.21%) and lowest PBMC viability (93.52%). S61, S62 and S63 were further tested with clarithromycin-AMP interaction assays and found that 5/10 (50%) of selected isolates exhibited a synergistic interaction with 0.02–0.41 FICI values. This present study demonstrated the potential application of novel AMPs as an adjunctive treatment with clarithromycin against drug resistant Mab infection.
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Affiliation(s)
- Phantitra Sudadech
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand
| | - Sittiruk Roytrakul
- Genome Institute, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand
| | - Orawee Kaewprasert
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand
| | - Auttawit Sirichoat
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand
| | - Ploenchan Chetchotisakd
- Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand
- Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sakawrat Kanthawong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand
| | - Kiatichai Faksri
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand
- * E-mail:
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Gong W, Wu X. Differential Diagnosis of Latent Tuberculosis Infection and Active Tuberculosis: A Key to a Successful Tuberculosis Control Strategy. Front Microbiol 2021; 12:745592. [PMID: 34745048 PMCID: PMC8570039 DOI: 10.3389/fmicb.2021.745592] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/24/2021] [Indexed: 12/16/2022] Open
Abstract
As an ancient infectious disease, tuberculosis (TB) is still the leading cause of death from a single infectious agent worldwide. Latent TB infection (LTBI) has been recognized as the largest source of new TB cases and is one of the biggest obstacles to achieving the aim of the End TB Strategy. The latest data indicate that a considerable percentage of the population with LTBI and the lack of differential diagnosis between LTBI and active TB (aTB) may be potential reasons for the high TB morbidity and mortality in countries with high TB burdens. The tuberculin skin test (TST) has been used to diagnose TB for > 100 years, but it fails to distinguish patients with LTBI from those with aTB and people who have received Bacillus Calmette–Guérin vaccination. To overcome the limitations of TST, several new skin tests and interferon-gamma release assays have been developed, such as the Diaskintest, C-Tb skin test, EC-Test, and T-cell spot of the TB assay, QuantiFERON-TB Gold In-Tube, QuantiFERON-TB Gold-Plus, LIAISON QuantiFERON-TB Gold Plus test, and LIOFeron TB/LTBI. However, these methods cannot distinguish LTBI from aTB. To investigate the reasons why all these methods cannot distinguish LTBI from aTB, we have explained the concept and definition of LTBI and expounded on the immunological mechanism of LTBI in this review. In addition, we have outlined the research status, future directions, and challenges of LTBI differential diagnosis, including novel biomarkers derived from Mycobacterium tuberculosis and hosts, new models and algorithms, omics technologies, and microbiota.
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Affiliation(s)
- Wenping Gong
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
| | - Xueqiong Wu
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
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Mongy NNE, Hilal RF. How far is vitamin D implicated in cutaneous infections. Clin Dermatol 2021; 40:198-205. [PMID: 34893391 DOI: 10.1016/j.clindermatol.2021.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Vitamin D is an important cornerstone in the immunologic cascade of many skin infections, systemic infections with cutaneous presentations, and other infectious dermatologic diseases where infections could be a culprit. Vitamin D supplementation is proposed as a protective measure against their occurrence and exacerbation, especially with the emergence of several viral pandemics in recent years. Vitamin D plays a key role in the maintenance of a balanced immunologic profile which could be reflected by a lowered incidence and morbidity of infections. Vitamin D screening and supplementation in patients with deficiencies or insufficiencies should be a part of the dermatologic approach to patients with these diseases.
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Affiliation(s)
- Naglaa Nabil El Mongy
- Professor of Dermatology, Kasr Al Ainy Teaching Hospital, Cairo University, Cairo, Egypt
| | - Rana Fathy Hilal
- Associate Professor of Dermatology, Kasr Al Ainy Teaching Hospital, Cairo University, Cairo, Egypt.
