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Smith SG, Bowness R, Cliff JM. Host-directed therapy in diabetes and tuberculosis comorbidity toward global tuberculosis elimination. Int J Infect Dis 2025; 155:107877. [PMID: 40068707 DOI: 10.1016/j.ijid.2025.107877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/04/2025] [Accepted: 03/05/2025] [Indexed: 04/04/2025] Open
Abstract
Host-directed therapy could potentially revolutionize tuberculosis control as an adjunct to traditional antibiotics for the treatment of tuberculosis disease and as a strategy to prevent disease progression following Mycobacterium tuberculosis infection. The growing type 2 diabetes pandemic is hampering tuberculosis control worldwide, as people with diabetes have an increased risk of developing tuberculosis disease as well as worse treatment outcomes. Pulmonary tuberculosis is characterized by an inflammatory response that can cause alveolar tissue destruction and cavitation, and this inflammation is exacerbated in people with tuberculosis-diabetes comorbidity. Thus, the reduction of the inflammatory response is a key goal of host-directed therapy to dampen immunopathology, but it is vital that the inflammatory response is not suppressed too much, or the immune system will not be able to react to M. tuberculosis and mycobacterial replication will intensify. Furthermore, the type I interferon response and host cell metabolism are further dysregulated in tuberculosis-diabetes comorbidity, likely contributing to poor treatment outcomes. Achieving the right balance in terms of modulating the inflammatory and immune responses, both quantitatively and temporally, is more complex in tuberculosis-diabetes comorbidity, and this population should be included specifically in clinical trials of new regimens. In this regard, mathematical modeling has a key role in elucidating which biologic pathways should be targeted in different people. Host-directed therapy for people with tuberculosis-diabetes comorbidity will reduce immunopathology and post-tuberculosis lung disease, as well as boost microbiologic cure and treatment outcomes, and thus help in the fight toward global tuberculosis elimination.
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Affiliation(s)
- Steven G Smith
- Centre for Inflammation Research and Translational Medicine, Department of Biosciences, Brunel University of London, London, United Kingdom
| | - Ruth Bowness
- Centre for Mathematical Biology, Department of Mathematical Sciences, University of Bath, Bath, United Kingdom
| | - Jacqueline M Cliff
- Centre for Inflammation Research and Translational Medicine, Department of Biosciences, Brunel University of London, London, United Kingdom.
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2
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Ye Z, Li L, Yang L, Zhuang L, Aspatwar A, Wang L, Gong W. Impact of diabetes mellitus on tuberculosis prevention, diagnosis, and treatment from an immunologic perspective. EXPLORATION (BEIJING, CHINA) 2024; 4:20230138. [PMID: 39439490 PMCID: PMC11491313 DOI: 10.1002/exp.20230138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 02/02/2024] [Indexed: 10/25/2024]
Abstract
The coexistence of diabetes mellitus (DM) and tuberculosis (TB) presents a significant global burden, with DM being recognized as a major risk factor for TB. This review comprehensively analyzes the immunological aspects of DM-TB comorbidity, shedding light on the impact of DM on TB pathogenesis and immune responses. It reveals that high blood glucose levels in TB patients contribute to reduced innate immune cell count, compromised phagocytic function, and delayed antigen presentation. These factors ultimately impair the clearance of Mycobacterium tuberculosis (MTB) and delay adaptive immune responses. With the interaction between TB and DM, there is an increase in inflammation and elevated secretion of pro-inflammatory cytokines by immune cells. This exacerbates the inflammatory response and contributes to poor treatment outcomes in TB. Moreover, the review explores the effects of DM on TB prevention, diagnosis, and treatment. It highlights how poor glycemic control, insulin resistance (IR), DM complications, and genetic factors increase the risk of MTB infection in individuals with DM. Additionally, DM-related immune suppression adversely affects the sensitivity of traditional diagnostic tests for TB, potentially resulting in underdiagnosis and delayed intervention. To mitigate the burden of TB in DM patients, the review emphasizes the need for further research on the mechanisms underlying DM reactivation in latent TB infection (LTBI). It shows how important it is to find and treat LTBI in DM patients as soon as possible and suggests looking into biomarkers that are specific to DM to make diagnosis more accurate.
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Affiliation(s)
- Zhaoyang Ye
- Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and TreatmentSenior Department of TuberculosisThe Eighth Medical Center of PLA General HospitalBeijingChina
- Hebei North UniversityZhangjiakouHebeiChina
- Department of GeriatricsThe Eighth Medical Center of PLA General HospitalBeijingChina
| | | | - Ling Yang
- Hebei North UniversityZhangjiakouHebeiChina
| | - Li Zhuang
- Hebei North UniversityZhangjiakouHebeiChina
| | - Ashok Aspatwar
- Faculty of Medicine and Health TechnologyTampere UniversityTampereFinland
| | - Liang Wang
- Department of GeriatricsThe Eighth Medical Center of PLA General HospitalBeijingChina
| | - Wenping Gong
- Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and TreatmentSenior Department of TuberculosisThe Eighth Medical Center of PLA General HospitalBeijingChina
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Shetty S, Pappachan JM, Fernandez CJ. Diabetes and tuberculosis: An emerging dual threat to healthcare. World J Diabetes 2024; 15:1409-1416. [PMID: 39099826 PMCID: PMC11292341 DOI: 10.4239/wjd.v15.i7.1409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/21/2024] [Accepted: 04/24/2024] [Indexed: 07/08/2024] Open
Abstract
Tuberculosis (TB) remains a huge global healthcare challenge even in the 21st century though the prevalence has dropped in developed countries in recent decades. Diabetes mellitus (DM) is an important risk factor for the development and perpetuation of TB owing to the immune dysfunction in patients with DM. The coexistence of both diseases in the same individual also aggravates disease severity, complications, and chance of treatment failure because of gross immune alterations posed by DM as well as TB. Various complex cellular and humoral immunological factors are involved in the dangerous interaction between TB and DM, some of which remain unknown even today. It is highly important to identify the risk factors for TB in patients with DM, and vice versa, to ensure early diagnosis and management to prevent complications from this ominous coexistence. In their research study published in the recent issue of the World Journal of Diabetes, Shi et al elaborate on the factors associated with the development of TB in a large cohort of DM patients from China. More such research output from different regions of the world is expected to improve our knowledge to fight the health devastation posed by TB in patients with diabetes.
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Affiliation(s)
- Sahana Shetty
- Department of Endocrinology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
| | - Cornelius James Fernandez
- Department of Endocrinology & Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
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Vankayalapati A, Durojaye O, Mukherjee T, Paidipally P, Owusu-Afriyie B, Vankayalapati R, Radhakrishnan RK. Metabolic changes enhance necroptosis of type 2 diabetes mellitus mice infected with Mycobacterium tuberculosis. PLoS Pathog 2024; 20:e1012148. [PMID: 38728367 PMCID: PMC11086854 DOI: 10.1371/journal.ppat.1012148] [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: 08/30/2023] [Accepted: 03/25/2024] [Indexed: 05/12/2024] Open
Abstract
Previously, we found that Mycobacterium tuberculosis (Mtb) infection in type 2 diabetes mellitus (T2DM) mice enhances inflammatory cytokine production which drives pathological immune responses and mortality. In the current study, using a T2DM Mtb infection mice model, we determined the mechanisms that make T2DM mice alveolar macrophages (AMs) more inflammatory upon Mtb infection. Among various cell death pathways, necroptosis is a major pathway involved in inflammatory cytokine production by T2DM mice AMs. Anti-TNFR1 antibody treatment of Mtb-infected AMs from T2DM mice significantly reduced expression of receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) (necroptosis markers) and IL-6 production. Metabolic profile comparison of Mtb-infected AMs from T2DM mice and Mtb-infected AMs of nondiabetic control mice indicated that 2-ketohexanoic acid and deoxyadenosine monophosphate were significantly abundant, and acetylcholine and pyridoxine (Vitamin B6) were significantly less abundant in T2DM mice AMs infected with Mtb. 2-Ketohexanoic acid enhanced expression of TNFR1, RIPK3, MLKL and inflammatory cytokine production in the lungs of Mtb-infected nondiabetic mice. In contrast, pyridoxine inhibited RIPK3, MLKL and enhanced expression of Caspase 3 (apoptosis marker) in the lungs of Mtb-infected T2DM mice. Our findings demonstrate that metabolic changes in Mtb-infected T2DM mice enhance TNFR1-mediated necroptosis of AMs, which leads to excess inflammation and lung pathology.
