|
1
|
Londt R, Semple L, Esmail A, Pooran A, Meldau R, Davids M, Dheda K, Tomasicchio M. Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to Mycobacterium tuberculosis. Microorganisms 2025; 13:345. [PMID: 40005712 PMCID: PMC11857998 DOI: 10.3390/microorganisms13020345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025] Open
Abstract
Extensively drug-resistant tuberculosis (XDR-TB) is a public health concern as drug resistance is outpacing the drug development pipeline. Alternative immunotherapeutic approaches are needed. Peripheral blood mononuclear cells (PBMCs) were isolated from pre-XDR/XDR-TB (n = 25) patients and LTBI (n = 18) participants. Thereafter, monocytic-derived dendritic cells (mo-DCs) were co-cultured with M. tb antigens, with/without a maturation cocktail (interferon-γ, interferon-α, CD40L, IL-1β, and TLR3 and TLR7/8 agonists). Two peptide pools were evaluated: (i) an ECAT peptide pool (ESAT6, CFP10, Ag85B, and TB10.4 peptides) and (ii) a PE/PPE peptide pool. Sonicated lysate of the M. tb HN878 strain served as a control. Mo-DCs were assessed for DC maturation markers, Th1 cytokines, and the ability of the DC-primed PBMCs to restrict the growth of M. tb-infected monocyte-derived macrophages. In pre-XDR/XDR-TB, mo-DCs matured with M. tb antigens (ECAT or PE/PPE peptide pool, or HN878 lysate) + cocktail, compared to mo-DCs matured with M. tb antigens only, showed higher upregulation of co-stimulatory molecules and IL-12p70 (p < 0.001 for both comparisons). The matured mo-DCs had enhanced antigen-specific CD8+ T-cell responses to ESAT-6 (p = 0.05) and Ag85B (p = 0.03). Containment was higher with mo-DCs matured with the PE/PPE peptide pool cocktail versus mo-DCs matured with the PE/PPE peptide pool (p = 0.0002). Mo-DCs matured with the PE/PPE peptide pool + cocktail achieved better containment than the ECAT peptide pool + cocktail [50%, (IQR:39-75) versus 46%, (IQR:15-62); p = 0.02]. In patients with pre-XDR/XDR-TB, an effector response primed by mo-DCs matured with an ECAT or PE/PPE peptide pool + cocktail was capable of restricting the growth of M. tb in vitro.
Collapse
Affiliation(s)
- Rolanda Londt
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South Africa
- South Africa MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town 7925, South Africa
| | - Lynn Semple
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South Africa
- South Africa MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town 7925, South Africa
| | - Aliasgar Esmail
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South Africa
- South Africa MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town 7925, South Africa
| | - Anil Pooran
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South Africa
- South Africa MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town 7925, South Africa
| | - Richard Meldau
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South Africa
- South Africa MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town 7925, South Africa
| | - Malika Davids
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South Africa
- South Africa MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town 7925, South Africa
| | - Keertan Dheda
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South Africa
- South Africa MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town 7925, South Africa
- Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
- Faculty of Infectious and Tropical Diseases, Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Michele Tomasicchio
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South Africa
- South Africa MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town 7925, South Africa
| |
Collapse
|
|
2
|
Nisa A, Pinto R, Britton WJ, Triccas JA, Counoupas C. Immunogenicity and Protective Efficacy of a Multi-Antigen Mycobacterium tuberculosis Subunit Vaccine in Mice. Vaccines (Basel) 2024; 12:997. [PMID: 39340027 PMCID: PMC11435920 DOI: 10.3390/vaccines12090997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 09/30/2024] Open
Abstract
There is an urgent need for an effective TB vaccine capable of controlling both acute and chronic Mycobacterium tuberculosis infection in populations with diverse genetic backgrounds. In this study, we characterised the immunogenicity and protective efficacy of a novel protein-in-adjuvant subunit vaccine. The protein component is a fusion protein of three different M. tuberculosis antigens, which we termed CysVac5: CysD, a major component of the M. tuberculosis sulfate activation pathway that is highly expressed during the chronic stage of M. tuberculosis infection, is fused with two major secreted mycobacterial antigens, Ag85B and MPT83. Vaccination of C57BL/6 mice with CysVac5, formulated in a monophosphoryl lipid A (MPLA) and dimethyldioctadecylammonium (DDA) adjuvant combination, resulted in the potent generation of polyfunctional CD4+ T cells secreting multiple cytokines, including IFN-γ, IL-2, TNF and IL-17, against each of the three components of the fusion protein. Furthermore, vaccination with CysVac5-MPLA/DDA conferred significant protection against infection in mouse lungs, which was greater than that afforded by BCG at extended time points post-challenge. The generation of antigen-specific and protective immunity was also observed in CysVac5 vaccinated BALB/c mice, indicating the vaccine could display efficacy across multiple genetic backgrounds. These results indicate that the CysVac5 vaccine has broad immunogenicity, is effective in controlling both acute and chronic phases of M. tuberculosis infection in mice, and warrants further investigation to assess its potential to control pulmonary TB.
Collapse
Affiliation(s)
- Annuurun Nisa
- Faculty of Medicine and Health, The University of Sydney Infectious Diseases Institute (Sydney ID), Camperdown, NSW 2050, Australia; (A.N.); (R.P.)
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
| | - Rachel Pinto
- Faculty of Medicine and Health, The University of Sydney Infectious Diseases Institute (Sydney ID), Camperdown, NSW 2050, Australia; (A.N.); (R.P.)
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
| | - Warwick J. Britton
- Centre for Infection and Immunity, Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia;
- Department of Clinical Immunology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
| | - James A. Triccas
- Faculty of Medicine and Health, The University of Sydney Infectious Diseases Institute (Sydney ID), Camperdown, NSW 2050, Australia; (A.N.); (R.P.)
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
- Centre for Infection and Immunity, Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia;
| | - Claudio Counoupas
- Faculty of Medicine and Health, The University of Sydney Infectious Diseases Institute (Sydney ID), Camperdown, NSW 2050, Australia; (A.N.); (R.P.)
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
- Centre for Infection and Immunity, Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia;
| |
Collapse
|
|
3
|
Khanna H, Gupta S, Sheikh Y. Cell-Mediated Immune Response Against Mycobacterium tuberculosis and Its Potential Therapeutic Impact. J Interferon Cytokine Res 2024; 44:244-259. [PMID: 38607324 DOI: 10.1089/jir.2024.0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2024] Open
Abstract
Cell-mediated immune response is critical for Mycobacterium tuberculosis (M.tb) control. Understanding of pathophysiology and role played by different cell mediators is essential for vaccine development and better management of patients with M.tb. A complex array of cytokines and chemokines are involved in the immune response against M.tb; however, their relative contribution in protection remains to be further explored. The purpose of this review is to summarize the current understanding regarding the cytokine and chemokine profiles in M.tb infection in order to assist research in the field to pursue new direction in prevention and control. We have also summarized recent findings on vaccine trials that have been developed and or are under trials that are targeting these molecules.
Collapse
Affiliation(s)
- Harshika Khanna
- Department of Pediatrics, King George's Medical University, Lucknow, India
| | | | - Yasmeen Sheikh
- Department of Pediatrics, King George's Medical University, Lucknow, India
| |
Collapse
|
|
4
|
Naik L, Patel S, Kumar A, Ghosh A, Mishra A, Das M, Nayak DK, Saha S, Mishra A, Singh R, Behura A, Dhiman R. 4-(Benzyloxy)phenol-induced p53 exhibits antimycobacterial response triggering phagosome-lysosome fusion through ROS-dependent intracellular Ca 2+ pathway in THP-1 cells. Microbiol Res 2024; 282:127664. [PMID: 38422860 DOI: 10.1016/j.micres.2024.127664] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/02/2024]
Abstract
Drug-resistant tuberculosis (TB) outbreak has emerged as a global public health crisis. Therefore, new and innovative therapeutic options like host-directed therapies (HDTs) through novel modulators are urgently required to overcome the challenges associated with TB. In the present study, we have investigated the anti-mycobacterial effect of 4-(Benzyloxy)phenol. Cell-viability assay asserted that 50 μM of 4-(Benzyloxy)phenol was not cytotoxic to phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 (dTHP-1) cells. It was observed that 4-(Benzyloxy)phenol activates p53 expression by hindering its association with KDM1A. Increased ROS, intracellular Ca2+ and phagosome-lysosome fusion, were also observed upon 4-(Benzyloxy)phenol treatment. 4-(Benzyloxy)phenol mediated killing of intracellular mycobacteria was abrogated in the presence of specific inhibitors of ROS, Ca2+ and phagosome-lysosome fusion like NAC, BAPTA-AM, and W7, respectively. We further demonstrate that 4-(Benzyloxy)phenol mediated enhanced ROS production is mediated by acetylation of p53. Blocking of p53 acetylation by Pifithrin-α (PFT- α) enhanced intracellular mycobacterial growth by blocking the mycobactericidal effect of 4-(Benzyloxy)phenol. Altogether, the results showed that 4-(Benzyloxy)phenol executed its anti-mycobacterial effect by modulating p53-mediated ROS production to regulate phagosome-lysosome fusion through Ca2+ production.
Collapse
Affiliation(s)
- Lincoln Naik
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India
| | - Salina Patel
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India
| | - Ashish Kumar
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India
| | - Abhirupa Ghosh
- Divison of Bioinformatics, Bose Institute Kolkata, West Bengal 700054, India
| | - Abtar Mishra
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India
| | - Mousumi Das
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India
| | - Dev Kiran Nayak
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India
| | - Sudipto Saha
- Divison of Bioinformatics, Bose Institute Kolkata, West Bengal 700054, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India
| | - Ramandeep Singh
- Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad-Gurugram Expressway, 3rd Milestone, PO Box # 4, Faridabad, Haryana 121001, India
| | - Assirbad Behura
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
| | - Rohan Dhiman
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
| |
Collapse
|
|
5
|
Nyazema KB, Shey BA, Sei CJ, Peters RP, Maningi NE, Fischer GW, Bernard Fourie P. In vitro evaluation of the binding activity of novel mouse IgG1 opsonic monoclonal antibodies to Mycobacterium tuberculosis and other selected mycobacterial species. J Clin Tuberc Other Mycobact Dis 2024; 35:100435. [PMID: 38601919 PMCID: PMC11004620 DOI: 10.1016/j.jctube.2024.100435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2024] Open
Abstract
Antimicrobial resistance alongside other challenges in tuberculosis (TB) therapeutics have stirred renewed interest in host-directed interventions, including the role of antibodies as adjunct therapeutic agents. This study assessed the binding efficacy of two novel IgG1 opsonic monoclonal antibodies (MABs; GG9 & JG7) at 5, 10, and 25 µg/mL to live cultures of Mycobacterium tuberculosis, M. avium, M. bovis, M. fortuitum, M. intracellulare, and M. smegmatis American Type Culture Collection laboratory reference strains, as well as clinical susceptible, multi-drug resistant, and extensively drug resistant M. tuberculosis strains using indirect enzyme-linked immunosorbent assays. These three MAB concentrations were selected from a range of concentrations used in previous optimization (binding and functional) assays. Both MABs bound to all mycobacterial species and sub-types tested, albeit to varying degrees. Statistically significant differences in MAB binding activity were observed when comparing the highest and lowest MAB concentrations (p < 0.05) for both MABs GG9 and JG7, irrespective of the M. tuberculosis resistance profile. Binding affinity increased with an increase in MAB concentration, and optimal binding was observed at 25 µg/mL. JG7 showed better binding activity than GG9. Both MABs also bound to five MOTT species, albeit at varied levels. This non-selective binding to different mycobacterial species suggests a potential role for GG9 and JG7 as adjunctive agents in anti-TB chemotherapy with the aim to enhance bacterial killing.
Collapse
Affiliation(s)
- Kudzai B. Nyazema
- Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, South Africa
| | - Bong-Akee Shey
- Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, South Africa
| | - Clara J. Sei
- Vaccine and Antibody Development, Longhorn Vaccines and Diagnostics, Gaithersburg, MD, USA
| | - Remco P.H. Peters
- Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, South Africa
- Foundation for Professional Development, Research Unit, East London, South Africa
| | - Nontuthuko E. Maningi
- Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, South Africa
- Department of Microbiology, School of Life Sciences, University of KwaZulu-Natal, South Africa
| | - Gerald W. Fischer
- Vaccine and Antibody Development, Longhorn Vaccines and Diagnostics, Gaithersburg, MD, USA
| | - P. Bernard Fourie
- Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, South Africa
| |
Collapse
|
|
6
|
Gries R, Chhen J, van Gumpel E, Theobald SJ, Sonnenkalb L, Utpatel C, Metzen F, Koch M, Dallenga T, Djaout K, Baulard A, Dal Molin M, Rybniker J. Discovery of dual-active ethionamide boosters inhibiting the Mycobacterium tuberculosis ESX-1 secretion system. Cell Chem Biol 2024; 31:699-711.e6. [PMID: 38181799 DOI: 10.1016/j.chembiol.2023.12.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 08/22/2023] [Accepted: 12/08/2023] [Indexed: 01/07/2024]
Abstract
Drug-resistant Mycobacterium tuberculosis (Mtb) remains a major public health concern requiring complementary approaches to standard anti-tuberculous regimens. Anti-virulence molecules or compounds that enhance the activity of antimicrobial prodrugs are promising alternatives to conventional antibiotics. Exploiting host cell-based drug discovery, we identified an oxadiazole compound (S3) that blocks the ESX-1 secretion system, a major virulence factor of Mtb. S3-treated mycobacteria showed impaired intracellular growth and a reduced ability to lyse macrophages. RNA sequencing experiments of drug-exposed bacteria revealed strong upregulation of a distinct set of genes including ethA, encoding a monooxygenase activating the anti-tuberculous prodrug ethionamide. Accordingly, we found a strong ethionamide boosting effect in S3-treated Mtb. Extensive structure-activity relationship experiments revealed that anti-virulence and ethionamide-boosting activity can be uncoupled by chemical modification of the primary hit molecule. To conclude, this series of dual-active oxadiazole compounds targets Mtb via two distinct mechanisms of action.