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Mattila JT, Beaino W, White AG, Nyiranshuti L, Maiello P, Tomko J, Frye LJ, Fillmore D, Scanga CA, Lin PL, Flynn JL, Anderson CJ. Retention of 64Cu-FLFLF, a Formyl Peptide Receptor 1-Specific PET Probe, Correlates with Macrophage and Neutrophil Abundance in Lung Granulomas from Cynomolgus Macaques. ACS Infect Dis 2021; 7:2264-2276. [PMID: 34255474 PMCID: PMC8744071 DOI: 10.1021/acsinfecdis.0c00826] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Neutrophilic inflammation correlates with severe tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb). Granulomas are lesions that form in TB, and a PET probe for following neutrophil recruitment to granulomas could predict disease progression. We tested the formyl peptide receptor 1 (FPR1)-targeting peptide FLFLF in Mtb-infected macaques. Preliminary studies in mice demonstrated specificity for neutrophils. In macaques, 64Cu-FLFLF was retained in lung granulomas and analysis of lung granulomas identified positive correlations between 64Cu-FLFLF and neutrophil and macrophage numbers (R2 = 0.8681 and 0.7643, respectively), and weaker correlations for T cells and B cells (R2 = 0.5744 and 0.5908, respectively), suggesting that multiple cell types drive 64Cu-FLFLF avidity. By PET/CT imaging, we found that granulomas retained 64Cu-FLFLF but with less avidity than the glucose analog 18F-FDG. These studies suggest that neutrophil-specific probes have potential PET/CT applications in TB, but important issues need to be addressed before they can be used in nonhuman primates and humans.
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Affiliation(s)
- Joshua T Mattila
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh PA, 15260, United States
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh PA, 15260, United States
| | - Wissam Beaino
- Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15260, United States
| | - Alexander G White
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh PA, 15260, United States
| | - Lea Nyiranshuti
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, United States
| | - Pauline Maiello
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh PA, 15260, United States
| | - Jaime Tomko
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh PA, 15260, United States
| | - L James Frye
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh PA, 15260, United States
| | - Daniel Fillmore
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh PA, 15260, United States
| | - Charles A Scanga
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh PA, 15260, United States
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh PA, 15260, United States
| | - Philana Ling Lin
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh PA, 15260, United States
- Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, United States
| | - JoAnne L Flynn
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh PA, 15260, United States
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, United States
| | - Carolyn J Anderson
- Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15260, United States
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, United States
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15260, United States
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, 15260, United States
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260, United States
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Parallel in vivo experimental evolution reveals that increased stress resistance was key for the emergence of persistent tuberculosis bacilli. Nat Microbiol 2021; 6:1082-1093. [PMID: 34294904 DOI: 10.1038/s41564-021-00938-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 06/18/2021] [Indexed: 12/31/2022]
Abstract
Pathogenomic evidence suggests that Mycobacterium tuberculosis (MTB) evolved from an environmental ancestor similar to Mycobacterium canettii, a rare human pathogen. Although the adaptations responsible for this transition are poorly characterized, the ability to persist in humans seems to be important. We set out to identify the adaptations contributing to the evolution of persistence in MTB. We performed an experimental evolution of eight M. canettii populations in mice; four populations were derived from the isolate STB-K (phylogenomically furthest from MTB) and four from STB-D (closest to MTB), which were monitored for 15 and 6 cycles, respectively. We selected M. canettii mutants with enhanced persistence in vivo compared with the parental strains, which were phenotypically closer to MTB. Genome sequencing of 140 mutants and complementation analysis revealed that mutations in two loci were responsible for enhanced persistence. Most of the tested mutants were more resistant than their parental strains to nitric oxide, an important effector of immunity. Modern MTB were similarly more resistant to nitric oxide than M. canettii. Our findings demonstrate phenotypic convergence during experimental evolution of M. canettii, which mirrors natural evolution of MTB. Furthermore, they indicate that the ability to withstand host-induced stresses was key for the emergence of persistent MTB.