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Affiliation(s)
- Abhinav Vankayalapati
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Olamipejo Durojaye
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Tanmoy Mukherjee
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Padmaja Paidipally
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Bismark Owusu-Afriyie
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Ramakrishna Vankayalapati
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Rajesh Kumar Radhakrishnan
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
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López-González JA, Martínez-Soto JM, Avila-Cervantes C, Mata-Pineda AL, Álvarez-Hernández G, Álvarez-Meza JB, Bolado-Martínez E, Candia-Plata MDC. Evaluation of Systemic Inflammation Before and After Standard Anti-tuberculosis Treatment in Patients With Active Pulmonary Tuberculosis and Diabetes Mellitus. Cureus 2024; 16:e55391. [PMID: 38562330 PMCID: PMC10984244 DOI: 10.7759/cureus.55391] [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] [Accepted: 02/29/2024] [Indexed: 04/04/2024] Open
Abstract
Background Diabetes mellitus (DM) is a common comorbidity of active pulmonary tuberculosis (APTB) that increases the risk of treatment failure during anti-tuberculosis chemotherapy. Evaluating systemic inflammatory response could help determine differences in response to treatment between APTB patients and those with APTB and DM. Methodology To explore changes in systemic inflammation, measured by a set of inflammatory mediators in subjects with APTB and TBDM before and after six months of anti-tuberculosis chemotherapy, 30 APTB and nine TBDM subjects underwent cytokine testing, including interleukin (IL)-6, IL-8, IL-10, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta 1 (TGF-β1) by enzyme-linked immunosorbent assay, C-reactive protein by nephelometry, and sialic acid by colorimetric assay at baseline and following six months of standard anti-tuberculosis treatment. Sputum smear microscopy or molecular biology (Xpert MTB/RIF) was used for diagnosis, and sputum smear microscopy was performed monthly during the treatment of the patient with pulmonary tuberculosis to evaluate his evolution. Principal component analysis examined changes in the inflammatory status. Results Both groups showed negative sputum smear microscopy in the sixth month after starting anti-tuberculosis chemotherapy. TGF-β1 was found to be significantly higher in subjects with TBDM before treatment compared to APTB patients (p<0.001), and systemic inflammation continued only in TBDM subjects after treatment (accumulation and persistence of inflammatory mediators like IL-6, IL-8, IL-10, IFN-γ, TNF-α, TGF-β1, C-reactive protein, and sialic acid in blood). On the other hand, the mediators IFN-γ, C-reactive protein, and total sialic acid were found to be most influential in distinguishing pre- and post-treatment inflammatory response in subjects with APTB without DM. Conclusions Inflammatory mediators analyzed in combination, including IFN-γ, CRP, and total sialic acid, may be useful in evaluating the systemic inflammatory response in subjects with APTB and TBDM before and after anti-tuberculosis treatment. Determining these mediators revealed persistent systemic inflammation in TBDM subjects after six months of standard tuberculosis treatment, despite negative sputum smear microscopy results and good glycemic control. This suggests a need for inflammation-modulating therapies during tuberculosis control. Finally, monitoring sputum smear microscopy results alongside the determination of proposed inflammatory mediators (IFN-γ, CRP, and total sialic acid) are effective in evaluating the response to anti-tuberculosis treatment in APTB subjects without DM, warranting further investigation.
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Chaudhary S, Pahwa F, Nanda RK. Dysregulated cysteine metabolism leads to worsened liver pathology in diabetes-tuberculosis comorbid condition. J Biol Chem 2024; 300:105634. [PMID: 38199571 PMCID: PMC10850780 DOI: 10.1016/j.jbc.2024.105634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 12/11/2023] [Accepted: 12/26/2023] [Indexed: 01/12/2024] Open
Abstract
Diabetes mellitus (DM) is a risk factor for developing active tuberculosis (TB) with a 3-fold increase in susceptibility and a 4-fold higher relapse rate. With increasing DM prevalence in TB endemic regions, understanding pathophysiological changes associated with DM-TB comorbidity is imperative. In this study, streptozotocin (STZ)-induced DM C57BL/6 mice were aerosol infected with low dose (100-120 CFU) Mycobacterium tuberculosis H37Rv. At 3 weeks post infection (w.p.i.), multiple tissue mycobacterial load and metabolites were profiled. The liver proteome of DM-TB and controls were analyzed using quantitative proteomics, and multi-omics data were integrated. DM-TB mice showed dysregulated multi-tissue (lungs, liver, brain, kidney and thigh muscle) metabolism. In contrast, the mycobacterial burden in the lung, spleen and liver was similar at 3 w.p.i. in DM-TB and TB groups. Enrichment analysis of deregulated liver metabolites (n = 20; log2DM-TB/TB>±1.0) showed significant perturbation in cysteine-methionine, glycine-serine, BCAA and fatty acid metabolism. 60 out of 1660 identified liver proteins showed deregulation (log2DM-TB/TB>±1.0) and contributed from perturbed cysteine-methionine metabolism corroborating metabolomics data. In addition, amino acid biosynthesis, retinol metabolism and polyol biosynthetic process were also differentially enriched in the livers of DM-TB groups. Global correlation analysis of liver metabolome and proteome data showed a strong association between aspartic acid, pyruvic acid, leucine and isoleucine with CYP450 enzymes involved in retinol metabolism, while iminodiacetic acid, isoleucine and γ-aminobutyric acid (GABA) strong positive correlation involved in cysteine metabolism. Targeting perturbed cysteine metabolism using micro molecules, like DL-Propargylglycine, might help prevent liver damage in DM-TB comorbid conditions.
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Affiliation(s)
- Shweta Chaudhary
- Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Falak Pahwa
- Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Ranjan K Nanda
- Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
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7
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Zhao L, Fan K, Sun X, Li W, Qin F, Shi L, Gao F, Zheng C. Host-directed therapy against mycobacterium tuberculosis infections with diabetes mellitus. Front Immunol 2024; 14:1305325. [PMID: 38259491 PMCID: PMC10800548 DOI: 10.3389/fimmu.2023.1305325] [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: 10/01/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Tuberculosis (TB) is caused by the bacterial pathogen Mycobacterium tuberculosis (MTB) and is one of the principal reasons for mortality and morbidity worldwide. Currently, recommended anti-tuberculosis drugs include isoniazid, rifampicin, ethambutol, and pyrazinamide. TB treatment is lengthy and inflicted with severe side-effects, including reduced patient compliance with treatment and promotion of drug-resistant strains. TB is also prone to other concomitant diseases such as diabetes and HIV. These drug-resistant and complex co-morbid characteristics increase the complexity of treating MTB. Host-directed therapy (HDT), which effectively eliminates MTB and minimizes inflammatory tissue damage, primarily by targeting the immune system, is currently an attractive complementary approach. The drugs used for HDT are repositioned drugs in actual clinical practice with relative safety and efficacy assurance. HDT is a potentially effective therapeutic intervention for the treatment of MTB and diabetic MTB, and can compensate for the shortcomings of current TB therapies, including the reduction of drug resistance and modulation of immune response. Here, we summarize the state-of-the-art roles and mechanisms of HDT in immune modulation and treatment of MTB, with a special focus on the role of HDT in diabetic MTB, to emphasize the potential of HDT in controlling MTB infection.
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Affiliation(s)
- Li Zhao
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Ke Fan
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Xuezhi Sun
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Wei Li
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Fenfen Qin
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Liwen Shi
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
| | - Feng Gao
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chunlan Zheng
- Department of Tuberculosis III, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
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8
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Peng YF. Pulmonary tuberculosis and diabetes mellitus: Epidemiology, pathogenesis and therapeutic management (Review). MEDICINE INTERNATIONAL 2024; 4:4. [PMID: 38204892 PMCID: PMC10777470 DOI: 10.3892/mi.2023.128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 11/22/2023] [Indexed: 01/12/2024]
Abstract
The dual burden of pulmonary tuberculosis (PTB) and diabetes mellitus (DM) is a major global public health concern. There is increasing evidence to indicate an association between PTB and DM. DM is associated with immune dysfunction and altered immune components. Hyperglycemia weakens the innate immune response by affecting the function of macrophages, dendritic cells, neutrophils, and natural killer cells, and also disrupts the adaptive immune response, thus promoting the susceptibility of PTB in patients with DM. Antituberculosis drugs often cause the impairment of liver and kidney function in patients with PTB, and the infection with Mycobacterium tuberculosis weaken pancreatic endocrine function by causing islet cell amyloidosis, which disrupts glucose metabolism and thus increases the risk of developing DM in patients with PTB. The present review discusses the association between PTB and DM from the perspective of epidemiology, pathogenesis, and treatment management. The present review aims to provide information for the rational formulation of treatment strategies for patients with PTB-DM.