Collapse
Affiliation(s)
- Raphael Gries
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 50931 Cologne, Germany
| | - Jason Chhen
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Edeltraud van Gumpel
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Sebastian J Theobald
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Lindsay Sonnenkalb
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, 23845 Borstel, Germany; Molecular and Experimental Mycobacteriology, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany
| | - Christian Utpatel
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, 23845 Borstel, Germany; Molecular and Experimental Mycobacteriology, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany
| | - Fabian Metzen
- Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Manuel Koch
- Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Tobias Dallenga
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, 23845 Borstel, Germany; Cellular Microbiology, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany
| | - Kamel Djaout
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Alain Baulard
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, 59000 Lille, France
| | - Michael Dal Molin
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Jan Rybniker
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 50931 Cologne, Germany.
| |
Collapse
|
|
7
|
da Costa C, Benn CS, Nyirenda T, Mpabalwani E, Grewal HMS, Ahmed R, Kapata N, Nyasulu PS, Maeurer M, Hui DS, Goletti D, Zumla A. Perspectives on development and advancement of new tuberculosis vaccines. Int J Infect Dis 2024; 141S:106987. [PMID: 38417616 DOI: 10.1016/j.ijid.2024.106987] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/17/2024] [Accepted: 02/23/2024] [Indexed: 03/01/2024] Open
Abstract
Tuberculosis (TB) remains a leading cause of death worldwide and is estimated to have caused 1.3 million deaths worldwide in 2022. Approximately one quarter of the world's population are infected with Mycobacterium tuberculosis, of whom up to 10% will progress to developing active TB disease. Achieving the World Health Organization End TB Strategy targets of a 95% reduction in TB mortality and a 90% reduction in TB incidence worldwide by 2035 remains a daunting task. The continuing spread of multidrug-resistant TB adds another obstacle to achieving global TB control. Larger funding pledges coupled with technological advances have recently enabled the enhancement of TB vaccine development efforts. These are yielding a pipeline of over 17 products currently in different stages of clinical trials. Emerging promising phase I and II trial results and advancement to phase III trials have necessitated "vaccine preparedness" in parallel so that a smooth transition from any positive clinical trial result to phase IV evaluation and implementation into policy and practice can follow. Promotion of a human rights-based approach, which recognizes and upholds the fundamental rights of all affected by the disease, is essential to ensure universal access to quality TB vaccines, regardless of their background or personal circumstances.
Collapse
Affiliation(s)
- Christopher da Costa
- Harvard T.H. Chan School of Public Health, Department of Global Health and Population, Boston, MA, USA; Coalition for Epidemic Preparedness Innovations, Research and Development Division, Washington, DC, USA.
| | - Christine S Benn
- Bandim Health Project, University of Southern Denmark, Department of Clinical Research and Danish Institute for Advanced Study, Odense, Denmark
| | - Thomas Nyirenda
- European Developing Countries Clinical Trials partnership (EDCTP) Africa Office, Cape Town, South Africa
| | - Evans Mpabalwani
- University Teaching Hospital, University of Zambia School of Medicine, Department of Paediatrics and Child Health, Lusaka, Zambia
| | - Harleen M S Grewal
- University of Bergen, Department of Clinical Science, Bergen Integrated Diagnostic Stewardship Cluster, Bergen, Norway
| | - Rizwan Ahmed
- Department of Respiratory Medicine, Royal Bolton Hospital, and University of Bolton, Farnworth, Bolton, UK
| | - Nathan Kapata
- Zambia National Public Health Institute, Ministry of Health, Lusaka, Zambia
| | - Peter S Nyasulu
- Stellenbosch University, Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Cape Town, South Africa
| | - Markus Maeurer
- Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal; Johannes Gutenberg University, I Medizinische Klinik, Mainz, Germany
| | - David S Hui
- The Chinese University of Hong Kong, Department of Medicine and Therapeutics and S. H. Ho Research Center for Infectious Diseases, Hong Kong, China
| | - Delia Goletti
- National Institute for Infectious Diseases L. Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico, Translational Research Unit, Department of Epidemiology and Preclinical Research, Rome, Italy
| | - Alimuddin Zumla
- University College London, Center for Clinical Microbiology, Division of Infection and Immunity, and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK
| |
Collapse
|
|
8
|
Bernardini R, Tengattini S, Li Z, Piubelli L, Bavaro T, Modolea AB, Mattei M, Conti P, Marini S, Zhang Y, Pollegioni L, Temporini C, Terreni M. Effect of glycosylation on the affinity of the MTB protein Ag85B for specific antibodies: towards the design of a dual-acting vaccine against tuberculosis. Biol Direct 2024; 19:11. [PMID: 38268026 PMCID: PMC10809592 DOI: 10.1186/s13062-024-00454-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/18/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND To create a dual-acting vaccine that can fight against tuberculosis, we combined antigenic arabino-mannan analogues with the Ag85B protein. To start the process, we studied the impact of modifying different parts of the Ag85B protein on its ability to be recognized by antibodies. RESULTS Through our research, we discovered that three modified versions of the protein, rAg85B-K30R, rAg85B-K282R, and rAg85B-K30R/K282R, retained their antibody reactivity in healthy individuals and those with tuberculosis. To further test the specificity of the sugar AraMan for AraMan antibodies, we used Human Serum Albumin glycosylated with AraMan-IME and Ara3Man-IME. Our findings showed that this specific sugar was fully and specifically modified. Bio-panning experiments revealed that patients with active tuberculosis exhibited a higher antibody response to Ara3Man, a sugar found in lipoarabinomannan (LAM), which is a major component of the mycobacterial cell wall. Bio-panning with anti-LAM plates could eliminate this increased response, suggesting that the enhanced Ara3Man response was primarily driven by antibodies targeting LAM. These findings highlight the importance of Ara3Man as an immunodominant epitope in LAM and support its role in eliciting protective immunity against tuberculosis. Further studies evaluated the effects of glycosylation on the antibody affinity of recombinant Ag85B and its variants. The results indicated that rAg85B-K30R/K282R, when conjugated with Ara3Man-IME, demonstrated enhanced antibody recognition compared to unconjugated or non-glycosylated versions. CONCLUSIONS Coupling Ara3Man to rAg85B-K30R/K282R could lead to the development of effective dual-acting vaccines against tuberculosis, stimulating protective antibodies against both AraMan and Ag85B, two key tuberculosis antigens.
Collapse
Affiliation(s)
- Roberta Bernardini
- Department of Translational Medicine, University of Tor Vergata, Via Montpellier 1, Rome, 00133, Italy.
- Interdepartmental Center for Comparative Medicine, Alternative Techniques and Aquaculture (CIMETA), University of Rome "Tor Vergata", Via Montpellier 1, Rome, 00133, Italy.
| | - Sara Tengattini
- Drug Sciences Department, University of Pavia, Viale Taramelli 12, Pavia, 27100, Italy.
| | - Zhihao Li
- Parisian Institute of Molecular Chemistry, Sorbonne University, UMR CNRS 8232, 4 Place Jussieu, Paris, 75005, France
| | - Luciano Piubelli
- Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant, 3, Insubria, Varese, 21100, Italy
| | - Teodora Bavaro
- Drug Sciences Department, University of Pavia, Viale Taramelli 12, Pavia, 27100, Italy
| | - Anamaria Bianca Modolea
- Interdepartmental Center for Comparative Medicine, Alternative Techniques and Aquaculture (CIMETA), University of Rome "Tor Vergata", Via Montpellier 1, Rome, 00133, Italy
| | - Maurizio Mattei
- Interdepartmental Center for Comparative Medicine, Alternative Techniques and Aquaculture (CIMETA), University of Rome "Tor Vergata", Via Montpellier 1, Rome, 00133, Italy
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Paola Conti
- Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, Milan, 20133, Italy
| | - Stefano Marini
- Department of Translational Medicine, University of Tor Vergata, Via Montpellier 1, Rome, 00133, Italy
| | - Yongmin Zhang
- Parisian Institute of Molecular Chemistry, Sorbonne University, UMR CNRS 8232, 4 Place Jussieu, Paris, 75005, France
| | - Loredano Pollegioni
- Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant, 3, Insubria, Varese, 21100, Italy
| | - Caterina Temporini
- Drug Sciences Department, University of Pavia, Viale Taramelli 12, Pavia, 27100, Italy
| | - Marco Terreni
- Drug Sciences Department, University of Pavia, Viale Taramelli 12, Pavia, 27100, Italy
| |
Collapse
|
|
9
|
Chen J, Tang F, Li H, Wu X, Yang Y, Liu Z, Huang X, Wang J, Zheng R, Wang L, Liu H, Xu J, Wang P, Liu F. Mycobacterium tuberculosis suppresses APLP2 expression to enhance its survival in macrophage. Int Immunopharmacol 2023; 124:111058. [PMID: 37844466 DOI: 10.1016/j.intimp.2023.111058] [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: 08/17/2023] [Revised: 10/04/2023] [Accepted: 10/09/2023] [Indexed: 10/18/2023]
Abstract
Mycobacterium tuberculosis (M.tb), the most successful pathogen responsible for approximately 1.6 million deaths in 2021, employs various strategies to evade host antibacterial defenses, including mechanisms to counteract nitric oxide (NO) and certain cytokines. While Amyloid β (A4) precursor-like protein 2 (Aplp2) has been implicated in various physiological and pathological processes, its role in tuberculosis (TB) pathogenesis remains largely uncharted. This study unveils a significant reduction in Aplp2 levels in TB patients, M.tb-infected macrophages, and mice. Intriguingly, Aplp2 mutation or knockdown results in diminished macrophage-mediated killing of M.tb, accompanied by decreased inducible nitric oxide synthase (iNOS) expression and reduced cytokine production, notably interleukin-1β (Il-1β). Notably, Aplp2 mutant mice exhibit heightened susceptibility to mycobacterial infection, evident through aggravated histopathological damage and increased lung bacterial loads, in contrast to Mycobacterium bovis BCG-infected wild-type (WT) mice. Mechanistically, the cleaved product of APLP2, AICD2, generated by γ-secretase, translocates to the nucleus, where it interacts with p65, culminating in enhanced the nuclear factor κB (NF-κB) transcriptional activity. This interaction triggers the upregulation of Il-1β and iNOS expression. Collectively, our findings illuminate Aplp2's pivotal role in safeguarding against mycobacterial infections by promoting M.tb clearance through NO- or IL-1β-mediated bactericidal effects. Therefore, we unveil a novel immune evasion strategy employed by M.tb, which could potentially serve as a target for innovative TB interventions.
Collapse
Affiliation(s)
- Jianxia Chen
- Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Fen Tang
- Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Haohao Li
- Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Xiangyang Wu
- Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Yong Yang
- Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Zhonghua Liu
- Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Xiaochen Huang
- Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Jie Wang
- Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Ruijuan Zheng
- Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Lin Wang
- Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Haipeng Liu
- Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Junfang Xu
- Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Peng Wang
- Department of TB, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
| | - Feng Liu
- Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai JiaoTong University, Shanghai Sixth People's Hospital Affiliated to JiaoTong University Medical School, Shanghai 200233, China.
| |
Collapse
|
|
10
|
Gupta PK, Jahagirdar P, Tripathi D, Devarajan PV, Kulkarni S. Macrophage targeted polymeric curcumin nanoparticles limit intracellular survival of Mycobacterium tuberculosis through induction of autophagy and augment anti-TB activity of isoniazid in RAW 264.7 macrophages. Front Immunol 2023; 14:1233630. [PMID: 37583694 PMCID: PMC10424441 DOI: 10.3389/fimmu.2023.1233630] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/12/2023] [Indexed: 08/17/2023] Open
Abstract
Rapid emergence of antibiotic resistance in tuberculosis has left us with limited resources to treat and manage multi drug resistant (MDR) cases of tuberculosis, prompting the development of novel therapeutics. Mycobacterium tuberculosis (MTB) perturbs the host protective pathways for its survival, therefore host directed therapeutic (HDT) interventions offer an attractive alternative strategy. Curcumin (CMN), the principle curcuminoid from Curcuma longa is known to have anti-TB activity against MDR strains of MTB in macrophages. We discovered that treatment of CMN induced autophagy in uninfected and MTB infected macrophages which was evident by conversion of LC3-I to LC3-II and degradation of p62. Inhibition of autophagy by a pharmacological inhibitor 3-MA resulted in significant inhibition of intracellular killing activity of CMN, suggesting the involvement of autophagy in intracellular clearance of MTB. Moreover, annexin v-FITC/PI staining data suggested induction of apoptosis in uninfected and MTB infected macrophages post CMN treatment. This finding was further corroborated by up-regulated expression of pro-apoptotic proteins, Bax, cleaved caspase-3 and PARP and diminished expression of anti-apoptotic protein Bcl-2 as evaluated by immunoblotting. Using GFP-MTB H37Rv and Lysotracker Red staining we demonstrated co-localization of GFP-MTB H37Rv containing phagosome to lysosome after CMN treatment, indicating enhanced phagosome lysosome fusion. Due to poor bioavailability of CMN, its clinical use is limited, therefore to overcome this issue, CMN was encapsulated in Poly(lactic-co-glycolic) acid (PLGA) shell, resulting in polymeric CMN nano particles (ISCurNP). Flow cytometric evaluation suggested >99% uptake of ISCurNP after 3h of treatment. In BALB/c mice, oral dose of ISCurNP resulted in 6.7-fold increase in the bioavailability compared to free CMN. Moreover, ISCurNP treatment resulted in significant decrease in the intracellular survival of MTB H37Rv through induction of autophagy. Adjunct action of ISCurNP and CMN in combination with isoniazid (INH) revealed >99% decrease in intracellular survival of MTB in macrophage as compared to ISCurNP, CMN or INH alone. In conclusion, our findings suggest the role of ISCurNP as novel host directed formulation to combat both sensitive and MDR strains of MTB by induction of autophagy.