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Tamburini B, Badami GD, Azgomi MS, Dieli F, La Manna MP, Caccamo N. Role of hematopoietic cells in Mycobacterium tuberculosis infection. Tuberculosis (Edinb) 2021; 130:102109. [PMID: 34315045 DOI: 10.1016/j.tube.2021.102109] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 07/05/2021] [Accepted: 07/20/2021] [Indexed: 10/20/2022]
Abstract
Tuberculosis remains one of the most significant causes of mortality worldwide and the current situation shows a re-emergence of TB due to the emergence of new antibiotic-resistant strains and the widespread of disease caused by immunodeficiencies. For these reasons, a big effort is made to improve the therapeutic strategies against Mycobacterium tuberculosis and to perform new therapeutic and diagnostic strategies. This review analyzes the various hematopoietic populations, their role and the different changes they undergo during Mycobacterium tuberculosis infection or disease. We have examined the population of lymphocytes, monocytes, neutrophils, eosinophils and platelets, in orderto understand how each of them is modulated during the course of infection/disease. In this way it will be possible to highlight the correlations between these cell populations and the different stages of tubercular infection. In fact, Mycobacterium tuberculosis is able to influence both proliferation and differentiation of hematopoietic stem cells. Several studies have highlighted that Mycobacterium tuberculosis can also infect progenitor cells in the bone marrow during active disease driving towards an increase of myeloid differentiation. This review focuses how the different stages of tubercular infection could impact on the different hematopoietic populations, with the aim to correlate the changes of different populations as biomarkers useful to discriminate infection from disease and to evaluate the effectiveness of new therapies.
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Affiliation(s)
- Bartolo Tamburini
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Italy; Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.); University of Palermo, Palermo 90127, Italy
| | - Giusto Davide Badami
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Italy; Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.); University of Palermo, Palermo 90127, Italy
| | - Mojtaba Shekarkar Azgomi
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Italy; Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.); University of Palermo, Palermo 90127, Italy
| | - Francesco Dieli
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Italy; Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.); University of Palermo, Palermo 90127, Italy
| | - Marco Pio La Manna
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Italy; Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.); University of Palermo, Palermo 90127, Italy
| | - Nadia Caccamo
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Italy; Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.); University of Palermo, Palermo 90127, Italy.
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Remot A, Carreras F, Coupé A, Doz-Deblauwe É, Boschiroli ML, Browne JA, Marquant Q, Descamps D, Archer F, Aseffa A, Germon P, Gordon SV, Winter N. Mycobacterial Infection of Precision-Cut Lung Slices Reveals Type 1 Interferon Pathway Is Locally Induced by Mycobacterium bovis but Not M. tuberculosis in a Cattle Breed. Front Vet Sci 2021; 8:696525. [PMID: 34307535 PMCID: PMC8299756 DOI: 10.3389/fvets.2021.696525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/02/2021] [Indexed: 11/13/2022] Open
Abstract
Tuberculosis exacts a terrible toll on human and animal health. While Mycobacterium tuberculosis (Mtb) is restricted to humans, Mycobacterium bovis (Mb) is present in a large range of mammalian hosts. In cattle, bovine TB (bTB) is a noticeable disease responsible for important economic losses in developed countries and underestimated zoonosis in the developing world. Early interactions that take place between mycobacteria and the lung tissue early after aerosol infection govern the outcome of the disease. In cattle, these early steps remain poorly characterized. The precision-cut lung slice (PCLS) model preserves the structure and cell diversity of the lung. We developed this model in cattle in order to study the early lung response to mycobacterial infection. In situ imaging of PCLS infected with fluorescent Mb revealed bacilli in the alveolar compartment, in adjacent or inside alveolar macrophages, and in close contact with pneumocytes. We analyzed the global transcriptional lung inflammation signature following infection of PCLS with Mb and Mtb in two French beef breeds: Blonde d'Aquitaine and Charolaise. Whereas, lungs from the Blonde d'Aquitaine produced high levels of mediators of neutrophil and monocyte recruitment in response to infection, such signatures were not observed in the Charolaise in our study. In the Blonde d'Aquitaine lung, whereas the inflammatory response was highly induced by two Mb strains, AF2122 isolated from cattle in the UK and Mb3601 circulating in France, the response against two Mtb strains, H37Rv, the reference laboratory strain, and BTB1558, isolated from zebu in Ethiopia, was very low. Strikingly, the type I interferon pathway was only induced by Mb but not Mtb strains, indicating that this pathway may be involved in mycobacterial virulence and host tropism. Hence, the PCLS model in cattle is a valuable tool to deepen our understanding of early interactions between lung host cells and mycobacteria. It revealed striking differences between cattle breeds and mycobacterial strains. This model could help in deciphering biomarkers of resistance vs. susceptibility to bTB in cattle as such information is still critically needed for bovine genetic selection programs and would greatly help the global effort to eradicate bTB.