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Affiliation(s)
- You-Fan Peng
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
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9
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Martinez N, Smulan LJ, Jameson ML, Smith CM, Cavallo K, Bellerose M, Williams J, West K, Sassetti CM, Singhal A, Kornfeld H. Glycerol contributes to tuberculosis susceptibility in male mice with type 2 diabetes. Nat Commun 2023; 14:5840. [PMID: 37730757 PMCID: PMC10511404 DOI: 10.1038/s41467-023-41519-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 09/01/2023] [Indexed: 09/22/2023] Open
Abstract
Diabetes mellitus increases risk for tuberculosis disease and adverse outcomes. Most people with both conditions have type 2 diabetes, but it is unknown if type 1 and type 2 diabetes have identical effects on tuberculosis susceptibility. Here we show that male mice receiving a high-fat diet and streptozotocin to model type 2 diabetes, have higher mortality, more lung pathology, and higher bacterial burden following Mycobacterium tuberculosis infection compared to mice treated with streptozotocin or high-fat diet alone. Type 2 diabetes model mice have elevated plasma glycerol, which is a preferred carbon source for M. tuberculosis. Infection studies with glycerol kinase mutant M. tuberculosis reveal that glycerol utilization contributes to the susceptibility of the type 2 diabetes mice. Hyperglycemia impairs protective immunity against M. tuberculosis in both forms of diabetes, but our data show that elevated glycerol contributes to an additional adverse effect uniquely relevant to type 2 diabetes.
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Affiliation(s)
- Nuria Martinez
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Lorissa J Smulan
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Michael L Jameson
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Clare M Smith
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Kelly Cavallo
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Michelle Bellerose
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - John Williams
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Kim West
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Christopher M Sassetti
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Amit Singhal
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- A*STAR Infectious Diseases Labs (ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 636921, Singapore
| | - Hardy Kornfeld
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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10
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Ssekamatte P, Sande OJ, van Crevel R, Biraro IA. Immunologic, metabolic and genetic impact of diabetes on tuberculosis susceptibility. Front Immunol 2023; 14:1122255. [PMID: 36756113 PMCID: PMC9899803 DOI: 10.3389/fimmu.2023.1122255] [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: 12/12/2022] [Accepted: 01/12/2023] [Indexed: 01/24/2023] Open
Abstract
Due to the increasing prevalence of diabetes mellitus (DM) globally, the interaction between DM and major global diseases like tuberculosis (TB) is of great public health significance, with evidence of DM having about a three-fold risk for TB disease. TB defense may be impacted by diabetes-related effects on immunity, metabolism, and gene transcription. An update on the epidemiological aspects of DM and TB, and the recent trends in understanding the DM-associated immunologic, metabolic, and genetic mechanisms of susceptibility to TB will be discussed in this review. This review highlights gaps in the incomplete understanding of the mechanisms that may relate to TB susceptibility in type 2 DM (T2DM). Understanding these three main domains regarding mechanisms of TB susceptibility in T2DM patients can help us build practical treatment plans to lessen the combined burden of the diseases in rampant areas.
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Affiliation(s)
- Phillip Ssekamatte
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Obondo James Sande
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Reinout van Crevel
- Department of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Irene Andia Biraro
- Department of Internal Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda
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11
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Mouse Models for Mycobacterium tuberculosis Pathogenesis: Show and Do Not Tell. Pathogens 2022; 12:pathogens12010049. [PMID: 36678397 PMCID: PMC9865329 DOI: 10.3390/pathogens12010049] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 11/29/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022] Open
Abstract
Science has been taking profit from animal models since the first translational experiments back in ancient Greece. From there, and across all history, several remarkable findings have been obtained using animal models. One of the most popular models, especially for research in infectious diseases, is the mouse. Regarding research in tuberculosis, the mouse has provided useful information about host and bacterial traits related to susceptibility to the infection. The effect of aging, sexual dimorphisms, the route of infection, genetic differences between mice lineages and unbalanced immunity scenarios upon Mycobacterium tuberculosis infection and tuberculosis development has helped, helps and will help biomedical researchers in the design of new tools for diagnosis, treatment and prevention of tuberculosis, despite various discrepancies and the lack of deep study in some areas of these traits.
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12
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Yao Q, Xie Y, Xu D, Qu Z, Wu J, Zhou Y, Wei Y, Xiong H, Zhang XL. Lnc-EST12, which is negatively regulated by mycobacterial EST12, suppresses antimycobacterial innate immunity through its interaction with FUBP3. Cell Mol Immunol 2022; 19:883-897. [PMID: 35637281 PMCID: PMC9149337 DOI: 10.1038/s41423-022-00878-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 05/02/2022] [Indexed: 02/07/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of intracellular pathogens. However, the role and mechanism of the important lncRNAs in Mycobacterium tuberculosis (M.tb) infection remain largely unexplored. Recently, we found that a secreted M.tb Rv1579c (an early secreted target with a molecular weight of 12 kDa, named EST12) protein activates NLRP3-gasdermin D (GSDMD)-mediated pyroptosis and plays a pivotal role in M.tb-induced immunity. In the present study, M.tb and the EST12 protein negatively regulated the expression of a key lncRNA (named lnc-EST12) in mouse macrophages by activating the JAK2-STAT5a signaling pathway. Lnc-EST12, with a size of 1583 bp, is mainly expressed in immune-related organs (liver, lung and spleen). Lnc-EST12 not only reduces the expression of the proinflammatory cytokines IL-1β, IL-6, and CCL5/8 but also suppresses the NLRP3 inflammasome and GSDMD pyroptosis-IL-1β immune pathway through its interaction with the transcription factor far upstream element-binding protein 3 (FUBP3). The KH3 and KH4 domains of FUBP3 are the critical sites for binding to lnc-EST12. Deficiency of mouse lnc-EST12 or FUBP3 in macrophages increased M.tb clearance and inflammation in mouse macrophages or mice. In conclusion, we report a new immunoregulatory mechanism in which mouse lnc-EST12 negatively regulates anti-M.tb innate immunity through FUBP3.
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Affiliation(s)
- Qili Yao
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Yan Xie
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Dandan Xu
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Zilu Qu
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Jian Wu
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Yuanyuan Zhou
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Yuying Wei
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Huan Xiong
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
| | - Xiao-Lian Zhang
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.
- State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
- Department of Allergy, Zhongnan Hospital, Wuhan University, Wuhan, China.
- Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China.
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13
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Cheng P, Wang L, Gong W. Cellular Immunity of Patients with Tuberculosis Combined with Diabetes. J Immunol Res 2022; 2022:6837745. [PMID: 35692502 PMCID: PMC9177301 DOI: 10.1155/2022/6837745] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/19/2022] [Indexed: 12/17/2022] Open
Abstract
Tuberculosis (TB) is one of humanity's three major infectious diseases. Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia due to impaired insulin secretion or impaired insulin function. It has been reported that DM is a primary risk factor for TB disease. Given the increasing public health threat to people's health, more and more studies have focused on diabetes complicated by TB. Hyperglycemia can affect the function of human immune cells, promote primary infections and reactivation of TB, and increase the susceptibility and severity of TB. However, the immunological mechanism behind it is still not clear. By reviewing the related articles on tuberculosis complicated with diabetes published in recent years, this paper expounds on the effect of hyperglycemia on innate immunity and adaptive immunity of patients with TB. This review provides new insights for elucidating the immunological mechanism of TB complicated with DM and lays the foundation for finding potential targets for preventing and treating TB combined with DM.