Collapse
Affiliation(s)
- Pramod Kumar Gupta
- Tuberculosis Immunology and Immunoassay Development Section, Radiation Medicine Centre, Bhabha Atomic Research Centre, Mumbai, India
- Faculty of Life Science, Homi Bhabha National Institute, Mumbai, India
| | - Priyanka Jahagirdar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
| | - Devavrat Tripathi
- Tuberculosis Immunology and Immunoassay Development Section, Radiation Medicine Centre, Bhabha Atomic Research Centre, Mumbai, India
| | - Padma V. Devarajan
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
| | - Savita Kulkarni
- Tuberculosis Immunology and Immunoassay Development Section, Radiation Medicine Centre, Bhabha Atomic Research Centre, Mumbai, India
- Faculty of Life Science, Homi Bhabha National Institute, Mumbai, India
| |
Collapse
|
|
11
|
Singh B, Moodley C, Singh DK, Escobedo RA, Sharan R, Arora G, Ganatra SR, Shivanna V, Gonzalez O, Hall-Ursone S, Dick EJ, Kaushal D, Alvarez X, Mehra S. Inhibition of indoleamine dioxygenase leads to better control of tuberculosis adjunctive to chemotherapy. JCI Insight 2023; 8:e163101. [PMID: 36692017 PMCID: PMC9977315 DOI: 10.1172/jci.insight.163101] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 11/30/2022] [Indexed: 01/24/2023] Open
Abstract
The expression of indoleamine 2,3-dioxygenase (IDO), a robust immunosuppressant, is significantly induced in macaque tuberculosis (TB) granulomas, where it is expressed on IFN-responsive macrophages and myeloid-derived suppressor cells. IDO expression is also highly induced in human TB granulomas, and products of its activity are detected in patients with TB. In vivo blockade of IDO activity resulted in the reorganization of the granuloma with substantially greater T cells being recruited to the core of the lesions. This correlated with better immune control of TB and reduced lung M. tuberculosis burdens. To study if the IDO blockade strategy can be translated to a bona fide host-directed therapy in the clinical setting of TB, we studied the effect of IDO inhibitor 1-methyl-d-tryptophan adjunctive to suboptimal anti-TB chemotherapy. While two-thirds of controls and one-third of chemotherapy-treated animals progressed to active TB, inhibition of IDO adjunctive to the same therapy protected macaques from TB, as measured by clinical, radiological, and microbiological attributes. Although chemotherapy improved proliferative T cell responses, adjunctive inhibition of IDO further enhanced the recruitment of effector T cells to the lung. These results strongly suggest the possibility that IDO inhibition can be attempted adjunctive to anti-TB chemotherapy in clinical trials.
Collapse
|
|
12
|
Udinia S, Suar M, Kumar D. Host-directed therapy against tuberculosis: Concept and recent developments. J Biosci 2023; 48:54. [PMID: 38088376 DOI: 10.1007/s12038-023-00374-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 02/28/2023] [Indexed: 01/04/2025]
Abstract
Tuberculosis (TB) continues to remain at the forefront of the infectious disease burden globally, albeit with some aberrations during the COVID-19 pandemic. Among many factors, the emergence of drug resistance or antimicrobial resistance (AMR) has necessitated a renewed focus on developing novel and repurposed drugs against TB. Host-directed therapy (HDT) has emerged as an attractive alternative and a complementary strategy to the conventional antibiotic-based therapy of tuberculosis since HDT enjoys the advantage of disarming the pathogen of its ability to develop drug resistance. Considering the imminent threat of AMR across the spectrum of bacterial pathogens, HDT promises to overcome the drug shortage against superbugs. While all these make HDT a very attractive strategy, identifying the right set of host targets to develop HDT remains a challenge, despite remarkable development in the field over the past decade. In this review, we examine the host mechanisms, that either inadvertently or through targeted perturbation by the pathogen, help TB pathogenesis, and we discuss the latest developments in the targeting of some of the key pathways to achieve newer TB therapeutics.
Collapse
Affiliation(s)
- Sonakshi Udinia
- Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | | | | |
Collapse
|
|
13
|
Schaberg T, Brinkmann F, Feiterna-Sperling C, Geerdes-Fenge H, Hartmann P, Häcker B, Hauer B, Haas W, Heyckendorf J, Lange C, Maurer FP, Nienhaus A, Otto-Knapp R, Priwitzer M, Richter E, Salzer HJ, Schoch O, Schönfeld N, Stahlmann R, Bauer T. Tuberkulose im Erwachsenenalter. Pneumologie 2022; 76:727-819. [DOI: 10.1055/a-1934-8303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
ZusammenfassungDie Tuberkulose ist in Deutschland eine seltene, überwiegend gut behandelbare Erkrankung. Weltweit ist sie eine der häufigsten Infektionserkrankungen mit ca. 10 Millionen Neuerkrankungen/Jahr. Auch bei einer niedrigen Inzidenz in Deutschland bleibt Tuberkulose insbesondere aufgrund der internationalen Entwicklungen und Migrationsbewegungen eine wichtige Differenzialdiagnose. In Deutschland besteht, aufgrund der niedrigen Prävalenz der Erkrankung und der damit verbundenen abnehmenden klinischen Erfahrung, ein Informationsbedarf zu allen Aspekten der Tuberkulose und ihrer Kontrolle. Diese Leitlinie umfasst die mikrobiologische Diagnostik, die Grundprinzipien der Standardtherapie, die Behandlung verschiedener Organmanifestationen, den Umgang mit typischen unerwünschten Arzneimittelwirkungen, die Besonderheiten in der Diagnostik und Therapie resistenter Tuberkulose sowie die Behandlung bei TB-HIV-Koinfektion. Sie geht darüber hinaus auf Versorgungsaspekte und gesetzliche Regelungen wie auch auf die Diagnosestellung und präventive Therapie einer latenten tuberkulösen Infektion ein. Es wird ausgeführt, wann es der Behandlung durch spezialisierte Zentren bedarf.Die Aktualisierung der S2k-Leitlinie „Tuberkulose im Erwachsenenalter“ soll allen in der Tuberkuloseversorgung Tätigen als Richtschnur für die Prävention, die Diagnose und die Therapie der Tuberkulose dienen und helfen, den heutigen Herausforderungen im Umgang mit Tuberkulose in Deutschland gewachsen zu sein.
Collapse
Affiliation(s)
- Tom Schaberg
- Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose e. V. (DZK), Berlin
| | - Folke Brinkmann
- Abteilung für pädiatrische Pneumologie/CF-Zentrum, Universitätskinderklinik der Ruhr-Universität Bochum, Bochum
| | - Cornelia Feiterna-Sperling
- Klinik für Pädiatrie mit Schwerpunkt Pneumologie, Immunologie und Intensivmedizin, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Berlin
| | | | - Pia Hartmann
- Labor Dr. Wisplinghoff Köln, Klinische Infektiologie, Köln
- Department für Klinische Infektiologie, St. Vinzenz-Hospital, Köln
| | - Brit Häcker
- Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose e. V. (DZK), Berlin
| | | | | | - Jan Heyckendorf
- Klinik für Innere Medizin I, Universitätsklinikum Schleswig-Holstein, Campus Kiel
| | - Christoph Lange
- Klinische Infektiologie, Forschungszentrum Borstel
- Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hamburg-Lübeck-Borstel-Riems
- Respiratory Medicine and International Health, Universität zu Lübeck, Lübeck
- Baylor College of Medicine and Texas Childrenʼs Hospital, Global TB Program, Houston, TX, USA
| | - Florian P. Maurer
- Nationales Referenzzentrum für Mykobakterien, Forschungszentrum Borstel, Borstel
- Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Hamburg-Eppendorf, Hamburg
| | - Albert Nienhaus
- Institut für Versorgungsforschung in der Dermatologie und bei Pflegeberufen (IVDP), Universitätsklinikum Hamburg Eppendorf (UKE), Hamburg
| | - Ralf Otto-Knapp
- Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose e. V. (DZK), Berlin
| | | | | | | | | | | | - Ralf Stahlmann
- Institut für klinische Pharmakologie und Toxikologie, Charité Universitätsmedizin, Berlin
| | - Torsten Bauer
- Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose e. V. (DZK), Berlin
- Lungenklinik Heckeshorn, Helios Klinikum Emil von Behring, Berlin
| |
Collapse
|
|
14
|
Novel Antibacterial Activity of Febuxostat, an FDA-Approved Antigout Drug against Mycobacterium tuberculosis Infection. Antimicrob Agents Chemother 2022; 66:e0076222. [PMID: 36040172 PMCID: PMC9487535 DOI: 10.1128/aac.00762-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Accumulating evidence suggests that drug repurposing has drawn attention as an anticipative strategy for controlling tuberculosis (TB), considering the dwindling drug discovery and development pipeline. In this study, we explored the antigout drug febuxostat and evaluated its antibacterial activity against Mycobacterium species. Based on MIC evaluation, we found that febuxostat treatment significantly inhibited mycobacterial growth, especially that of Mycobacterium tuberculosis (Mtb) and its phylogenetically close neighbors, M. bovis, M. kansasii, and M. shinjukuense, but these microorganisms were not affected by allopurinol and topiroxostat, which belong to a similar category of antigout drugs. Febuxostat concentration-dependently affected Mtb and durably mediated inhibitory functions (duration, 10 weeks maximum), as evidenced by resazurin microtiter assay, time-kill curve analysis, phenotypic susceptibility test, and the Bactec MGIT 960 system. Based on these results, we determined whether the drug shows antimycobacterial activity against Mtb inside murine bone marrow-derived macrophages (BMDMs). Notably, febuxostat markedly suppressed the intracellular growth of Mtb in a dose-dependent manner without affecting the viability of BMDMs. Moreover, orally administered febuxostat was efficacious in a murine model of TB with reduced bacterial loads in both the lung and spleen without the exacerbation of lung inflammation, which highlights the drug potency. Taken together, unexpectedly, our data demonstrated that febuxostat has the potential for treating TB.
Collapse
|
|
15
|
Kim H, Shin SJ. Pathological and protective roles of dendritic cells in Mycobacterium tuberculosis infection: Interaction between host immune responses and pathogen evasion. Front Cell Infect Microbiol 2022; 12:891878. [PMID: 35967869 PMCID: PMC9366614 DOI: 10.3389/fcimb.2022.891878] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Dendritic cells (DCs) are principal defense components that play multifactorial roles in translating innate immune responses to adaptive immunity in Mycobacterium tuberculosis (Mtb) infections. The heterogeneous nature of DC subsets follows their altered functions by interacting with other immune cells, Mtb, and its products, enhancing host defense mechanisms or facilitating pathogen evasion. Thus, a better understanding of the immune responses initiated, promoted, and amplified or inhibited by DCs in Mtb infection is an essential step in developing anti-tuberculosis (TB) control measures, such as host-directed adjunctive therapy and anti-TB vaccines. This review summarizes the recent advances in salient DC subsets, including their phenotypic classification, cytokine profiles, functional alterations according to disease stages and environments, and consequent TB outcomes. A comprehensive overview of the role of DCs from various perspectives enables a deeper understanding of TB pathogenesis and could be useful in developing DC-based vaccines and immunotherapies.
Collapse
|
|
16
|
Prathapan P. A determination of pan-pathogen antimicrobials? MEDICINE IN DRUG DISCOVERY 2022; 14:100120. [PMID: 35098103 PMCID: PMC8785259 DOI: 10.1016/j.medidd.2022.100120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/01/2022] [Accepted: 01/17/2022] [Indexed: 11/29/2022] Open
Abstract
While antimicrobial drug development has historically mitigated infectious diseases that are known, COVID-19 revealed a dearth of 'in-advance' therapeutics suitable for infections by pathogens that have not yet emerged. Such drugs must exhibit a property that is antithetical to the classical paradigm of antimicrobial development: the ability to treat infections by any pathogen. Characterisation of such 'pan-pathogen' antimicrobials requires consolidation of drug repositioning studies, a new and growing field of drug discovery. In this review, a previously-established system for evaluating repositioning studies is used to highlight 4 therapeutics which exhibit pan-pathogen properties, namely azithromycin, ivermectin, niclosamide, and nitazoxanide. Recognition of the pan-pathogen nature of these antimicrobials is the cornerstone of a novel paradigm of antimicrobial development that is not only anticipatory of pandemics and bioterrorist attacks, but cognisant of conserved anti-infective mechanisms within the host-pathogen interactome which are only now beginning to emerge. Ultimately, the discovery of pan-pathogen antimicrobials is concomitantly the discovery of a new class of antivirals, and begets significant implications for pandemic preparedness research in a world after COVID-19.