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Affiliation(s)
- Aude Remot
- INRAE, Université de Tours, Nouzilly, France
| | | | | | | | - Maria L Boschiroli
- Paris-Est University, National Reference Laboratory for Tuberculosis, Animal Health Laboratory, Anses, Maisons-Alfort, France
| | - John A Browne
- UCD School of Agriculture and Food Science, University College Dublin, Dublin, Ireland
| | | | | | - Fabienne Archer
- INRAE, UMR754, Viral Infections and Comparative Pathology, IVPC, Univ Lyon, Université Claude Bernard Lyon 1, EPHE, Lyon, France
| | - Abraham Aseffa
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
| | | | - Stephen V Gordon
- UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Dublin, Ireland
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Kathamuthu GR, Moideen K, Sridhar R, Baskaran D, Babu S. Reduced neutrophil granular proteins and post-treatment modulation in tuberculous lymphadenitis. PLoS One 2021; 16:e0253534. [PMID: 34153068 PMCID: PMC8216526 DOI: 10.1371/journal.pone.0253534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/07/2021] [Indexed: 11/29/2022] Open
Abstract
Background Neutrophils are important for host innate immune defense and mediate inflammatory responses. Pulmonary tuberculosis (PTB) is associated with increased neutrophil granular protein (NGP) levels in the circulation. However, the systemic levels of neutrophil granular proteins were not examined in tuberculous lymphadenitis (TBL) disease. Methods We measured the systemic levels of NGP (myeloperoxidase [MPO], elastase and proteinase 3 [PRTN3]) in TBL and compared them to latent tuberculosis (LTB) and healthy control (HC) individuals. We also measured the pre-treatment (Pre-T) and post-treatment (Post-T) systemic levels of neutrophil granular proteins in TBL individuals upon anti-tuberculosis treatment (ATT) completion. In addition, we studied the correlation and discriminatory ability of NGPs using receiver operating characteristic (ROC) analysis. Results Our data suggests that systemic levels of NGPs (MPO, PRTN3, elastase) were significantly reduced in TBL individuals compared to LTB and HC individuals. Similarly, after ATT, the plasma levels of MPO and elastase but not PRTN3 were significantly elevated compared to pre-treatment levels. NGPs (except PRTN3) were positively correlated with absolute neutrophil count of TBL, LTB and HC individuals. Further, NGPs were able to significantly discriminate TBL from LTB and HC individuals. Conclusion Hence, we conclude reduced neutrophil granular protein levels might be associated with disease pathogenesis in TBL.
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Affiliation(s)
- Gokul Raj Kathamuthu
- National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai, India
- National Institute for Research in Tuberculosis (NIRT), Chennai, India
- * E-mail:
| | - Kadar Moideen
- National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai, India
| | | | - Dhanaraj Baskaran
- National Institute for Research in Tuberculosis (NIRT), Chennai, India
| | - Subash Babu
- National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai, India
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
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Bok J, Hofland RW, Evans CA. Whole Blood Mycobacterial Growth Assays for Assessing Human Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis. Front Immunol 2021; 12:641082. [PMID: 34046032 PMCID: PMC8144701 DOI: 10.3389/fimmu.2021.641082] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 03/08/2021] [Indexed: 01/20/2023] Open
Abstract
Background Whole blood mycobacterial growth assays (WBMGA) quantify mycobacterial growth in fresh blood samples and may have potential for assessing tuberculosis vaccines and identifying individuals at risk of tuberculosis. We evaluated the evidence for the underlying assumption that in vitro WBMGA results can predict in vivo tuberculosis susceptibility. Methods A systematic search was done for studies assessing associations between WBMGA results and tuberculosis susceptibility. Meta-analyses were performed for eligible studies by calculating population-weighted averages. Results No studies directly assessed whether WBMGA results predicted tuberculosis susceptibility. 15 studies assessed associations between WBMGA results and proven correlates of tuberculosis susceptibility, which we divided in two categories. Firstly, WBMGA associations with factors believed to reduce tuberculosis susceptibility were statistically significant in all eight studies of: BCG vaccination; vitamin D supplementation; altitude; and HIV-negativity/therapy. Secondly, WBMGA associations with probable correlates of tuberculosis susceptibility were statistically significant in three studies of tuberculosis disease, in a parasitism study and in two of the five studies of latent tuberculosis infection. Meta-analyses for associations between WBMGA results and BCG vaccination, tuberculosis infection, tuberculosis disease and HIV infection revealed consistent effects. There was considerable methodological heterogeneity. Conclusions The study results generally showed significant associations between WBMGA results and correlates of tuberculosis susceptibility. However, no study directly assessed whether WBMGA results predicted actual susceptibility to tuberculosis infection or disease. We recommend optimization and standardization of WBMGA methodology and prospective studies to determine whether WBMGA predict susceptibility to tuberculosis disease.