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Affiliation(s)
- Peng Cheng
- 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 100091, China
- Hebei North University, Zhangjiakou, 075000 Hebei, China
| | - Liang Wang
- Department of Geriatrics, The 8th Medical Center of PLA General Hospital, Beijing 100091, China
| | - 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 100091, China
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14
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Wei R, Li P, Xue Y, Liu Y, Gong W, Zhao W. Impact of Diabetes Mellitus on the Immunity of Tuberculosis Patients: A Retrospective, Cross-Sectional Study. Risk Manag Healthc Policy 2022; 15:611-627. [PMID: 35431587 PMCID: PMC9005360 DOI: 10.2147/rmhp.s354377] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/26/2022] [Indexed: 12/27/2022] Open
Abstract
Background Tuberculosis (TB) is an infectious disease that poses a significant health threat and is one of the leading causes of death worldwide. Diabetes mellitus (DM) has high morbidity and mortality rates. Previous studies have reported that comorbidities can influence one another and aggravate immune disorders. A systematic and comprehensive evaluation of the immune status of patients with TB and DM (TB-DM) is helpful for early clinical immune intervention and for promoting the recovery of patients with TB-DM. Methods This study included 159 patients with TB without DM (TB-NDM) and 168 patients with TB-DM. Interferon-γ (IFN-γ) release assays (IGRAs) and TB-specific antibodies against 38kD+16kD proteins were used to detect humoral and cellular immune responses. Flow cytometry was used to analyze the absolute counts of the lymphocyte subsets. Results There was no significant difference in the positive rate of enzyme-linked immunospot (ELISPOT) assays, enzyme linked immunosorbent assay (ELISA), and 38kD+16kD antibodies between the TB-DM and TB-NDM groups. Pulmonary lobe lesion and cavity formation rates were significantly higher in patients with TB-DM with poor glycemic control than patients with TB-NDM and TB-DM with normal glycemic control. The absolute counts of T lymphocytes, CD8+ T lymphocytes, and B lymphocytes in patients with TB-DM were markedly lower than those in patients with TB-NDM. The absolute counts of T lymphocytes and CD8+ T lymphocytes in patients with TB-DM and hyperglycemia were lower than those in patients with euglycemia. Linear regression analysis revealed that the absolute counts of total T lymphocytes, CD8+ T lymphocytes, and NK cells in patients with TB-DM significantly decreased with increasing fasting blood glucose (FBG) levels. Conclusion Hyperglycemia is a risk factor for pulmonary cavity formation and lobe lesions in patients with TB-DM and suppresses the absolute counts of total T lymphocytes, CD8+ T lymphocytes, and NK cells in patients with TB-DM. The potential mechanism may involve the downregulation of innate and adaptive immune responses.
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Affiliation(s)
- Ruda Wei
- Senior Department of Respiratory and Critical Care Medicine, The Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China
- Hebei North University, Zhangjiakou, 075000, Hebei, People’s Republic of China
| | - Pengchuan Li
- Hebei North University, Zhangjiakou, 075000, Hebei, People’s Republic of China
- Army Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, the Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China
| | - Yong Xue
- Army Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, the Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China
| | - Yinping Liu
- Army Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, the Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China
| | - Wenping Gong
- Army Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, the Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China
| | - Weiguo Zhao
- Senior Department of Respiratory and Critical Care Medicine, The Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China
- Hebei North University, Zhangjiakou, 075000, Hebei, People’s Republic of China
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15
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Jung BG, Samten B, Dean K, Wallace RJ, Brown-Elliott BA, Tucker T, Idell S, Philley JV, Vankayalapati R. Early IL-17A production helps establish Mycobacterium intracellulare infection in mice. PLoS Pathog 2022; 18:e1010454. [PMID: 35363832 PMCID: PMC9007361 DOI: 10.1371/journal.ppat.1010454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 04/13/2022] [Accepted: 03/17/2022] [Indexed: 12/24/2022] Open
Abstract
Nontuberculous mycobacteria (NTM) infection is common in patients with structural lung damage. To address how NTM infection is established and causes lung damage, we established an NTM mouse model by intranasal inoculation of clinical isolates of M. intracellulare. During the 39-week course of infection, the bacteria persistently grew in the lung and caused progressive granulomatous and fibrotic lung damage with mortality exceeding 50%. Lung neutrophils were significantly increased at 1 week postinfection, reduced at 2 weeks postinfection and increased again at 39 weeks postinfection. IL-17A was increased in the lungs at 1-2 weeks of infection and reduced at 3 weeks postinfection. Depletion of neutrophils during early (0-2 weeks) and late (32-34 weeks) infection had no effect on mortality or lung damage in chronically infected mice. However, neutralization of IL-17A during early infection significantly reduced bacterial burden, fibrotic lung damage, and mortality in chronically infected mice. Since it is known that IL-17A regulates matrix metalloproteinases (MMPs) and that MMPs contribute to the pathogenesis of pulmonary fibrosis, we determined the levels of MMPs in the lungs of M. intracellulare-infected mice. Interestingly, MMP-3 was significantly reduced by anti-IL-17A neutralizing antibody. Moreover, in vitro data showed that exogenous IL-17A exaggerated the production of MMP-3 by lung epithelial cells upon M. intracellulare infection. Collectively, our findings suggest that early IL-17A production precedes and promotes organized pulmonary M. intracellulare infection in mice, at least in part through MMP-3 production.
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Affiliation(s)
- Bock-Gie Jung
- Department of Pulmonary Immunology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Buka Samten
- Department of Pulmonary Immunology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Kristin Dean
- Department of Pulmonary Immunology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Richard J. Wallace
- Department of Microbiology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Barbara A. Brown-Elliott
- Department of Microbiology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Torry Tucker
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Steven Idell
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
- The Texas Lung Injury Institute, Tyler, Texas, United States of America
| | - Julie V. Philley
- Department of Medicine, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Ramakrishna Vankayalapati
- Department of Pulmonary Immunology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
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16
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Linge I, Tsareva A, Kondratieva E, Dyatlov A, Hidalgo J, Zvartsev R, Apt A. Pleiotropic Effect of IL-6 Produced by B-Lymphocytes During Early Phases of Adaptive Immune Responses Against TB Infection. Front Immunol 2022; 13:750068. [PMID: 35154093 PMCID: PMC8828505 DOI: 10.3389/fimmu.2022.750068] [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: 07/30/2021] [Accepted: 01/10/2022] [Indexed: 12/30/2022] Open
Abstract
The role of B cells migrating to the lung and forming follicles during tuberculosis (TB) inflammation is still the subject of debate. In addition to their antibody production and antigen-presenting functions, B cells secrete different cytokines and chemokines, thus participating in complex networks of innate and adaptive immunity. Importantly, lung B-cells produce high amounts of the pleiotropic gp130 cytokine IL-6. Its role during TB infection remains controversial, partly due to the fact that IL-6 is produced by different cell types. To investigate the impact of IL-6 produced by B cells on TB susceptibility and immune responses, we established a mouse strain with specific IL-6 deficiency in B cells (CD19cre-IL-6fl/fl, B-IL-6KO) on the B6 genetic background. Selective abrogation of IL-6 in B cells resulted in shortening the lifespan of TB-infected B-IL-6KO mice compare to the wild-type controls. We provide evidence that at the initial TB stages B cells serve as a critical source of IL-6. In the lung, the effect of IL-6 deficiency in B cells is associated rather with B and T cell functioning, than with macrophage polarization. TB-infected B-IL-6KO mice displayed diminished sizes of B cells themselves, CD4+IFN-γ+, Th17+, and CD4+CXCR5+ follicular T cell populations. The pleiotropic effect of B-cell-derived IL-6 on T-cells demonstrated in our study bridges two major lymphocyte populations and sheds some light on B- and T-cells interactions during the stage of anti-TB response when the host switches on a plethora of acquired immune reactions.
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Affiliation(s)
- Irina Linge
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
| | - Anastasiya Tsareva
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
| | - Elena Kondratieva
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
| | - Alexander Dyatlov
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
| | - Juan Hidalgo
- Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ruslan Zvartsev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Alexander Apt
- Laboratory for Immunogenetics, Department of Immunology, Central Institute for Tuberculosis, Moscow, Russia
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17
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Ngo MD, Bartlett S, Ronacher K. Diabetes-Associated Susceptibility to Tuberculosis: Contribution of Hyperglycemia vs. Dyslipidemia. Microorganisms 2021; 9:2282. [PMID: 34835407 PMCID: PMC8620310 DOI: 10.3390/microorganisms9112282] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetes is a major risk factor for tuberculosis (TB). Diabetes increases the risk of the progression from latent tuberculosis infection (LTBI) to active pulmonary TB and TB patients with diabetes are at greater risk of more severe disease and adverse TB treatment outcomes compared to TB patients without co-morbidities. Diabetes is a complex disease, characterised not only by hyperglycemia but also by various forms of dyslipidemia. However, the relative contribution of these underlying metabolic factors to increased susceptibility to TB are poorly understood. This review summarises our current knowledge on the epidemiology and clinical manifestation of TB and diabetes comorbidity. We subsequently dissect the relative contributions of body mass index, hyperglycemia, elevated cholesterol and triglycerides on TB disease severity and treatment outcomes. Lastly, we discuss the impact of selected glucose and cholesterol-lowering treatments frequently used in the management of diabetes on TB treatment outcomes.