Collapse
Affiliation(s)
- Praveen Prathapan
- New Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom
| |
Collapse
|
|
17
|
Zare S, Kabiri M, Amini Y, Najafi A, Mohammadpour F, Ayati SH, Nikpoor AR, Tafaghodi M. Immunological Assessment of Chitosan or Trimethyl Chitosan-Coated PLGA Nanospheres Containing Fusion Antigen as the Novel Vaccine Candidates Against Tuberculosis. AAPS PharmSciTech 2021; 23:15. [PMID: 34893923 DOI: 10.1208/s12249-021-02146-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 09/19/2021] [Indexed: 01/02/2023] Open
Abstract
The crucial challenge in tuberculosis (TB) as a chronic infectious disease is to present a novel vaccine candidate that improves current vaccination and provides efficient protection in individuals. The present study aimed to evaluate the immune efficacy of multi-subunit vaccines containing chitosan (CHT)- or trimethyl chitosan (TMC)-coated PLGA nanospheres to stimulate cell-mediated and mucosal responses against Mycobacterium Tuberculosis (Mtb) in an animal model. The surface-modified PLGA nanoparticles (NPs) containing tri-fusion protein from three Mtb antigens were produced by the double emulsion technique. The subcutaneously or nasally administered PLGA vaccines in the absence or presence of BCG were assessed to compare the levels of mucosal IgA, IgG1, and IgG2a production as well as secretion of IFN-γ, IL-17, IL-4, and TGF-β cytokines. According to the release profile, the tri-fusion encapsulated in modified PLGA NPs demonstrated a biphasic release profile including initial burst release on the first day and sustained release within 18 days. All designed PLGA vaccines induced a shift of Th1/Th2 balance toward Th1-dominant response. Although immunized mice through subcutaneous injection elicited higher cell-mediated responses relative to the nasal vaccination, the intranasally administered groups stimulated robust mucosal IgA immunity. The modified PLGA NPs using TMC cationic polymer were more efficient to elevate Th1 and mucosal responses in comparison with the CHT-coated PLGA nanospheres. Our findings highlighted that the tri-fusion loaded in TMC-PLGA NPs may represent an efficient prophylactic vaccine and can be considered as a novel candidate against TB.
Collapse
|
|
18
|
Bhatt K, Bhagavathula M, Verma S, Timmins GS, Deretic VP, Ellner JJ, Salgame P. Rapamycin modulates pulmonary pathology in a murine model of Mycobacterium tuberculosis infection. Dis Model Mech 2021; 14:dmm049018. [PMID: 34486033 PMCID: PMC8560501 DOI: 10.1242/dmm.049018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 09/01/2021] [Indexed: 12/14/2022] Open
Abstract
Tuberculosis (TB) treatment regimens are lengthy, causing non-adherence to treatment. Inadequate treatment can lead to relapse and the development of drug resistance TB. Furthermore, patients often exhibit residual lung damage even after cure, increasing the risk for relapse and development of other chronic respiratory illnesses. Host-directed therapeutics are emerging as an attractive means to augment the success of TB treatment. In this study, we used C3HeB/FeJ mice as an experimental model to investigate the potential role of rapamycin, a mammalian target of rapamycin inhibitor, as an adjunctive therapy candidate during the treatment of Mycobacterium tuberculosis infection with moxifloxacin. We report that administration of rapamycin with or without moxifloxacin reduced infection-induced lung inflammation, and the number and size of caseating necrotic granulomas. Results from this study strengthen the potential use of rapamycin and its analogs as adjunct TB therapy, and importantly underscore the utility of the C3HeB/FeJ mouse model as a preclinical tool for evaluating host-directed therapy candidates for the treatment of TB.
Collapse
Affiliation(s)
- Kamlesh Bhatt
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Madhuri Bhagavathula
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Sheetal Verma
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Graham S. Timmins
- Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA
| | - Vojo P. Deretic
- Autophagy Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Jerrold J. Ellner
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Padmini Salgame
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| |
Collapse
|
|
19
|
Heijmenberg I, Husain A, Sathkumara HD, Muruganandah V, Seifert J, Miranda-Hernandez S, Kashyap RS, Field MA, Krishnamoorthy G, Kupz A. ESX-5-targeted export of ESAT-6 in BCG combines enhanced immunogenicity & efficacy against murine tuberculosis with low virulence and reduced persistence. Vaccine 2021; 39:7265-7276. [PMID: 34420788 DOI: 10.1016/j.vaccine.2021.08.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/08/2021] [Accepted: 08/06/2021] [Indexed: 11/16/2022]
Abstract
Tuberculosis (TB) is the leading infectious cause of death globally. The only licensed TB vaccine, Bacille Calmette-Guérin (BCG), has low efficacy against TB in adults and is not recommended in people with impaired immunity. The incorporation of the Mycobacterium tuberculosis (Mtb) secretion system ESX-1 into BCG improves immunogenicity and protection against TB in animal models, which is associated with the secretion of the ESX-1-dependent protein ESAT-6. However, the resulting strain, BCG::ESX1Mtb, has been deemed unsafe as a human vaccine, due to prolonged persistence and increased virulence in immunocompromised mice. In this study, we describe a new recombinant BCG strain that uncouples the beneficial aspects of ESAT-6 secretion from the detrimental ESX-1effects on virulence and persistence. The strain was constructed by fusing the ESAT-6-encoding gene esxA to the general secretion signal for the mycobacterial type VII secretion pathway protein PE25. This new strain, BCG::ESAT6-PE25SS, secretes full-length ESAT-6 via the ESX-5 secretion system, which in contrast to ESX-1 is also present in BCG. In vivo testing revealed that ESX-5-targeted ESAT-6 export, induces cytosolic contact, generates ESAT-6-specific T cells and enhances the protective efficacy against TB disease, but is associated with low virulence and reduced persistence in immunocompetent and immunocompromised mice. Additionally, compared to BCG::ESX1Mtb and parental BCG, mucosal administration of BCG::ESAT6-PE25SS is associated with more rapid clearance from the lung. These results warrant further studies to evaluate BCG::ESAT6-PE25SS as a potential live attenuated vaccine candidate for TB.
Collapse
Affiliation(s)
- Isis Heijmenberg
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4878 & Townsville 4811, Queensland, Australia; Leiden University, Leiden 2311, the Netherlands
| | - Aliabbas Husain
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4878 & Townsville 4811, Queensland, Australia; Central India Institute of Medical Sciences, 88/2, Bajaj Nagar, Nagpur 10, India
| | - Harindra D Sathkumara
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4878 & Townsville 4811, Queensland, Australia
| | - Visai Muruganandah
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4878 & Townsville 4811, Queensland, Australia
| | - Julia Seifert
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4878 & Townsville 4811, Queensland, Australia
| | - Socorro Miranda-Hernandez
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4878 & Townsville 4811, Queensland, Australia
| | - Rajpal Singh Kashyap
- Central India Institute of Medical Sciences, 88/2, Bajaj Nagar, Nagpur 10, India
| | - Matt A Field
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4878 & Townsville 4811, Queensland, Australia; Centre for Tropical Bioinformatics and Molecular Biology, James Cook University, Cairns 4878, Queensland, Australia; John Curtin School of Medical Research, Australian National University, Canberra 2601, ACT, Australia
| | | | - Andreas Kupz
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4878 & Townsville 4811, Queensland, Australia.
| |
Collapse
|
|
20
|
Miow QH, Vallejo AF, Wang Y, Hong JM, Bai C, Teo FS, Wang AD, Loh HR, Tan TZ, Ding Y, She HW, Gan SH, Paton NI, Lum J, Tay A, Chee CB, Tambyah PA, Polak ME, Wang YT, Singhal A, Elkington PT, Friedland JS, Ong CW. Doxycycline host-directed therapy in human pulmonary tuberculosis. J Clin Invest 2021; 131:e141895. [PMID: 34128838 DOI: 10.1172/jci141895] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 06/11/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUNDMatrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.METHODSThirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care.RESULTSWhole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe.CONCLUSIONAdjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATIONClinicalTrials.gov NCT02774993.FUNDINGSingapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.
Collapse
Affiliation(s)
- Qing Hao Miow
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Andres F Vallejo
- Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Yu Wang
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jia Mei Hong
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Chen Bai
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Felicia Sw Teo
- Division of Respiratory and Critical Care Medicine, University Medicine Cluster, National University Hospital, National University Health System, Singapore
| | - Alvin Dy Wang
- Department of Medicine, Ng Teng Fong General Hospital, Singapore
| | - Hong Rong Loh
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Ying Ding
- National Centre for Infectious Diseases, Singapore
| | - Hoi Wah She
- Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore
| | - Suay Hong Gan
- Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore
| | - Nicholas I Paton
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Alicia Tay
- Singapore Immunology Network, A*STAR, Singapore
| | - Cynthia Be Chee
- Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore
| | - Paul A Tambyah
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Marta E Polak
- Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.,Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Yee Tang Wang
- Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore
| | | | - Paul T Elkington
- NIHR Respiratory Biomedical Research Centre, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | | | - Catherine Wm Ong
- Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Institute for Health Innovation and Technology, National University of Singapore, Singapore
| |
Collapse
|
|
21
|
Wu X, Wu Y, Zheng R, Tang F, Qin L, Lai D, Zhang L, Chen L, Yan B, Yang H, Wang Y, Li F, Zhang J, Wang F, Wang L, Cao Y, Ma M, Liu Z, Chen J, Huang X, Wang J, Jin R, Wang P, Sun Q, Sha W, Lyu L, Moura‐Alves P, Dorhoi A, Pei G, Zhang P, Chen J, Gao S, Randow F, Zeng G, Chen C, Ye X, Kaufmann SHE, Liu H, Ge B. Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection. EMBO Rep 2021; 22:e51678. [PMID: 33987949 PMCID: PMC8256295 DOI: 10.15252/embr.202051678] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 04/10/2021] [Accepted: 04/16/2021] [Indexed: 12/14/2022] Open
Abstract
Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.
Collapse
|
|
22
|
de Castro CP, Souza BM, Mancha-Agresti P, Pereira VB, Zurita-Turk M, Preisser TM, da Cunha VP, Dos Santos JSC, Leclercq SY, Azevedo V, Miyoshi A. Lactococcus lactis FNBPA + (pValac: e6ag85a) Induces Cellular and Humoral Immune Responses After Oral Immunization of Mice. Front Microbiol 2021; 12:676172. [PMID: 34093498 PMCID: PMC8173160 DOI: 10.3389/fmicb.2021.676172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/23/2021] [Indexed: 11/13/2022] Open
Abstract
The development of a new vaccine strategy against tuberculosis is urgently needed and has been greatly encouraged by the scientific community worldwide. In this work, we constructed a lactococcal DNA vaccine based on the fusion of two Mycobacterium tuberculosis antigens, ESAT-6 and Ag85A, and examined its immunogenicity. The coding sequences of the ESAT-6 and Ag85A genes were fused and cloned into the eukaryotic expression pValac vector, and the functionality of the vector was confirmed in vitro. Then, L. lactis FnBPA+ (pValac:e6ag85a) was obtained and used for oral immunization of mice. This strain induced significant increases in IFN-γ, TNF-α, and IL-17 cytokines in stimulated splenocyte cultures, and significant production of antigen-specific sIgA was observed in the colonic tissues of immunized mice. We demonstrated that L. lactis FnBPA+ (pValac:e6ag85a) generated a cellular and humoral immune response after oral immunization of mice. The strategy developed in this work may represent an interesting DNA mucosal vaccine candidate against tuberculosis, using the fusion of two highly immunogenic antigens delivered by safe lactic acid bacteria.
Collapse
Affiliation(s)
- Camila Prósperi de Castro
- Laboratory of Genetic Technology, Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Bianca Mendes Souza
- Laboratory of Genetic Technology, Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Pamela Mancha-Agresti
- Laboratory of Cellular and Molecular Genetics, Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Vanessa Bastos Pereira
- Laboratory of Genetic Technology, Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Meritxell Zurita-Turk
- Laboratory of Genetic Technology, Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Tatiane Melo Preisser
- Laboratory of Genetic Technology, Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Vanessa Pecini da Cunha
- Laboratory of Genetic Technology, Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Janete Soares Coelho Dos Santos
- Laboratory of Biotechnological Innovation, Research and Development Directorate, Ezequiel Dias Foundation (FUNED), Belo Horizonte, Brazil
| | - Sophie Yvette Leclercq
- Laboratory of Biotechnological Innovation, Research and Development Directorate, Ezequiel Dias Foundation (FUNED), Belo Horizonte, Brazil
| | - Vasco Azevedo
- Laboratory of Cellular and Molecular Genetics, Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Anderson Miyoshi
- Laboratory of Genetic Technology, Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| |
Collapse
|
|
23
|
Santiago-Carvalho I, de Almeida-Santos G, Bomfim CCB, de Souza PC, Silva JCSE, de Melo BMS, Amaral EP, Cione MVP, Lasunskaia E, Hirata MH, Alves-Filho JCF, Nakaya HI, Alvarez JM, D'Império Lima MR. P2x7 Receptor Signaling Blockade Reduces Lung Inflammation and Necrosis During Severe Experimental Tuberculosis. Front Cell Infect Microbiol 2021; 11:672472. [PMID: 34026666 PMCID: PMC8131868 DOI: 10.3389/fcimb.2021.672472] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/20/2021] [Indexed: 12/24/2022] Open
Abstract
The risk of developing severe forms of tuberculosis has increased by the acquired immunodeficiency syndrome (AIDS) epidemic, lack of effective drugs to eliminate latent infection and the emergence of drug-resistant mycobacterial strains. Excessive inflammatory response and tissue damage associated with severe tuberculosis contribute to poor outcome of the disease. Our previous studies using mice deficient in the ATP-gated ionotropic P2X7 receptor suggested this molecule as a promising target for host-directed therapy in severe pulmonary tuberculosis. In this study, we assessed the effects of P2X7 pharmacological blockade on disease severity. First, we observed an increase in P2RX7 gene expression in the peripheral blood of tuberculosis patients compared to healthy donors. Lung leukocytes of mice infected with hypervirulent mycobacteria also showed increased expression of the P2X7 receptor. P2X7 blockade in mice with advanced tuberculosis recapitulated in many aspects the disease in P2X7-deficient mice. P2X7-directed therapy reduced body weight loss and the development of inflammatory and necrotic lung lesions, as well as delayed mycobacterial growth. Lower TNF-α production by lung cells and a substantial reduction in the lung GR-1+ myeloid cell population were observed after P2X7 inhibition. The effector CD4+ T cell population also decreased, but IFN-γ production by lung cells increased. The presence of a large population with characteristics of myeloid dendritic cells, as well as the increase in IL-6 production by lung cells, also indicate a qualitative improvement in the pulmonary immune response due to P2X7 inhibition. These findings support the use of drugs that target the P2X7 receptor as a therapeutic strategy to improve the outcome of pulmonary tuberculosis.