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Affiliation(s)
- Jeroen Bok
- Department of Infectious Disease, Imperial College London, London, United Kingdom.,Innovation for Health and Development (IFHAD), Laboratory of Research and Development, Universidad Peruana Cayetano Heredia, Lima, Peru.,Innovacion Por la Salud Y el Desarrollo (IPSYD), Asociación Benéfica PRISMA, Lima, Peru.,Department of Pulmonology and Tuberculosis, University Medical Center Utrecht, Utrecht, Netherlands
| | - Regina W Hofland
- Department of Pulmonology and Tuberculosis, University Medical Center Utrecht, Utrecht, Netherlands
| | - Carlton A Evans
- Department of Infectious Disease, Imperial College London, London, United Kingdom.,Innovation for Health and Development (IFHAD), Laboratory of Research and Development, Universidad Peruana Cayetano Heredia, Lima, Peru.,Innovacion Por la Salud Y el Desarrollo (IPSYD), Asociación Benéfica PRISMA, Lima, Peru
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Foster M, Hill PC, Setiabudiawan TP, Koeken VACM, Alisjahbana B, van Crevel R. BCG-induced protection against Mycobacterium tuberculosis infection: Evidence, mechanisms, and implications for next-generation vaccines. Immunol Rev 2021; 301:122-144. [PMID: 33709421 PMCID: PMC8252066 DOI: 10.1111/imr.12965] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/12/2021] [Accepted: 02/13/2021] [Indexed: 12/20/2022]
Abstract
The tuberculosis (TB) vaccine Bacillus Calmette-Guérin (BCG) was introduced 100 years ago, but as it provides insufficient protection against TB disease, especially in adults, new vaccines are being developed and evaluated. The discovery that BCG protects humans from becoming infected with Mycobacterium tuberculosis (Mtb) and not just from progressing to TB disease provides justification for considering Mtb infection as an endpoint in vaccine trials. Such trials would require fewer participants than those with disease as an endpoint. In this review, we first define Mtb infection and disease phenotypes that can be used for mechanistic studies and/or endpoints for vaccine trials. Secondly, we review the evidence for BCG-induced protection against Mtb infection from observational and BCG re-vaccination studies, and discuss limitations and variation of this protection. Thirdly, we review possible underlying mechanisms for BCG efficacy against Mtb infection, including alternative T cell responses, antibody-mediated protection, and innate immune mechanisms, with a specific focus on BCG-induced trained immunity, which involves epigenetic and metabolic reprogramming of innate immune cells. Finally, we discuss the implications for further studies of BCG efficacy against Mtb infection, including for mechanistic research, and their relevance to the design and evaluation of new TB vaccines.
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Affiliation(s)
- Mitchell Foster
- Department of Microbiology and ImmunologyUniversity of OtagoDunedinNew Zealand
| | - Philip C. Hill
- Centre for International HealthUniversity of OtagoDunedinNew Zealand
| | - Todia Pediatama Setiabudiawan
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI)Radboud University Medical CenterNijmegenThe Netherlands
| | - Valerie A. C. M. Koeken
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI)Radboud University Medical CenterNijmegenThe Netherlands
- Department of Computational Biology for Individualised Infection MedicineCentre for Individualised Infection Medicine (CiiM) & TWINCOREJoint Ventures between The Helmholtz‐Centre for Infection Research (HZI) and The Hannover Medical School (MHH)HannoverGermany
| | - Bachti Alisjahbana
- Tuberculosis Working GroupFaculty of MedicineUniversitas PadjadjaranBandungIndonesia
| | - Reinout van Crevel
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI)Radboud University Medical CenterNijmegenThe Netherlands
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