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Affiliation(s)
- Minh Dao Ngo
- Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (M.D.N.); (S.B.)
| | - Stacey Bartlett
- Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (M.D.N.); (S.B.)
| | - Katharina Ronacher
- Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (M.D.N.); (S.B.)
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia
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18
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Dong G, Li Y, Zhao Q, Pang B, Qi X, Wei J, Hou W. Effects of diabetes on the development of radiation pneumonitis. Respir Res 2021; 22:160. [PMID: 34030688 PMCID: PMC8147083 DOI: 10.1186/s12931-021-01754-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 05/17/2021] [Indexed: 12/12/2022] Open
Abstract
Radiation pneumonia (RP) is a common adverse reaction to radiation therapy in patients with chest tumors. Recent studies have shown that diabetes mellitus (DM), which can cause systemic multisystem damage, specifically targets lungs, and the incidence of RP in patients with a history of diabetes is higher than that in other patients with tumors who have undergone radiotherapy. DM is an important risk factor for RP in tumor patients undergoing RT, and patients with DM should be treated with caution. This article reviews research on the clinical aspects, as well as the mechanism, of the effects of diabetes on RP and suggests future research needed to reduce RP.
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Affiliation(s)
- Guangtong Dong
- Department of Endocrinology, Guang'anmen Hospital of China Academy of Chinese Medical Sciences, 6 Floors of Inpatients Building, 5 Beixiange Street, Xicheng, Beijing, 100053, China
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuxiao Li
- Department of Oncology, Guang'anmen Hospital of China Academy of Chinese Medical Sciences, 7 Floors of Inpatients Building, 5 Beixiange Street, Xicheng, Beijing, 100053, China
| | - Qiyao Zhao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Bing Pang
- Department of Endocrinology, Guang'anmen Hospital of China Academy of Chinese Medical Sciences, 6 Floors of Inpatients Building, 5 Beixiange Street, Xicheng, Beijing, 100053, China
| | - Xin Qi
- Department of Oncology, Guang'anmen Hospital of China Academy of Chinese Medical Sciences, 7 Floors of Inpatients Building, 5 Beixiange Street, Xicheng, Beijing, 100053, China
| | - Junping Wei
- Department of Endocrinology, Guang'anmen Hospital of China Academy of Chinese Medical Sciences, 6 Floors of Inpatients Building, 5 Beixiange Street, Xicheng, Beijing, 100053, China.
| | - Wei Hou
- Department of Oncology, Guang'anmen Hospital of China Academy of Chinese Medical Sciences, 7 Floors of Inpatients Building, 5 Beixiange Street, Xicheng, Beijing, 100053, China.
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19
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Liao L, Yang GH. Clinical significance of cellular immunity function and inflammatory factors assays in alveolar lavage fluid for severe COVID-19 pneumonia. J Med Virol 2021; 93:2979-2987. [PMID: 33506950 PMCID: PMC8013331 DOI: 10.1002/jmv.26827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/10/2021] [Accepted: 01/25/2021] [Indexed: 01/05/2023]
Abstract
In this study, we aimed to investigate the changes of lymphocyte subsets (CD3+ , CD4+ , CD8+ ) and inflammatory factors (interleukin-6 [IL-6], hypersensitive C-reactive protein [HS-CRP], and procalcitonin [PCT]) of alveolar lavage fluid in patients with severe corona virus-2019 (COVID-19) pneumonia and their clinical impact on the assessment of disease severity and prognosis. Twenty-four patients with severe COVID-19 pneumonia were admitted to the intensive care unit (ICU) of the Ezhou Central Hospital from February 1 to March 22, 2020. According to the 28-day prognosis, they were assigned to a death group and a survival group. On the 3rd day of ICU admission, peripheral blood and alveolar lavage fluid were collected for examination of lymphocyte subsets and inflammatory factors by flow cytometry and immunoturbidimetry, respectively. The CD3+ , CD4+ , and CD8+ cell counts in alveolar lavage fluid and serum were significantly higher in the survival group than those of the death group (p < .05). The levels of IL-6, HS-CRP, and PCT in the alveolar lavage fluid and serum of the death group were statistically higher than those of the survival group (p < .05); The CD3+ , CD4+ cell count, and IL-6 level were negatively correlated with Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II scores, respectively (p < .05). The CD4+ cell and SOFA score have a regression relationship for the prognosis of COVID-19 severe patients. The CD3+ , CD4+ , CD8+ cells, and IL-6 levels are valuable in determining the prognosis of severe COVID-19 pneumonia and are strongly correlated with the severity of the disease; the CD4+ cell is an independent risk factor affecting the prognosis of COVID-19 pneumonia.
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Affiliation(s)
- Liang Liao
- School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou, China
| | - Guo-Hui Yang
- MICU, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
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20
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Kinsella RL, Zhu DX, Harrison GA, Mayer Bridwell AE, Prusa J, Chavez SM, Stallings CL. Perspectives and Advances in the Understanding of Tuberculosis. ANNUAL REVIEW OF PATHOLOGY 2021; 16:377-408. [PMID: 33497258 DOI: 10.1146/annurev-pathol-042120-032916] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a leading cause of death due to infection in humans. To more effectively combat this pandemic, many aspects of TB control must be developed, including better point of care diagnostics, shorter and safer drug regimens, and a protective vaccine. To address all these areas of need, better understanding of the pathogen, host responses, and clinical manifestations of the disease is required. Recently, the application of cutting-edge technologies to the study of Mtb pathogenesis has resulted in significant advances in basic biology, vaccine development, and antibiotic discovery. This leaves us in an exciting era of Mtb research in which our understanding of this deadly infection is improving at a faster rate than ever, and renews hope in our fight to end TB. In this review, we reflect on what is known regarding Mtb pathogenesis, highlighting recent breakthroughs that will provide leverage for the next leaps forward in the field.
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Affiliation(s)
- Rachel L Kinsella
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA;
| | - Dennis X Zhu
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA;
| | - Gregory A Harrison
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA;
| | - Anne E Mayer Bridwell
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA;
| | - Jerome Prusa
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA;
| | - Sthefany M Chavez
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA;
| | - Christina L Stallings
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA;
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21
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Ritter K, Rousseau J, Hölscher C. The Role of gp130 Cytokines in Tuberculosis. Cells 2020; 9:E2695. [PMID: 33334075 PMCID: PMC7765486 DOI: 10.3390/cells9122695] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/01/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022] Open
Abstract
Protective immune responses to Mycobacterium tuberculosis (Mtb) infection substantially depend on a delicate balance within cytokine networks. Thus, immunosuppressive therapy by cytokine blockers, as successfully used in the management of various chronic inflammatory diseases, is often connected with an increased risk for tuberculosis (TB) reactivation. Hence, identification of alternative therapeutics which allow the treatment of inflammatory diseases without compromising anti-mycobacterial immunity remains an important issue. On the other hand, in the context of novel therapeutic approaches for the management of TB, host-directed adjunct therapies, which combine administration of antibiotics with immunomodulatory drugs, play an increasingly important role, particularly to reduce the duration of treatment. In both respects, cytokines/cytokine receptors related to the common receptor subunit gp130 may serve as promising target candidates. Within the gp130 cytokine family, interleukin (IL)-6, IL-11 and IL-27 are most explored in the context of TB. This review summarizes the differential roles of these cytokines in protection and immunopathology during Mtb infection and discusses potential therapeutic implementations with respect to the aforementioned approaches.
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Affiliation(s)
- Kristina Ritter
- Infection Immunology, Research Centre Borstel, D-23845 Borstel, Germany; (K.R.); (J.R.)
| | - Jasmin Rousseau
- Infection Immunology, Research Centre Borstel, D-23845 Borstel, Germany; (K.R.); (J.R.)
| | - Christoph Hölscher
- Infection Immunology, Research Centre Borstel, D-23845 Borstel, Germany; (K.R.); (J.R.)