Collapse
Affiliation(s)
- Igor Santiago-Carvalho
- Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, Brazil
| | - Gislane de Almeida-Santos
- Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, Brazil
| | - Caio César Barbosa Bomfim
- Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, Brazil
| | - Paula Carolina de Souza
- Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, Brazil
| | - Juan Carlo Santos E Silva
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas (FCF), USP, São Paulo, Brazil
| | | | - Eduardo Pinheiro Amaral
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | | | - Elena Lasunskaia
- Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, Brazil
| | - Mario Hiroyuki Hirata
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas (FCF), USP, São Paulo, Brazil
| | | | - Helder Imoto Nakaya
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas (FCF), USP, São Paulo, Brazil
| | - José Maria Alvarez
- Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, Brazil
| | - Maria Regina D'Império Lima
- Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, Brazil
| |
Collapse
|
|
24
|
Safe and effective aerosolization of in vitro transcribed mRNA to the respiratory tract epithelium of horses without a transfection agent. Sci Rep 2021; 11:371. [PMID: 33432084 PMCID: PMC7801524 DOI: 10.1038/s41598-020-79855-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 12/10/2020] [Indexed: 01/06/2023] Open
Abstract
Vaccines and therapeutics using in vitro transcribed mRNA hold enormous potential for human and veterinary medicine. Transfection agents are widely considered to be necessary to protect mRNA and enhance transfection, but they add expense and raise concerns regarding quality control and safety. We found that such complex mRNA delivery systems can be avoided when transfecting epithelial cells by aerosolizing the mRNA into micron-sized droplets. In an equine in vivo model, we demonstrated that the translation of mRNA into a functional protein did not depend on the addition of a polyethylenimine (PEI)-derived transfection agent. We were able to safely and effectively transfect the bronchial epithelium of foals using naked mRNA (i.e., mRNA formulated in a sodium citrate buffer without a delivery vehicle). Endoscopic examination of the bronchial tree and histology of mucosal biopsies indicated no gross or microscopic adverse effects of the transfection. Our data suggest that mRNA administered by an atomization device eliminates the need for chemical transfection agents, which can reduce the cost and the safety risks of delivering mRNA to the respiratory tract of animals and humans.
Collapse
|
|
25
|
Bharti R, Srivastava A, Roy T, Verma K, Reddy DS, Shafi H, Verma S, Raman SK, Singh AK, Singh J, Ray L, Misra A. Transient Transfection of the Respiratory Epithelium with Gamma Interferon for Host-Directed Therapy in Pulmonary Tuberculosis. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 22:1121-1128. [PMID: 33110704 PMCID: PMC7581375 DOI: 10.1016/j.omtn.2020.10.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022]
Abstract
Nebulized gamma interferon (IFN-γ) protein has been studied for clinical safety and efficacy against pulmonary tuberculosis (TB). The protein is expensive, requires a cold chain, and is difficult to deploy in limited-resource, high-incidence settings. We generated a preclinical proof of concept (PoC) for a dry powder inhalation (DPI) containing DNA constructs to transiently transfect the lung and airway epithelium of mice with murine IFN-γ. Bacterial colony-forming units (CFU) in the lungs of mice infected with Mycobacterium tuberculosis (Mtb) reduced from about 106/g of tissue to ~104 after four doses given once a week. Nodular inflammatory lesions in the lungs reduced significantly in number. Immunohistochemistry of infected lung sections for LC3-1 and LAMP-1 indicated autophagy induction between 18 and 48 h after inhalation. ELISA on bronchoalveolar lavage (BAL) fluid showed differences in kinetics of IFN-γ concentrations in the epithelial lining fluid of healthy versus infected mice. Uninfected mice receiving DNA constructs expressing a fluorescent protein were live-imaged. The fluorescence signals from the intracellular protein peaked at about 36 h after inhalation and declined by 48 h. These results establish preclinical PoC of the efficacy of a DPI and dosing regimen as a host-directed and transient gene therapy of experimental pulmonary TB in mice, justifying preclinical development.
Collapse
Affiliation(s)
- Reena Bharti
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - Ashish Srivastava
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - Trisha Roy
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - Khushboo Verma
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - D.V. Siva Reddy
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - Hasham Shafi
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - Sonia Verma
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - Sunil K. Raman
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - Amit K. Singh
- National JALMA Institute for Leprosy and Other Mycobacterial Disease, Agra 282004, UP, India
| | - Jyotsna Singh
- CSIR-Indian Institute of Toxicology Research, Lucknow 226001, UP, India
| | - Lipika Ray
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| | - Amit Misra
- CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
| |
Collapse
|
|
26
|
Liu W, Zhou J, Niu F, Pu F, Wang Z, Huang M, Zhao X, Yang L, Tao P, Xia P, Feng J. Mycobacterium tuberculosis infection increases the number of osteoclasts and inhibits osteoclast apoptosis by regulating TNF-α-mediated osteoclast autophagy. Exp Ther Med 2020; 20:1889-1898. [PMID: 32782497 PMCID: PMC7401307 DOI: 10.3892/etm.2020.8903] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023] Open
Abstract
Osteoarticular tuberculosis, a chronic inflammatory disease characterized by Mycobacterium tuberculosis (M.tb) infection, has become a serious problem in China. The present study was conducted to determine the mechanism of action of tumor necrosis factor (TNF)-α in the pathogenesis of osteoarticular tuberculosis. The number of osteoclasts in osteoarticular tuberculosis tissue samples was detected by tartrate-resistant acid phosphatase staining. Autophagy and apoptosis of osteoclasts were detected by western blotting, reverse transcription-quantitative PCR, transmission electron microscopy and TUNEL staining. The results showed that autophagy and the number of osteoclasts increased in the lesions of patients with osteoarticular tuberculosis compared with osteoarthritis samples. Moreover, activation of osteoclast autophagy inhibited the apoptosis of osteoclasts infected with M.tb, and increased the expression level of TNF-α. The results showed that TNF-α enhanced the autophagic activity of M.tb-infected osteoclasts and inhibited cell apoptosis. These findings indicated that M.tb infection induced osteoclast production and inhibited osteoclast apoptosis by regulating TNF-α-mediated osteoclast autophagy, revealing a new mechanism for TNF-α in the pathogenesis of osteoarticular tuberculosis.
Collapse
Affiliation(s)
- Wei Liu
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Juan Zhou
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Fei Niu
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Feifei Pu
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Zhiwei Wang
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Mi Huang
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Xiaolong Zhao
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Lin Yang
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Pengfei Tao
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Ping Xia
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Jing Feng
- Department of Orthopaedics, First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| |
Collapse
|
|
27
|
Liu H, Xiong X, Zhu T, Zhu Y, Peng Y, Zhu X, Wang J, Chen H, Chen Y, Guo A. Differential nitric oxide induced by Mycobacterium bovis and BCG leading to dendritic cells apoptosis in a caspase dependent manner. Microb Pathog 2020; 149:104303. [PMID: 32504845 DOI: 10.1016/j.micpath.2020.104303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 03/14/2020] [Accepted: 05/29/2020] [Indexed: 12/25/2022]
Abstract
Dendritic cells (DCs) are critical for both innate and adaptive immunity. Meanwhile, nitric oxide (NO) is a member of reactive nitrogen species (RNS) generally considered to play a key role in the bactericidal process in innate immunity against Mycobacterium tuberculosis complex infection. The present study therefore investigated the mechanism of NO production in murine DCs induced by Mycobacterium bovis (M.bovis) and its attenuated strain Bacillus Calmette-Guérin (BCG) infection. The expression of genes Slc7A1, Slc7A2, iNOS, and ArgI essential to NO synthesis was up-regulated in M.bovis/BCG infected DCs. IFN-γ addition further increased, while the iNOS inhibitor L-NMMA significantly inhibited their expression. Accordingly, the end products of arginine metabolism, NO and urea, were found to be significantly increased. In addition, BCG induced significantly higher levels of apoptosis in DCs compared to M.bovis shown by higher levels of DNA fragmentation using flow cytometry and release of mitochondrial Cytochrome C, and up-regulation of the genes caspase-3, caspase-8, caspase-9 and dffa critical to apoptosis by qRT-PCR detection and western blot analysis. Furthermore, IFN-γ increased, but L-NMMA decreased apoptosis of M.bovis/BCG infected DCs. In addition, mycobacterial intracellular survival was significantly reduced by IFN-γ treatment in BCG infected DCs, while slightly increased by L-NMMA treatment. Taken altogether, our data show that NO synthesis was differentially increased and associated with apoptosis in M.bovis/BCG infected DCs. These findings may significantly contribute to elucidate the pathogenesis of M.bovis.
Collapse
Affiliation(s)
- Han Liu
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
| | - Xuekai Xiong
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
| | - Tingting Zhu
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
| | - Yifan Zhu
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
| | - Yongchong Peng
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
| | - Xiaojie Zhu
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
| | - Jieru Wang
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
| | - Huanchun Chen
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
| | - Yingyu Chen
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
| | - Aizhen Guo
- The National Key Laboratory of Agricultural Microbiology, Wuhan, China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Development of Veterinary Diagnostic Products, Key Laboratory of Ruminant Bio-products, Huazhong Agricultural University, Wuhan, 430070, China; Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, 430070, China.
| |
Collapse
|
|
28
|
Ma S, Huang Y, Xie F, Gong Z, Zhang Y, Stojkoska A, Xie J. Transport mechanism of Mycobacterium tuberculosis MmpL/S family proteins and implications in pharmaceutical targeting. Biol Chem 2020; 401:331-348. [DOI: 10.1515/hsz-2019-0326] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 09/06/2019] [Indexed: 12/13/2022]
Abstract
AbstractTuberculosis caused by Mycobacterium tuberculosis remains a serious threat to public health. The M. tuberculosis cell envelope is closely related to its virulence and drug resistance. Mycobacterial membrane large proteins (MmpL) are lipid-transporting proteins of the efflux pump resistance nodulation cell division (RND) superfamily with lipid substrate specificity and non-transport lipid function. Mycobacterial membrane small proteins (MmpS) are small regulatory proteins, and they are also responsible for some virulence-related effects as accessory proteins of MmpL. The MmpL transporters are the candidate targets for the development of anti-tuberculosis drugs. This article summarizes the structure, function, phylogenetics of M. tuberculosis MmpL/S proteins and their roles in host immune response, inhibitors and regulatory system.
Collapse
Affiliation(s)
- Shuang Ma
- Institute of Modern Biopharmaceuticals, 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, Southwest University, Chongqing 400700, China
| | - Yu Huang
- Institute of Modern Biopharmaceuticals, 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, Southwest University, Chongqing 400700, China
| | - Fuling Xie
- Institute of Modern Biopharmaceuticals, 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, Southwest University, Chongqing 400700, China
| | - Zhen Gong
- Institute of Modern Biopharmaceuticals, 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, Southwest University, Chongqing 400700, China
| | - Yuan Zhang
- Institute of Modern Biopharmaceuticals, 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, Southwest University, Chongqing 400700, China
| | - Andrea Stojkoska
- Institute of Modern Biopharmaceuticals, 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, Southwest University, Chongqing 400700, China
| | - Jianping Xie
- Institute of Modern Biopharmaceuticals, 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, Southwest University, Chongqing 400700, China
| |
Collapse
|
|
29
|
Lérias JR, Paraschoudi G, de Sousa E, Martins J, Condeço C, Figueiredo N, Carvalho C, Dodoo E, Castillo-Martin M, Beltrán A, Ligeiro D, Rao M, Zumla A, Maeurer M. Microbes as Master Immunomodulators: Immunopathology, Cancer and Personalized Immunotherapies. Front Cell Dev Biol 2020; 7:362. [PMID: 32039196 PMCID: PMC6989410 DOI: 10.3389/fcell.2019.00362] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 12/12/2019] [Indexed: 12/12/2022] Open
Abstract
The intricate interplay between the immune system and microbes is an essential part of the physiological homeostasis in health and disease. Immunological recognition of commensal microbes, such as bacterial species resident in the gut or lung as well as dormant viral species, i.e., cytomegalovirus (CMV) or Epstein-Barr virus (EBV), in combination with a balanced immune regulation, is central to achieve immune-protection. Emerging evidence suggests that immune responses primed to guard against commensal microbes may cause unexpected pathological outcomes, e.g., chronic inflammation and/or malignant transformation. Furthermore, translocation of immune cells from one anatomical compartment to another, i.e., the gut-lung axis via the lymphatics or blood has been identified as an important factor in perpetrating systemic inflammation, tissue destruction, as well as modulating host-protective immune responses. We present in this review immune response patterns to pathogenic as well as non-pathogenic microbes and how these immune-recognition profiles affect local immune responses or malignant transformation. We discuss personalized immunological therapies which, directly or indirectly, target host biological pathways modulated by antimicrobial immune responses.
Collapse
Affiliation(s)
- Joana R. Lérias
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | | | - Eric de Sousa
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - João Martins
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Carolina Condeço
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Nuno Figueiredo
- Digestive Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Carlos Carvalho
- Digestive Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | | | | | - Antonio Beltrán
- Department of Pathology, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Dário Ligeiro
- Lisbon Centre for Blood and Transplantation, Instituto Português do Sangue e Transplantação, Lisbon, Portugal
| | - Martin Rao
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Alimuddin Zumla
- Division of Infection and Immunity, NIHR Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, University College London, London, United Kingdom
| | - Markus Maeurer
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| |
Collapse
|
|
30
|
Daniel-Wayman S, Abate G, Barber DL, Bermudez LE, Coler RN, Cynamon MH, Daley CL, Davidson RM, Dick T, Floto RA, Henkle E, Holland SM, Jackson M, Lee RE, Nuermberger EL, Olivier KN, Ordway DJ, Prevots DR, Sacchettini JC, Salfinger M, Sassetti CM, Sizemore CF, Winthrop KL, Zelazny AM. Advancing Translational Science for Pulmonary Nontuberculous Mycobacterial Infections. A Road Map for Research. Am J Respir Crit Care Med 2020; 199:947-951. [PMID: 30428263 DOI: 10.1164/rccm.201807-1273pp] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Shelby Daniel-Wayman
- 1 Epidemiology Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases
| | - Getahun Abate
- 2 Division of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri
| | - Daniel L Barber
- 3 T Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases
| | - Luiz E Bermudez
- 4 Department of Biomedical Sciences and.,5 Department of Microbiology, Oregon State University, Corvallis, Oregon
| | - Rhea N Coler
- 6 Infectious Disease Research Institute, Seattle, Washington.,7 Department of Global Health, University of Washington, Seattle, Washington
| | - Michael H Cynamon
- 8 Veterans Administration Medical Center, Syracuse, New York.,9 State University of New York Upstate Medical Center, Syracuse, New York
| | - Charles L Daley
- 10 Division of Mycobacterial and Respiratory Infections, Department of Medicine
| | | | - Thomas Dick
- 12 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,13 Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey
| | - R Andres Floto
- 14 Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | | | - Steven M Holland
- 16 Division of Intramural Research, National Institute of Allergy and Infectious Diseases
| | - Mary Jackson
- 17 Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado
| | - Richard E Lee
- 18 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Eric L Nuermberger
- 19 Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.,20 Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Kenneth N Olivier
- 21 Laboratory of Chronic Airway Infection, Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, and
| | - Diane J Ordway
- 17 Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado
| | - D Rebecca Prevots
- 1 Epidemiology Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases
| | - James C Sacchettini
- 22 Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas
| | - Max Salfinger
- 23 Mycobacteriology and Pharmacokinetics Laboratories, National Jewish Health, Denver, Colorado.,24 College of Public Health, University of South Florida, Tampa, Florida
| | - Christopher M Sassetti
- 25 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts; and
| | - Christine F Sizemore
- 26 Tuberculosis, Leprosy, and other Mycobacterial Diseases Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland
| | - Kevin L Winthrop
- 15 OHSU-PSU School of Public Health and.,27 Division of Infectious Disease, Department of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Adrian M Zelazny
- 28 Microbiology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
| |
Collapse
|
|
31
|
Keshavjee S, Amanullah F, Cattamanchi A, Chaisson R, Dobos KM, Fox GJ, Gendelman HE, Gordon R, Hesseling A, Le Van H, Kampmann B, Kana B, Khuller G, Lewinsohn DM, Lewinsohn DA, Lin PL, Lu LL, Maartens G, Owen A, Protopopova M, Rengarajan J, Rubin E, Salgame P, Schurr E, Seddon JA, Swindells S, Tobin DM, Udwadia Z, Walzl G, Srinivasan S, Rustomjee R, Nahid P. Moving toward Tuberculosis Elimination. Critical Issues for Research in Diagnostics and Therapeutics for Tuberculosis Infection. Am J Respir Crit Care Med 2020; 199:564-571. [PMID: 30335466 DOI: 10.1164/rccm.201806-1053pp] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Affiliation(s)
- Salmaan Keshavjee
- 1 Harvard Medical School, Boston, Massachusetts.,2 Harvard Medical School Center for Global Health Delivery-Dubai, Dubai, United Arab Emirates
| | | | - Adithya Cattamanchi
- 4 University of California San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, California
| | - Richard Chaisson
- 5 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Gregory J Fox
- 7 University of Sydney, Sydney, New South Wales, Australia
| | | | - Richard Gordon
- 9 South African Medical Research Council, Cape Town, Western Cape, South Africa
| | | | - Hoi Le Van
- 11 National Lung Hospital, Hanoi, Vietnam.,12 National TB Program in Vietnam, Hanoi, Vietnam
| | - Beate Kampmann
- 13 London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Bavesh Kana
- 14 University of Witwatersrand, National Health Laboratory Service, Johannesburg, South Africa.,15 Centre for the AIDS Programme of Research in South Africa, CAPRISA, Durban, South Africa
| | - Gopal Khuller
- 16 Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - David M Lewinsohn
- 17 Oregon Health & Science University, Portland, Oregon.,18 Portland VA Medical Center, Portland, Oregon
| | | | - Philiana Ling Lin
- 19 University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Lenette Lin Lu
- 20 Massachusetts General Hospital, Boston, Massachusetts
| | - Gary Maartens
- 21 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Andrew Owen
- 22 University of Liverpool, Liverpool, England
| | - Marina Protopopova
- 23 Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, Rockville, Maryland
| | | | - Eric Rubin
- 25 Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | | | | | - James A Seddon
- 13 London School of Hygiene and Tropical Medicine, London, United Kingdom
| | | | - David M Tobin
- 28 Duke University School of Medicine, Durham, North Carolina; and
| | - Zarir Udwadia
- 29 Hinduja Hospital & Research Center, Mumbai, India
| | - Gerhard Walzl
- 30 Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa.,14 University of Witwatersrand, National Health Laboratory Service, Johannesburg, South Africa
| | - Sudha Srinivasan
- 23 Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, Rockville, Maryland
| | - Roxana Rustomjee
- 23 Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, Rockville, Maryland
| | - Payam Nahid
- 4 University of California San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, California
| |
Collapse
|
|
32
|
Development of a diagnostic compatible BCG vaccine against Bovine tuberculosis. Sci Rep 2019; 9:17791. [PMID: 31780694 PMCID: PMC6882907 DOI: 10.1038/s41598-019-54108-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 08/27/2019] [Indexed: 12/31/2022] Open
Abstract
Bovine tuberculosis (BTB) caused by Mycobacterium bovis remains a major problem in both the developed and developing countries. Control of BTB in the UK is carried out by test and slaughter of infected animals, based primarily on the tuberculin skin test (PPD). Vaccination with the attenuated strain of the M. bovis pathogen, BCG, is not used to control bovine tuberculosis in cattle at present, due to its variable efficacy and because it interferes with the PPD test. Diagnostic tests capable of Differentiating Infected from Vaccinated Animals (DIVA) have been developed that detect immune responses to M. bovis antigens absent in BCG; but these are too expensive and insufficiently sensitive to be used for BTB control worldwide. To address these problems we aimed to generate a synergistic vaccine and diagnostic approach that would permit the vaccination of cattle without interfering with the conventional PPD-based surveillance. The approach was to widen the pool of M. bovis antigens that could be used as DIVA targets, by identifying antigenic proteins that could be deleted from BCG without affecting the persistence and protective efficacy of the vaccine in cattle. Using transposon mutagenesis we identified genes that were essential and those that were non-essential for persistence in bovine lymph nodes. We then inactivated selected immunogenic, but non-essential genes in BCG Danish to create a diagnostic-compatible triple knock-out ΔBCG TK strain. The protective efficacy of the ΔBCG TK was tested in guinea pigs experimentally infected with M. bovis by aerosol and found to be equivalent to wild-type BCG. A complementary diagnostic skin test was developed with the antigenic proteins encoded by the deleted genes which did not cross-react in vaccinated or in uninfected guinea pigs. This study demonstrates the functionality of a new and improved BCG strain which retains its protective efficacy but is diagnostically compatible with a novel DIVA skin test that could be implemented in control programmes.
Collapse
|
|
33
|
Lim J, Koh VHQ, Cho SSL, Periaswamy B, Choi DPS, Vacca M, De Sessions PF, Kudela P, Lubitz W, Pastorin G, Alonso S. Harnessing the Immunomodulatory Properties of Bacterial Ghosts to Boost the Anti-mycobacterial Protective Immunity. Front Immunol 2019; 10:2737. [PMID: 31824511 PMCID: PMC6883722 DOI: 10.3389/fimmu.2019.02737] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 11/08/2019] [Indexed: 12/19/2022] Open
Abstract
Tuberculosis (TB) pathogenesis is characterized by inadequate immune cell activation and delayed T cell response in the host. Recent immunotherapeutic efforts have been directed at stimulating innate immunity and enhancing interactions between antigen presenting cells and T cells subsets to improve the protective immunity against TB. In this study, we investigated the immunostimulatory properties of bacterial ghosts (BG) as a novel approach to potentiate the host immunity against mycobacterial infection. BG are intact cytoplasm-free Escherichia coli envelopes and have been developed as bacterial vaccines and adjuvant/delivery system in cancer immunotherapy. However, BG have yet to be exploited as immunopotentiators in the context of infectious diseases. Here, we showed that BG are potent inducers of dendritic cells (DC), which led to enhanced T cell proliferation and differentiation into effector cells. BG also induced macrophage activation, which was associated with enhanced nitric oxide production, a key anti-mycobacterial weapon. We further demonstrated that the immunostimulatory capability of BG far exceeds that of LPS and involves both TLR4-dependent and independent pathways. Consistently, BG treatment, but not LPS treatment, reduced the bacterial burden in infected mice, which correlated with increased influx of innate and adaptive effector immune cells and increased production of key cytokines in the lungs. Finally and importantly, enhanced bacilli killing was seen in mice co-administered with BG and second-line TB drugs bedaquiline and delamanid. Overall, this work paves the way for BG as potent immunostimulators that may be harnessed to improve mycobacteria killing at the site of infection.
Collapse
Affiliation(s)
- Jieling Lim
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Vanessa Hui Qi Koh
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Sharol Su Lei Cho
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Balamurugan Periaswamy
- Genome Institute of Singapore, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Dawn Poh Sum Choi
- Genome Institute of Singapore, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Maurizio Vacca
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Paola Florez De Sessions
- Genome Institute of Singapore, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Pavol Kudela
- Biotech Innovation Research Development & Consulting (BIRD-C), Vienna, Austria
| | - Werner Lubitz
- Biotech Innovation Research Development & Consulting (BIRD-C), Vienna, Austria
| | - Giorgia Pastorin
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore
| | - Sylvie Alonso
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| |
Collapse
|
|
34
|
Zheng R, Liu H, Zhou Y, Yan D, Chen J, Ma D, Feng Y, Qin L, Liu F, Huang X, Wang J, Ge B. Notch4 Negatively Regulates the Inflammatory Response to Mycobacterium tuberculosis Infection by Inhibiting TAK1 Activation. J Infect Dis 2019; 218:312-323. [PMID: 29228365 DOI: 10.1093/infdis/jix636] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 12/06/2017] [Indexed: 12/12/2022] Open
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis infection, remains a global threat to human health, but knowledge of the molecular mechanisms underlying the pathogenesis of tuberculosis is still limited. Although Notch4, a member of the Notch receptor family, is involved in the initiation of mammary tumors, its function in M. tuberculosis infection remains unclear. In this study, we found that Notch4-deficient mice were more resistant to M. tuberculosis infection, with a much lower bacterial burden and fewer pathological changes in the lungs. Notch4 inhibited M. tuberculosis-induced production of proinflammatory cytokines by interaction with TAK1 and inhibition of its activation. Furthermore, we found that Notch intracellular domain 4 prevented TRAF6 autoubiquitination and suppressed TRAF6-mediated TAK1 polyubiquitination. Finally, Notch inhibitors made mice more resistant to M. tuberculosis infection. These results suggest that Notch4 is a negative regulator of M. tuberculosis-induced inflammatory response, and treatment with a Notch inhibitor could serve as a new therapeutic strategy for tuberculosis.