- German Centre for Infection Research (DZIF), Partner Site Hamburg-Borstel-Lübeck-Riems, D-23845 Borstel, Germany
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22
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Increased susceptibility to Mycobacterium tuberculosis infection in a diet-induced murine model of type 2 diabetes. Microbes Infect 2020; 22:303-311. [PMID: 32234542 DOI: 10.1016/j.micinf.2020.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 02/05/2020] [Accepted: 03/19/2020] [Indexed: 12/18/2022]
Abstract
Tuberculosis (TB)-type 2 diabetes mellitus (T2D) comorbidity is re-emerging as a global public health problem. T2D is a major risk factor for increased susceptibility to TB infection and reactivation leading to higher morbidity and mortality. The pathophysiological mechanisms of T2D contributing to TB susceptibility are not fully understood, but likely involve dysregulated immune responses. In this study, a diet-induced murine model that reflects the cardinal features of human T2D was used to assess the immune responses following an intravenous Mycobacterium tuberculosis (Mtb) infection. In this study, T2D significantly increased mortality, organ bacillary burden and inflammatory lesions compared to non-diabetic controls. Organ-specific pro-inflammatory cytokine responses were dysregulated as early as one day post-infection in T2D mice. Macrophages derived from T2D mice showed reduced bacterial internalization and killing capacity. An early impairment of antimycobacterial functions of macrophages in diabetes is a key mechanism that leads to increased susceptibility of T2D.
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23
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Radhakrishnan RK, Thandi RS, Tripathi D, Paidipally P, McAllister MK, Mulik S, Samten B, Vankayalapati R. BCG vaccination reduces the mortality of Mycobacterium tuberculosis-infected type 2 diabetes mellitus mice. JCI Insight 2020; 5:133788. [PMID: 32161191 DOI: 10.1172/jci.insight.133788] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 01/30/2020] [Indexed: 12/12/2022] Open
Abstract
Diabetes is a significant risk factor for the development of active tuberculosis. In this study, we used a mouse model of type 2 diabetes mellitus (T2DM) to determine the effect of prior Bacillus Calmette-Guérin (BCG) vaccination on immune responses to Mycobacterium tuberculosis (Mtb) infection. We found that, at 6-7 months after Mtb infection, 90% of the Mtb-infected T2DM mice died, whereas only 50% of BCG-vaccinated T2DM-Mtb-infected mice died. Moreover, 40% of the PBS-treated uninfected T2DM mice and 30% of the uninfected BCG-vaccinated T2DM mice died, whereas all uninfected and infected nondiabetic mice survived. BCG vaccination was less effective in reducing the lung bacterial burden of Mtb-infected T2DM mice compared with Mtb-infected nondiabetic mice. BCG vaccination significantly reduced lung inflammation in Mtb-infected T2DM mice compared with that of unvaccinated T2DM mice infected with Mtb. Furthermore, reduced mortality of BCG-vaccinated Mtb-infected T2DM mice is associated with expansion of IL-13-producing CXCR3+ Tregs in the lungs of Mtb-infected T2DM mice. Recombinant IL-13 and Tregs from BCG-vaccinated Mtb-infected T2DM mice converted proinflammatory M1 macrophages to antiinflammatory M2 macrophages. Our findings suggest a potentially novel role for BCG in preventing excess inflammation and mortality in T2DM mice infected with Mtb.
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24
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Ali MK, Zhen G, Nzungize L, Stojkoska A, Duan X, Li C, Duan W, Xu J, Xie J. Mycobacterium tuberculosis PE31 ( Rv3477) Attenuates Host Cell Apoptosis and Promotes Recombinant M. smegmatis Intracellular Survival via Up-regulating GTPase Guanylate Binding Protein-1. Front Cell Infect Microbiol 2020; 10:40. [PMID: 32117813 PMCID: PMC7020884 DOI: 10.3389/fcimb.2020.00040] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 01/21/2020] [Indexed: 12/23/2022] Open
Abstract
The Mycobacterium (M.) tuberculosis comprising proline–glutamic acid (PE) subfamily proteins associate with virulence, pathogenesis, and host-immune modulations. While the functions of most of this family members are not yet explored. Here, we explore the functions of “PE only” subfamily member PE31 (Rv3477) in virulence and host-pathogen interactions. We have expressed the M. tuberculosis PE31 in non-pathogenic Mycobacterium smegmatis strain (Ms_PE31) and demonstrated that PE31 significantly altered the cell facet features including colony morphology and biofilm formation. PE31 expressing M. smegmatis showed more resistant to the low pH, diamide, H2O2 and surface stress. Moreover, Ms_PE31 showed higher intracellular survival in macrophage THP-1 cells. Ms_PE31 significantly down-regulated the production of IL-12p40 and IL-6, while up-regulates the production of IL-10 in macrophages. Ms_PE31 also induced the expression of guanylate-binding protein-1 (GBP-1) in macrophages. Further analysis demonstrates that Ms_PE31 inhibits the caspase-3 activation and reduces the macrophages apoptosis. Besides, the NF-κB signaling pathway involves the interplay between Ms_PE31 and macrophages. Collectively, our finding identified that PE31 act as a functionally relevant virulence factor of M. tuberculosis.
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Affiliation(s)
- Md Kaisar Ali
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
| | - Gong Zhen
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
| | - Lambert Nzungize
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
| | - Andrea Stojkoska
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
| | - Xiangke Duan
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
| | - Chunyan Li
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
| | - Wei Duan
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
| | - Junqi Xu
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
| | - Jianping Xie
- State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China
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Tripathi D, Radhakrishnan RK, Sivangala Thandi R, Paidipally P, Devalraju KP, Neela VSK, McAllister MK, Samten B, Valluri VL, Vankayalapati R. IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis. PLoS Pathog 2019; 15:e1008140. [PMID: 31809521 PMCID: PMC6919622 DOI: 10.1371/journal.ppat.1008140] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 12/18/2019] [Accepted: 10/09/2019] [Indexed: 12/14/2022] Open
Abstract
Previously, we found that pathological immune responses enhance the mortality rate of Mycobacterium tuberculosis (Mtb)-infected mice with type 2 diabetes mellitus (T2DM). In the current study, we evaluated the role of the cytokine IL-22 (known to play a protective role in bacterial infections) and type 3 innate lymphoid cells (ILC3s) in regulating inflammation and mortality in Mtb-infected T2DM mice. IL-22 levels were significantly lower in Mtb-infected T2DM mice than in nondiabetic Mtb-infected mice. Similarly, serum IL-22 levels were significantly lower in tuberculosis (TB) patients with T2DM than in TB patients without T2DM. ILC3s were an important source of IL-22 in mice infected with Mtb, and recombinant IL-22 treatment or adoptive transfer of ILC3s prolonged the survival of Mtb-infected T2DM mice. Recombinant IL-22 treatment reduced serum insulin levels and improved lipid metabolism. Recombinant IL-22 treatment or ILC3 transfer prevented neutrophil accumulation near alveoli, inhibited neutrophil elastase 2 (ELA2) production and prevented epithelial cell damage, identifying a novel mechanism for IL-22 and ILC3-mediated inhibition of inflammation in T2DM mice infected with an intracellular pathogen. Our findings suggest that the IL-22 pathway may be a novel target for therapeutic intervention in T2DM patients with active TB disease.
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Affiliation(s)
- Deepak Tripathi
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Rajesh Kumar Radhakrishnan
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Ramya Sivangala Thandi
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Padmaja Paidipally
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Kamakshi Prudhula Devalraju
- Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India
| | - Venkata Sanjeev Kumar Neela
- Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India
| | - Madeline Kay McAllister
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Buka Samten
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Vijaya Lakshmi Valluri
- Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India
| | - Ramakrishna Vankayalapati
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
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Cadena J, Rathinavelu S, Lopez-Alvarenga JC, Restrepo BI. The re-emerging association between tuberculosis and diabetes: Lessons from past centuries. Tuberculosis (Edinb) 2019; 116S:S89-S97. [PMID: 31085129 DOI: 10.1016/j.tube.2019.04.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 11/02/2018] [Indexed: 12/11/2022]
Abstract
The association between tuberculosis (TB) and diabetes mellitus (DM) had a common place in the literature up to the first half of the 20th century, but virtually disappeared with the discovery of insulin to treat DM and antibiotics to cure TB. In the late 1990s the literature began to re-emerge with the worldwide increase in type 2 DM, particularly in TB-endemic countries. Today, type 2 DM is the most prevalent comorbidity among TB patients and the World Health Organization considers it a threat to TB control. We summarize the literature on TB and DM up to the 1960s. Then we evaluate unique aspects of this comorbidity in older times, such as the frequent diabetic comas that suggest challenges for proper DM management as insulin was being implemented, or the absence of antibiotics to cure TB. Despite the unique aspects of each study period, the literature across times is consistent in key aspects of the association. Namely, a higher TB prevalence among DM (versus non-DM patients), the importance of glucose control and chronic DM on TB susceptibility and the higher risk of death among patients with the co-morbidity. From the older literature, we can infer the likely contribution of type 1 DM to TB (in addition to type 2), regardless of their differing autoimmune or metabolic pathophysiology, respectively. Furthermore, in the older literature there was a notable reporting of DM development among TB patients, even though DM usually preceded TB. This observation deserves further epidemiological and basic studies to elucidate this intriguing aspect of the relationship between TB and DM.
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Affiliation(s)
- Jose Cadena
- University of Texas Health, San Antonio, TX 78229, USA; South Texas Veterans Health Care System, San Antonio TX 78229, USA.
| | - Selvalakshmi Rathinavelu
- University of Texas Health Houston, School of Public Health, Brownsville Campus, Brownsville, TX 78520, USA.
| | - Juan C Lopez-Alvarenga
- University of Texas Rio Grande Valley, South Texas Diabetes and Obesity Institute, School of Medicine, Edinburg, TX 78541, USA
| | - Blanca I Restrepo
- University of Texas Health Houston, School of Public Health, Brownsville Campus, Brownsville, TX 78520, USA; University of Texas Rio Grande Valley, South Texas Diabetes and Obesity Institute, School of Medicine, Edinburg, TX 78541, USA.
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Alim MA, Sikder S, Sathkumara H, Kupz A, Rush CM, Govan BL, Ketheesan N. Dysregulation of key cytokines may contribute to increased susceptibility of diabetic mice to Mycobacterium bovis BCG infection. Tuberculosis (Edinb) 2019; 115:113-120. [PMID: 30948165 DOI: 10.1016/j.tube.2019.02.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 02/11/2019] [Accepted: 02/17/2019] [Indexed: 12/24/2022]
Abstract
Diabetes is one of the major co-morbidities contributing to the high global burden of tuberculosis (TB). The increased susceptibility of individuals with type 2 diabetes (T2D) to TB is multifactorial and may influence the efficacy of vaccines. This study was undertaken to determine the early immune responses that occur following infection with Mycobacterium bovis Bacille Calmette-Guérin (BCG) in a diet-induced murine model of T2D. The phagocytic capabilities of alveolar (AM) and resident peritoneal macrophages (RPM) were assessed using ex vivo assays. Compared to macrophages from non-diabetic mice, macrophages from diabetic animals showed decreased BCG uptake and killing and inflammatory cytokine production (TNF-α, MCP-1, IL-6, IL-1β). In vivo susceptibility to BCG was determined following intravenous infection and diabetic mice showed a trend towards increased mortality, higher bacterial burden in the lung, liver and spleen and increased inflammatory lesions compared to controls. Differences between tissue cytokines were observed as early as one day post-infection and by days 14 and 35, lung and liver TNF-α and IFN-γ levels were decreased in diabetic mice compared to controls. These results suggest that early dysregulated immune responses may influence the susceptibility of T2D mice to BCG infection.
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Affiliation(s)
- Md Abdul Alim
- College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia.
| | - Suchandan Sikder
- College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia.
| | - Harindra Sathkumara
- College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia.
| | - Andreas Kupz
- Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
| | - Catherine M Rush
- College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia.
| | - Brenda L Govan
- College of Public Health, Medical and Veterinary Sciences, Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia.
| | - Natkunam Ketheesan
- School of Science & Technology, University of New England, New South Wales, Australia.
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28
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PPE11 of Mycobacterium tuberculosis can alter host inflammatory response and trigger cell death. Microb Pathog 2018; 126:45-55. [PMID: 30366125 DOI: 10.1016/j.micpath.2018.10.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 08/09/2018] [Accepted: 10/22/2018] [Indexed: 01/23/2023]
Abstract
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), remains a serious global health problem. The PE/PPE family, featuring unique sequences, structures and expression in Mtb, is reported to interfere with the macrophage response to the pathogen and facilitate its infection. PPE11 (Rv0453) existed in pathogenic mycobacteria and was persistently expressed in the infected guinea pig lungs. However, the role it played in the pathogenesis remains unclear. Here, to investigate the interaction and potential mechanism of PPE11 between pathogens and hosts, we heterologously expressed PPE11 in non-pathogenic, rapidly growing Mycobacterium smegmatis strains. We found that the overexpression of the cell wall-associated protein, PPE11, can improve the viability of bacteria in the presence of lysozyme, hydrogen peroxide and acid stress. Expression of PPE11 enhanced the early survival of M. smegmatis in macrophages and sustained a higher bacterial load in mouse tissues that showed exacerbated organ pathology. Macrophages infected with recombinant M. smegmatis produced significantly greater amounts of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and an early decrease in IL-10 along with higher levels of host cell death. Similar cytokines changes were observed in the sera of infected mice. Accordingly, PPE11 protein causes histopathological changes by disrupting the dynamic balance of the inflammatory factors and promoting host-cell death, indicating a potential role in the virulence of Mtb.
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Walwyn-Brown K, Guldevall K, Saeed M, Pende D, Önfelt B, MacDonald AS, Davis DM. Human NK Cells Lyse Th2-Polarizing Dendritic Cells via NKp30 and DNAM-1. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 201:2028-2041. [PMID: 30120122 PMCID: PMC6139540 DOI: 10.4049/jimmunol.1800475] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 07/23/2018] [Indexed: 01/08/2023]
Abstract
Cross-talk between NK cells and dendritic cells (DCs) is important in Th1 immune responses, including antitumor immunity and responses to infections. DCs also play a crucial role in polarizing Th2 immunity, but the impact of NK cell-DC interactions in this context remains unknown. In this study, we stimulated human monocyte-derived DCs in vitro with different pathogen-associated molecules: LPS or polyinosinic-polycytidylic acid, which polarize a Th1 response, or soluble egg Ag from the helminth worm Schistosoma mansoni, a potent Th2-inducing Ag. Th2-polarizing DCs were functionally distinguishable from Th1-polarizing DCs, and both showed distinct morphology and dynamics from immature DCs. We then assessed the outcome of autologous NK cells interacting with these differently stimulated DCs. Confocal microscopy showed polarization of the NK cell microtubule organizing center and accumulation of LFA-1 at contacts between NK cells and immature or Th2-polarizing DCs but not Th1-polarizing DCs, indicative of the assembly of an activating immune synapse. Autologous NK cells lysed immature DCs but not DCs treated with LPS or polyinosinic-polycytidylic acid as reported previously. In this study, we demonstrated that NK cells also degranulated in the presence of Th2-polarizing DCs. Moreover, time-lapse live-cell microscopy showed that DCs that had internalized fluorescently labeled soluble egg Ag were efficiently lysed. Ab blockade of NK cell-activating receptors NKp30 or DNAM-1 abrogated NK cell lysis of Th2-polarizing DCs. Thus, these data indicate a previously unrecognized role of NK cell cytotoxicity and NK cell-activating receptors NKp30 and DNAM-1 in restricting the pool of DCs involved in Th2 immune responses.