Collapse
Affiliation(s)
- Ruijuan Zheng
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Haipeng Liu
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yilong Zhou
- Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| | - Dapeng Yan
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Key Laboratory of Medical Molecular Virology, Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jianxia Chen
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Dapeng Ma
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yonghong Feng
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lianhua Qin
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Feng Liu
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaochen Huang
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jie Wang
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Baoxue Ge
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China
| |
Collapse
|
|
35
|
Correia-Neves M, Sundling C, Cooper A, Källenius G. Lipoarabinomannan in Active and Passive Protection Against Tuberculosis. Front Immunol 2019; 10:1968. [PMID: 31572351 PMCID: PMC6749014 DOI: 10.3389/fimmu.2019.01968] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 08/05/2019] [Indexed: 12/14/2022] Open
Abstract
Glycolipids of the cell wall of Mycobacterium tuberculosis (Mtb) are important immunomodulators in tuberculosis. In particular, lipoarabinomannan (LAM) has a profound effect on the innate immune response. LAM and its structural variants can be recognized by and activate human CD1b-restricted T cells, and emerging evidence indicates that B cells and antibodies against LAM can modulate the immune response to Mtb. Anti-LAM antibodies are induced during Mtb infection and after bacille Calmette-Guerin (BCG) vaccination, and monoclonal antibodies against LAM have been shown to confer protection by passive administration in mice and guinea pigs. In this review, we describe the immune response against LAM and the potential use of the mannose-capped arabinan moiety of LAM in the construction of vaccine candidates against tuberculosis.
Collapse
Affiliation(s)
- Margarida Correia-Neves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's, PT Government Associate Laboratory, Braga, Guimarães, Portugal
- Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Christopher Sundling
- Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Andrea Cooper
- Leicester Tuberculosis Research Group (LTBRG), Department of Respiratory Sciences, University of Leicester, Leicester, United Kingdom
| | - Gunilla Källenius
- Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
36
|
Abstract
Are antibodies important for protection against tuberculosis? The jury has been out for more than 100 years. B cell depletion in experimental Mycobacterium tuberculosis infection failed to identify a major role for these cells in immunity to tuberculosis. However, recent identification of naturally occurring antibodies in humans that are protective during M. tuberculosis infection has reignited the debate. Here, we discuss the evidence for a protective role for antibodies in tuberculosis and consider the feasibility of designing novel tuberculosis vaccines targeting humoral immunity.
Collapse
Affiliation(s)
- Hao Li
- Centre for Global Health and Infectious Diseases, Collaborative Innovation Centre for the Diagnosis and Treatment of Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
| | - Babak Javid
- Centre for Global Health and Infectious Diseases, Collaborative Innovation Centre for the Diagnosis and Treatment of Infectious Diseases, Tsinghua University School of Medicine, Beijing, China.
| |
Collapse
|
|
37
|
Dheda K, Lenders L, Srivastava S, Magombedze G, Wainwright H, Raj P, Bush SJ, Pollara G, Steyn R, Davids M, Pooran A, Pennel T, Linegar A, McNerney R, Moodley L, Pasipanodya JG, Turner CT, Noursadeghi M, Warren RM, Wakeland E, Gumbo T. Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing. Am J Respir Crit Care Med 2019; 200:370-380. [PMID: 30694692 PMCID: PMC6680310 DOI: 10.1164/rccm.201807-1361oc] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 01/24/2019] [Indexed: 01/09/2023] Open
Abstract
Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis.Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity.Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection (n = 14) and healthy lung tissue from control subjects without tuberculosis (n = 10). RNA sequencing, immunohistochemistry, and bacterial load determination were performed at each cavity position. Differentially expressed genes were normalized to control subjects without tuberculosis, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways.Measurements and Main Results: The median (range) lung cavity volume on positron emission tomography/computed tomography scans was 50 cm3 (15-389 cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple proinflammatory pathways were upregulated in the cavity wall, whereas a downregulation "sink" in the central caseum-fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r > 0.6), whereas T-helper effector systems did not.Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.
Collapse
Affiliation(s)
- Keertan Dheda
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute and South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa
- Faculty of Infectious and Tropical Diseases, Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Laura Lenders
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute and South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa
| | - Shashikant Srivastava
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Gesham Magombedze
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
| | | | - Prithvi Raj
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Stephen J. Bush
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
| | - Gabriele Pollara
- Division of Infection and Immunity, University College London, London, United Kingdom; and
| | | | - Malika Davids
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute and South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa
| | - Anil Pooran
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute and South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa
| | - Timothy Pennel
- Chris Barnard Division of Cardiothoracic Surgery, Department of Surgery, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa
| | - Anthony Linegar
- Chris Barnard Division of Cardiothoracic Surgery, Department of Surgery, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa
| | - Ruth McNerney
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute and South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa
| | - Loven Moodley
- Chris Barnard Division of Cardiothoracic Surgery, Department of Surgery, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa
| | - Jotam G. Pasipanodya
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
| | - Carolin T. Turner
- Division of Infection and Immunity, University College London, London, United Kingdom; and
| | - Mahdad Noursadeghi
- Division of Infection and Immunity, University College London, London, United Kingdom; and
| | - Robin M. Warren
- South African Medical Research Council Centre for Tuberculosis Research/Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa
| | - Edward Wakeland
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tawanda Gumbo
- Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute and South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
| |
Collapse
|
|
38
|
Rani J, Silla Y, Borah K, Ramachandran S, Bajpai U. Repurposing of FDA-approved drugs to target MurB and MurE enzymes in Mycobacterium tuberculosis. J Biomol Struct Dyn 2019; 38:2521-2532. [PMID: 31244382 DOI: 10.1080/07391102.2019.1637280] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is one amongst the top 10 causes of death worldwide. The growing rise in antibiotic resistance compounded with slow and expensive drug discovery has further aggravated the situation. 'Drug repurposing' is a promising approach where known drugs are examined for a new indication. In the present study, we have attempted to identify drugs that could target MurB and MurE enzymes involved in the muramic acid synthesis pathway (Mur Pathway) in Mtb. FDA-approved drugs from two repositories i.e. Drug Bank (1932 drugs) and e-LEA3D (1852 drugs) were screened against these proteins. Several criteria were applied to study the protein-drug interactions and the consensus drugs were further studied by molecular dynamics (MD) simulation. Our study found Sulfadoxine (-7.3 kcal/mol) and Pyrimethamine (-7.8 kcal/mol) to show stable interaction with MurB while Lifitegrast (-10.5 kcal/mol) and Sildenafil (-9.1 kcal/mol) showed most reliable interaction with MurE. Furthermore, binding free energy (ΔGbind), RMSD and RMSF data and the number of hydrogen bonds corroborated the stability of interactions and hence these drugs for repurposing should be explored further.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Jyoti Rani
- Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi, New Delhi, India.,G. N. Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India
| | - Yumnam Silla
- Advanced Computation and Data Sciences Division, CSIR-North East Institute of Science and Technology, Jorhat, India
| | - Kasmika Borah
- Advanced Computation and Data Sciences Division, CSIR-North East Institute of Science and Technology, Jorhat, India
| | - Srinivasan Ramachandran
- G. N. Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India
| | - Urmi Bajpai
- Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi, New Delhi, India
| |
Collapse
|
|
39
|
Méndez-Samperio P. Current challenges and opportunities for bacillus Calmette-Guérin replacement vaccine candidates. Scand J Immunol 2019; 90:e12772. [PMID: 31055842 DOI: 10.1111/sji.12772] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 04/21/2019] [Indexed: 12/17/2022]
Abstract
Bacillus Calmette-Guérin (BCG) remains the only licensed vaccine against human tuberculosis (TB). BCG is a live-attenuated strain of Mycobacterium bovis, with limitations in efficacy against respiratory TB, the most common form of the disease responsible for transmission. However, continues to be used in the immunization programmes of different countries in the absence of another alternative. In order to improve BCG efficacy against pulmonary TB, in the current clinical TB vaccine pipeline, there are live-attenuated TB vaccines to replace BCG. This review discusses the current status of the development of live vaccine candidates designed to replace BCG from the rational strategies and immunological challenges to its clinical trial and identify key areas in the next years considered essential to confer improved safety and efficacy over BCG.
Collapse
|
|
40
|
Oxidization of TGFβ-activated kinase by MPT53 is required for immunity to Mycobacterium tuberculosis. Nat Microbiol 2019; 4:1378-1388. [PMID: 31110366 DOI: 10.1038/s41564-019-0436-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 03/25/2019] [Indexed: 02/05/2023]
Abstract
Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-β-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C210 on TAK1 to facilitate its interaction with TRAFs and TAB1, thus activating TAK1 to induce the expression of pro-inflammatory cytokines. Furthermore, MPT53 and its disulfide oxidoreductase activity is required for Mtb to induce the host inflammatory responses via TAK1. Our findings provide an alternative pathway for host signalling proteins to sense Mtb infection and may favour the improvement of current vaccination strategies.
Collapse
|
|
41
|
Zhang L, Du T, Ma D, Guo F, Li Z, Yan H. Retracted: Combined therapy using LHRH-PE40 and anti-CD40 dendritic cells substantially eliminate tumor cells. J Cell Biochem 2019; 120:8093-8100. [PMID: 30485508 DOI: 10.1002/jcb.28088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 10/29/2018] [Indexed: 01/24/2023]
Abstract
LHRH-PE40 was used to promote the proliferation of bone marrow derived cell (BMDC) and improve the antigen-presenting ability of BMDC as well as the immune function via the CD40 signal pathway. LHRH-PE40 was also implicated in cancer treatment, targeting a variety of cancer cells that express luteinizing hormone-releasing hormone receptor (LHRHR). In the present study, the mechanism and efficacy of LHRH-PE40 were addressed in the following three aspects. Enzyme-linked immunosorbent assay was performed to confirm the binding specificity of LHRH-PE40 to LHRHR. The killing effect of LHRH-PE40 on target cells was mediated by LHRHR, which specifically killed LHRHR-positive target cells while the minimal cytotoxicity of LHRHR-negative cells is negligible. Spiegelmers, a molecule mutually exclusive with GnRH and developed by Sven Klussmann and Dr Sven Klussmann of NOXXON Pharmaceuticals in Germany, demonstrated that LHRH-PE40 maintains a combinatory characteristics of LHRH and LHRHR. In the end, the mechanism of LHRH-PE40 underlying induction of apoptosis at low concentration and prolonged conditions was firstly demonstrated by the basic method of detecting apoptosis to induce apoptosis. It provided a scientific basis for clinical application of LHRH-PE40 and laid a foundation for the further study of LHRH-PE40 on inducing apoptosis of target cells. The target cells herein refer to tumor cells that overexpress LHRHR. This study shows that activated DC can more effectively promote the proliferation of CD4+ T cells, and initially proved that DC carrying anti-CD40 antibody promoted the immune treatment of the tumor. Combining LHRH-PE40 with anti-CD40 DCs achieved substantially improved efficacy in killing tumor cells.
Collapse
Affiliation(s)
- Limin Zhang
- The Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | | | - DongBin Ma
- Tianjin Medical University, Tianjin, China
| | - Fang Guo
- Tianjin Medical University, Tianjin, China
| | - ZhenWei Li
- Tianjin Medical University, Tianjin, China
| | - Hua Yan
- Tianjin Huanhu Hospital, Tianjin, China
| |
Collapse
|
|
42
|
Fry SHL, Barnabas SL, Cotton MF. Tuberculosis and HIV-An Update on the "Cursed Duet" in Children. Front Pediatr 2019; 7:159. [PMID: 32211351 PMCID: PMC7073470 DOI: 10.3389/fped.2019.00159] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 04/04/2019] [Indexed: 11/13/2022] Open
Abstract
HIV and tuberculosis (TB) often occur together with each exacerbating the other. Improvements in vertical transmission prevention has reduced the number of HIV-infected children being born and early antiretroviral therapy (ART) protects against tuberculosis. However, with delayed HIV diagnosis, HIV-infected infants often present with tuberculosis co-infection. The number of HIV exposed uninfected children has increased and these infants have high exposure to TB and may be more immunologically vulnerable due to HIV exposure in utero. Bacillus Calmette-Guérin (BCG) immunization shortly after birth is essential for preventing severe TB in infancy. With early infant HIV diagnosis and ART, disseminated BCG is no longer an issue. TB prevention therapy should be implemented for contacts of a source case and for all HIV-infected individuals over a year of age. Although infection can be identified through skin tests or interferon gamma release assays, the non-availability of these tests should not preclude prevention therapy, once active TB has been excluded. Therapeutic options have moved from isoniazid only for 6-9 months to shorter regimens. Prevention therapy after exposure to a source case with resistant TB should also be implemented, but should not prevent pivotal prevention trials already under way. A microbiological diagnosis for TB remains the gold standard because of increasing drug resistance. Antiretroviral therapy for rifampicin co-treatment requires adaptation for those on lopinavir-ritonavir, which requires super-boosting with additional ritonavir. For those with drug resistant TB, the main problems are identification and overlapping toxicity between antiretroviral and anti-TB therapy. In spite of renewed focus and improved interventions, infants are still vulnerable to TB.
Collapse
Affiliation(s)
| | | | - Mark F. Cotton
- Family Centre for Research with Ubuntu (FAM-CRU), Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
| |
Collapse
|
|
43
|
Su H, Peng B, Zhang Z, Liu Z, Zhang Z. The Mycobacterium tuberculosis glycoprotein Rv1016c protein inhibits dendritic cell maturation, and impairs Th1 /Th17 responses during mycobacteria infection. Mol Immunol 2019; 109:58-70. [PMID: 30856410 DOI: 10.1016/j.molimm.2019.02.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 02/13/2019] [Accepted: 02/27/2019] [Indexed: 12/20/2022]
Abstract
The myobacterial factors and the associated mechanism by which Mycobacterium tuberculosis (Mtb) evades the host immune surveillance system remain widely unexplored. Here, we found that overexpressing Rv1016c, a mannosylated protein of M. tuberculosis in BCG (rBCG-Rv1016c) led to increased virulence of the recombined BCG in the severe-combined immunodeficient (SCID) mice model and to a loss of protective efficacy in a zebrafish-M. marinum model, compared to wild type BCG. Further investigations on the effects of rBCG-Rv1016c on the host innate immunity revealed that rBCG-Rv1016c decreased the production of cytokines IL-2, IL-12p70, TGF-β, IL-6 as well as of the co-stimulatory molecules CD80, CD86, MHC-I and MHC-II by the infected DCs. These effects were mimicked by rBCG-Rv1016cHis, which carried an extra 6-His tag at the C-terminus of Rv1016c. Relatively to BCG infected DCs, the rBCG-Rv1016c-infected DCs failed to polarize naïve T cells to Th1- and Th17-type cells to secret IFN-γ and IL-17. Additionally, T lymphocytes from BCG- infected mice showed significantly less proliferation and production of IFN-γ and IL-17. Similarly, rBCG-Rv1016c mice released a higher level of IL-10 in response to rBCG-Rv1016c stimulation than wild type BCG infected mice. Furthermore, DCs from TLR-2 knockout mice showed no reduction in IL-6, IL-12 p70 and TGF-β secretion in response to rBCG-Rv1016c infection, compared to DCs infected with BCG. We propose that Rv1016c interferes in differentiation of the DCs by targeting suppressor of cytokine signaling (SOCS) 1 and SOCS3 expression, which subsequently leads to the reduction in STAT-1 and STAT-6 phosphorylation. These findings open new perspectives regarding the immunosuppressive strategies adopted by Mtb to survive in the host.
Collapse
Affiliation(s)
- Haibo Su
- GMU-GIBH Joint School of Life Science, Guangzhou Medical University, No. 195 Dongfengxi Road, Guangzhou, 510000, China; Guangdong Second Provincial General Hospital, No. 466 Xingang Road, Guangzhou, 510220, China
| | - Baozhou Peng
- GMU-GIBH Joint School of Life Science, Guangzhou Medical University, No. 195 Dongfengxi Road, Guangzhou, 510000, China
| | - Zhen Zhang
- Guangdong Second Provincial General Hospital, No. 466 Xingang Road, Guangzhou, 510220, China
| | - Zijian Liu
- GMU-GIBH Joint School of Life Science, Guangzhou Medical University, No. 195 Dongfengxi Road, Guangzhou, 510000, China
| | - Zhi Zhang
- Guangdong Second Provincial General Hospital, No. 466 Xingang Road, Guangzhou, 510220, China.
| |
Collapse
|
|
44
|
Abubakar I, Chakaya J, Maeurer M, Zumla A. Towards optimal treatment for latent Mycobacterium tuberculosis infection. THE LANCET RESPIRATORY MEDICINE 2019; 7:195-197. [PMID: 30823969 DOI: 10.1016/s2213-2600(19)30036-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 01/11/2019] [Indexed: 01/04/2023]
Affiliation(s)
- Ibrahim Abubakar
- University College London Institute for Global Health, University College London, London, UK
| | - Jeremiah Chakaya
- Union Headquarters, International Union Against Tuberculosis and Lung Disease, Paris, France; Department of Medicine, Kenyatta University, Nairobi, Kenya
| | - Markus Maeurer
- Champalimaud Foundation, Centre for the Unknown, Avenida Brasília, Lisbon, Portugal
| | - Alimuddin Zumla
- Division of Infection and Immunity, Center for Clinical Microbiology, University College London, London, UK; National Institute of Health Research Biomedical Research Centre, University College London Hospitals, London NW1 2PG, UK.
| |
Collapse
|
|
45
|
Yew WW, Chang KC, Chan DP, Zhang Y. Metformin as a host-directed therapeutic in tuberculosis: Is there a promise? Tuberculosis (Edinb) 2019; 115:76-80. [PMID: 30948180 DOI: 10.1016/j.tube.2019.02.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/21/2019] [Accepted: 02/10/2019] [Indexed: 10/27/2022]
Abstract
To complement the development of new or repurposed drugs for improving the treatment outcomes of drug-susceptible and drug-resistant tuberculosis, current insight also focuses on the use of host-directed therapy. Metformin, a drug often used in the management of type 2 diabetes mellitus, has attracted attention by virtue of its favourable activity as an adjunctive agent against tuberculosis, discovered through laboratory and clinical studies. To definitively establish its role as a host-directed therapeutic in tuberculosis, more preclinical and clinical research is still required to better delineate its mechanism(s) of action and optimal clinical use.
Collapse
Affiliation(s)
- Wing Wai Yew
- Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China
| | - Kwok Chiu Chang
- Tuberculosis and Chest Service, Department of Health, Hong Kong, China
| | - Denise P Chan
- Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China.
| | - Ying Zhang
- Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| |
Collapse
|
|
46
|
Dijkman K, Sombroek CC, Vervenne RAW, Hofman SO, Boot C, Remarque EJ, Kocken CHM, Ottenhoff THM, Kondova I, Khayum MA, Haanstra KG, Vierboom MPM, Verreck FAW. Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques. Nat Med 2019; 25:255-262. [PMID: 30664782 DOI: 10.1038/s41591-018-0319-9] [Citation(s) in RCA: 213] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/30/2018] [Indexed: 12/12/2022]
Abstract
Tuberculosis (TB) remains the deadliest infectious disease1, and the widely used Bacillus Calmette-Guérin (BCG) vaccine fails to curb the epidemic. An improved vaccination strategy could provide a cost-effective intervention to break the transmission cycle and prevent antimicrobial resistance2,3. Limited knowledge of the host responses critically involved in protective immunity hampers the development of improved TB vaccination regimens. Therefore, assessment of new strategies in preclinical models to select the best candidate vaccines before clinical vaccine testing remains indispensable. We have previously established in rhesus macaques (Macaca mulatta) that pulmonary mucosal BCG delivery reduces TB disease where standard intradermal injection fails4,5. Here, we show that pulmonary BCG prevents infection by using a repeated limiting-dose Mycobacterium tuberculosis challenge model and identify polyfunctional T-helper type 17 (TH17) cells, interleukin-10 and immunoglobulin A as correlates of local protective immunity. These findings warrant further research into mucosal immunization strategies and their translation to clinical application to more effectively prevent the spread of TB.
Collapse
Affiliation(s)
- Karin Dijkman
- Biomedical Primate Research Centre, Rijswijk, the Netherlands.
| | | | | | - Sam O Hofman
- Biomedical Primate Research Centre, Rijswijk, the Netherlands
| | - Charelle Boot
- Biomedical Primate Research Centre, Rijswijk, the Netherlands
| | | | | | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Centre, Leiden, the Netherlands
| | - Ivanela Kondova
- Biomedical Primate Research Centre, Rijswijk, the Netherlands
| | | | | | | | | |
Collapse
|
|
47
|
Mangtani P, Nguipdop-Djomo P, Keogh RH, Sterne JAC, Abubakar I, Smith PG, Fine PEM, Vynnycky E, Watson JM, Elliman D, Lipman M, Rodrigues LC. The duration of protection of school-aged BCG vaccination in England: a population-based case-control study. Int J Epidemiol 2019; 47:193-201. [PMID: 29025083 DOI: 10.1093/ije/dyx141] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2017] [Indexed: 11/12/2022] Open
Abstract
Background Evidence of protection from childhood Bacillus Calmette-Guerin (BCG) against tuberculosis (TB) in adulthood, when most transmission occurs, is important for TB control and resource allocation. Methods We conducted a population-based case-control study of protection by BCG given to children aged 12-13 years against tuberculosis occurring 10-29 years later. We recruited UK-born White subjects with tuberculosis and randomly sampled White community controls. Hazard ratios and 95% confidence intervals (CIs) were estimated using case-cohort Cox regression, adjusting for potential confounding factors, including socio-economic status, smoking, drug use, prison and homelessness. Vaccine effectiveness (VE = 1 - hazard ratio) was assessed at successive intervals more than 10 years following vaccination. Results We obtained 677 cases and 1170 controls after a 65% response rate in both groups. Confounding by deprivation, education and lifestyle factors was slight 10-20 years after vaccination, and more evident after 20 years. VE 10-15 years after vaccination was 51% (95% CI 21, 69%) and 57% (CI 33, 72%) at 15-20 years. Subsequently, BCG protection appeared to wane; 20-25 years VE = 25% (CI -14%, 51%) and 25-29 years VE = 1% (CI -84%, 47%). Based on multiple imputation of missing data (in 17% subjects), VE estimated in the same intervals after vaccination were similar [56% (CI 33, 72%), 57% (CI 36, 71%), 25% (-10, 48%), 21% (-39, 55%)]. Conclusions School-aged BCG vaccination offered moderate protection against tuberculosis for at least 20 years, which is longer than previously thought. This has implications for assessing the cost-effectiveness of BCG vaccination and when evaluating new TB vaccines.
Collapse
Affiliation(s)
- Punam Mangtani
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
| | - Patrick Nguipdop-Djomo
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
| | - Ruth H Keogh
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
| | - Jonathan A C Sterne
- School of Social and Community Medicine, University of Bristol, Bristol, BS8 2PS, UK
| | - Ibrahim Abubakar
- Institute for Global Health, University College London, London, WC1N 1EH, UK
| | - Peter G Smith
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
| | - Paul E M Fine
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
| | - Emilia Vynnycky
- Statistics Modelling and Economics Department, Public Health England, Colindale, London, NW9 5HT.,TB Modelling Group, Centre for Mathematical Modelling In Infectious Diseases and TB Centre, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
| | - John M Watson
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
| | - David Elliman
- Whittington Health, St Anns Hospital, Tottenham, N15 3TD, UK
| | - Marc Lipman
- Royal Free London NHS Foundation Trust, London & UCL Respiratory, Division of Medicine, University College London, London, NW3 2QG, UK
| | - Laura C Rodrigues
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
| |
Collapse
|
|
48
|
Hasnain SE, Ehtesham NZ, Grover S. Clinical Aspects and Principles of Management of Tuberculosis. MYCOBACTERIUM TUBERCULOSIS: MOLECULAR INFECTION BIOLOGY, PATHOGENESIS, DIAGNOSTICS AND NEW INTERVENTIONS 2019. [PMCID: PMC7120521 DOI: 10.1007/978-981-32-9413-4_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Tuberculosis over the ages, has killed more people than any other infection has. Notwithstanding the advances in modern science, clinical diagnosis sometimes remains elusive, owing principally to the frequent paucibacillary occurrence of the disease and the slow doubling time of the organism; empiric treatment is often fraught with risks in the era of increasing drug resistance. This chapter attempts to provide an overview of the disease, beginning with the pathogenesis and its protean clinical presentations. It also discusses the recent evolution of molecular methods that have lately provided an impetus to early diagnosis with a clear opportunity to unmask drug resistance before initiating “blind”, potentially ineffective, and sometimes harmful treatment with standard therapy. The chapter also provides insight into tuberculosis in special situations, and discusses briefly the treatments in uncomplicated cases as well as in special situations, and in instances of drug resistance. Preventive methods including current and upcoming vaccines are mentioned. Finally, a short discussion of the sequelae of tuberculosis—which have the potential to be confused with active disease—is presented.
Collapse
Affiliation(s)
| | - Nasreen Z. Ehtesham
- Inflammation Biology and Cell Signaling Laboratory, ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, Delhi India
| | - Sonam Grover
- JH Institute of Molecular Medicine, Jamia Hamdard, New Delhi, Delhi India
| |
Collapse
|
|
49
|
|
|
50
|
Gupta PK, Kulkarni S. Polysaccharide rich extract (PRE) from Tinospora cordifolia inhibits the intracellular survival of drug resistant strains of Mycobacterium tuberculosis in macrophages by nitric oxide induction. Tuberculosis (Edinb) 2018; 113:81-90. [PMID: 30514517 DOI: 10.1016/j.tube.2018.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 08/23/2018] [Accepted: 09/23/2018] [Indexed: 11/15/2022]
Abstract
Plethora of clinical and scientific information obtained in recent past has strengthened the idea that targeting critical constituents of host immune system may have beneficial outcomes for the treatment of tuberculosis. Macrophages being the primary host for Mycobacterium tuberculosis, offer an attractive target for modulation. Owing to their negligible toxicity, plant derived polysaccharides with the ability to activate macrophages; are suitable candidates for immunomodulation. In the present study, effects of polysaccharide rich extract (PRE) isolated from Tinospora cordifolia, on the survival of intracellular MTB strains and activation of macrophages were investigated. PRE treatment up regulated the expression of pro-inflammatory cytokines such as IL-β, TNF-α, IL-6, IL-12, and IFN-γ in RAW 264.7 cell line. Up regulation in the expression of NOS2 was observed along with concomitant enhanced nitric oxide production post PRE treatment. Surface expression of MHC-II and CD-86 was up regulated after PRE treatment. Above results suggested the classical activation of macrophages by PRE treatment. Furthermore, PRE treatment led to the activation of all the three classes of MAPK i.e p38, ERK and JNK MAPKs. Further, PRE up regulated the expression of cytokines, NOS-2, MHC-II and CD-86 in MTB infected macrophages. PRE treatment inhibited the intracellular survival of drug resistant MTB in macrophages which was partially attributed to PRE mediated NO induction. Thus our data demonstrate classical activation of macrophages by PRE treatment and killing of intracellular MTB by NO induction.
Collapse
Affiliation(s)
- Pramod Kumar Gupta
- Radiation Medicine Centre, Bhabha Atomic Research Centre, c/o TMH Annexe, Parel, Mumbai, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.
| | - Savita Kulkarni
- Radiation Medicine Centre, Bhabha Atomic Research Centre, c/o TMH Annexe, Parel, Mumbai, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.
| |
Collapse
|