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Affiliation(s)
- Katherine Walwyn-Brown
- Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9NT, United Kingdom
| | - Karolin Guldevall
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, SE-106 91 Stockholm, Sweden
| | - Mezida Saeed
- Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9NT, United Kingdom
| | - Daniela Pende
- Laboratorio Immunologia, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Policlinico San Martino, 16132 Genova, Italy; and
| | - Björn Önfelt
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, SE-106 91 Stockholm, Sweden
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Andrew S MacDonald
- Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9NT, United Kingdom
| | - Daniel M Davis
- Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9NT, United Kingdom;
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Preuß BE, Berg CP, Werner C, Plankenhorn S, Malek NP, Klein R. Sulphite oxidase (SO) - a mitochondrial autoantigen as target for humoral and cellular immune reactions in primary sclerosing cholangitis. BMC Gastroenterol 2018; 18:58. [PMID: 29720090 PMCID: PMC5932765 DOI: 10.1186/s12876-018-0787-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 04/24/2018] [Indexed: 12/22/2022] Open
Abstract
Background In a recent study we had evidence that sulphite oxidase (SO) may be a relevant autoantigen in primary sclerosing cholangitis (PSC). Aim of the present study was, therefore, to analyse humoral and cellular immune-reactivity towards SO in these patients in more detail. Methods Sera from 53 patients with PSC (30 untreated and 23 treated with ursodeoxycholic acid [UDCA] at time of analysis), from 422 patients with different hepatic and non-hepatic disorders, and from 50 healthy individuals were tested by ELISA for antibodies against full-length-SO (SO-fl) and its three major domains expressed in E.coli (SO-I, SO-II, SO-III). For epitope-mapping, 29 overlapping peptides were used. Peripheral blood mononuclear cells (PBMC) were obtained from 33 PSC-patients and analysed for SO-induced proliferation, production of cytokines, and expression of the activation marker cluster of differentiation (CD) 69. Results 43% of the 30 untreated and 26% of the 23 treated PSC-patients had IgG anti-SO-antibodies predominantly reacting with SO-fl, SO-I and SO-II. Antibody-reactivity decreased after UDCA-treatment. Prevalence and reactivity of anti-SO-antibodies were significantly higher in PSC than in patients with other hepatic and non-hepatic disorders. Epitope mapping revealed no distinct immuno-dominant regions within SO. Incubation of PBMC from PSC-patients (but not from controls) with SO-antigens revealed an activation of B-cells and a T-helper cell type-2 reaction pattern (production of interleukin [IL]-13, IL-10). Conclusions PSC-patients show humoral and cellular immune response towards SO. Antibodies may be predominantly directed against conformational epitopes. SO enhances in vitro especially T-helper cell type-2 immune-reactions, which may be pro-fibrotic. SO is a detoxifying enzyme present also in bacteria; further studies analysing its role in the aetiology and pathogenesis in PSC may, therefore, be important. Electronic supplementary material The online version of this article (10.1186/s12876-018-0787-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Beate E Preuß
- Department of Internal Medicine II, University of Tuebingen, Otfried-Mueller Str. 11, 72076, Tuebingen, Germany
| | - Christoph P Berg
- Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany
| | - Christoph Werner
- Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany
| | - Sandra Plankenhorn
- Department of Internal Medicine II, University of Tuebingen, Otfried-Mueller Str. 11, 72076, Tuebingen, Germany
| | - Nisar P Malek
- Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany
| | - Reinhild Klein
- Department of Internal Medicine II, University of Tuebingen, Otfried-Mueller Str. 11, 72076, Tuebingen, Germany.
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Ronacher K, van Crevel R, Critchley JA, Bremer AA, Schlesinger LS, Kapur A, Basaraba R, Kornfeld H, Restrepo BI. Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes: Part 2: Underlying Biologic Mechanisms. Chest 2017; 152:174-180. [PMID: 28434937 PMCID: PMC5577357 DOI: 10.1016/j.chest.2017.02.032] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 02/06/2017] [Accepted: 02/09/2017] [Indexed: 12/21/2022] Open
Abstract
There is growing interest in the re-emerging interaction between type 2 diabetes (DM) and TB, but the underlying biologic mechanisms are poorly understood despite their possible implications in clinical management. Experts in epidemiologic, public health, basic science, and clinical studies recently convened and identified research priorities for elucidating the underlying mechanisms for the co-occurrence of TB and DM. We identified gaps in current knowledge of altered immunity in patients with DM during TB, where most studies suggest an underperforming innate immunity, but exaggerated adaptive immunity to Mycobacterium tuberculosis. Various molecular mechanisms and pathways may underlie these observations in the DM host. These include signaling induced by excess advanced glycation end products and their receptor, higher levels of reactive oxidative species and oxidative stress, epigenetic changes due to chronic hyperglycemia, altered nuclear receptors, and/or differences in cell metabolism (immunometabolism). Studies in humans at different stages of DM (no DM, pre-DM, and DM) or TB (latent or active TB) should be complemented with findings in animal models, which provide the unique opportunity to study early events in the host-pathogen interaction. Such studies could also help identify biomarkers that will complement clinical studies in order to tailor the prevention of TB-DM, or to avoid the adverse TB treatment outcomes that are more likely in these patients. Such studies will also inform new approaches to host-directed therapies.
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Affiliation(s)
- Katharina Ronacher
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia; Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical TB Research/Medical Research Council Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
| | - Reinout van Crevel
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radbourd University Medical Center, Nijmegen, the Netherlands
| | - Julia A Critchley
- Population Health Research Institute, St George's, University of London, UK
| | - Andrew A Bremer
- Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Larry S Schlesinger
- Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH
| | - Anil Kapur
- World Diabetes Foundation, Copenhagen, Denmark
| | - Randall Basaraba
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO
| | - Hardy Kornfeld
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Blanca I Restrepo
- School of Public Health, University of Texas Health Science Center Houston, Brownsville, TX
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32
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Kumar Nathella P, Babu S. Influence of diabetes mellitus on immunity to human tuberculosis. Immunology 2017; 152:13-24. [PMID: 28543817 DOI: 10.1111/imm.12762] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 05/10/2017] [Accepted: 05/15/2017] [Indexed: 12/17/2022] Open
Abstract
Type 2 diabetes mellitus(DM) is a major risk factor for the development of active pulmonary tuberculosis (TB), with development of DM pandemic in countries where TB is also endemic. Understanding the impact of DM on TB and the determinants of co-morbidity is essential in responding to this growing public health problem with improved therapeutic approaches. Despite the clinical and public health significance posed by the dual burden of TB and DM, little is known about the immunological and biochemical mechanisms of susceptibility. One possible mechanism is that an impaired immune response in patients with DM facilitates either primary infection with Mycobacterium tuberculosis or reactivation of latent TB. Diabetes is associated with immune dysfunction and alterations in the components of the immune system, including altered levels of specific cytokines and chemokines. Some effects of DM on adaptive immunity that are potentially relevant to TB defence have been identified in humans. In this review, we summarize current findings regarding the alterations in the innate and adaptive immune responses and immunological mechanisms of susceptibility of patients with DM to M. tuberculosis infection and disease.
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Affiliation(s)
- Pavan Kumar Nathella
- National Institutes of Health-International Centre for Excellence in Research, Chennai, India.,National Institute for Research in Tuberculosis, Chennai, India
| | - Subash Babu
- National Institutes of Health-International Centre for Excellence in Research, Chennai, India.,Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Cheekatla SS, Tripathi D, Venkatasubramanian S, Nathella PK, Paidipally P, Ishibashi M, Welch E, Tvinnereim AR, Ikebe M, Valluri VL, Babu S, Kornfeld H, Vankayalapati R. NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection. PLoS Pathog 2016; 12:e1005972. [PMID: 27783671 PMCID: PMC5082658 DOI: 10.1371/journal.ppat.1005972] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 10/03/2016] [Indexed: 01/27/2023] Open
Abstract
In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas all control mice survived. In Mtb-infected mice, T2DM increased the bacterial burden and pro- and anti-inflammatory cytokine and chemokine production in the lungs relative to those in uninfected T2DM mice and infected control mice. Levels of IL-6 also increased. Anti-IL-6 monoclonal antibody treatment of Mtb-infected acute- and chronic-T2DM mice increased survival (to 100%) and reduced pro- and anti-inflammatory cytokine expression. CD11c+ cells were the major source of IL-6 in Mtb-infected T2DM mice. Pulmonary natural killer (NK) cells in Mtb-infected T2DM mice further increased IL-6 production by autologous CD11c+ cells through their activating receptors. Anti-NK1.1 antibody treatment of Mtb-infected acute-T2DM mice increased survival and reduced pro- and anti-inflammatory cytokine expression. Furthermore, IL-6 increased inflammatory cytokine production by T lymphocytes in pulmonary tuberculosis patients with T2DM. Overall, the results suggest that NK-CD11c+ cell interactions increase IL-6 production, which in turn drives the pathological immune response and mortality associated with Mtb infection in diabetic mice.
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Affiliation(s)
- Satyanarayana Swamy Cheekatla
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Deepak Tripathi
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Sambasivan Venkatasubramanian
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Pavan Kumar Nathella
- National Institutes of Health, International Center for Excellence in Research, Chennai, India
| | - Padmaja Paidipally
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Munenori Ishibashi
- Department of Cellular and Molecular Biology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Elwyn Welch
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Amy R. Tvinnereim
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Mitsuo Ikebe
- Department of Cellular and Molecular Biology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | | | - Subash Babu
- National Institutes of Health, International Center for Excellence in Research, Chennai, India
| | - Hardy Kornfeld
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States of America
| | - Ramakrishna Vankayalapati
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
- * E-mail:
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