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Proulx MK, Wiggins CD, Reames CJ, Wu C, Kiritsy MC, Xu P, Gallant JC, Grace PS, Fenderson BA, Smith CM, Lindestam Arlehamn CS, Alter G, Lauffenburger DA, Sassetti CM. Noncanonical T cell responses are associated with protection from tuberculosis in mice and humans. J Exp Med 2025; 222:e20241760. [PMID: 40192640 PMCID: PMC11974462 DOI: 10.1084/jem.20241760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 01/02/2025] [Accepted: 03/07/2025] [Indexed: 04/10/2025] Open
Abstract
While control of Mycobacterium tuberculosis (Mtb) infection is generally understood to require Th1 cells and IFNγ, infection produces a spectrum of immunological and pathological phenotypes in diverse human populations. By characterizing Mtb infection in mouse strains that model the genetic heterogeneity of an outbred population, we identified strains that control Mtb comparably to a standard IFNγ-dependent mouse model but with substantially lower lung IFNγ levels. We report that these mice have a significantly altered CD4 T cell profile that specifically lacks the terminal effector Th1 subset and that this phenotype is detectable before infection. These mice still require T cells to control bacterial burden but are less dependent on IFNγ signaling. Instead, noncanonical immune features such as Th17-like CD4 and γδT cells correlate with low bacterial burden. We find the same Th17 transcriptional programs are associated with resistance to Mtb infection in humans, implicating specific non-Th1 T cell responses as a common feature of Mtb control across species.
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Affiliation(s)
- Megan K. Proulx
- Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Christine D. Wiggins
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Charlotte J. Reames
- Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Claire Wu
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Michael C. Kiritsy
- Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Ping Xu
- Transgenic Animal Modeling Core, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Judith C. Gallant
- Transgenic Animal Modeling Core, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Patricia S. Grace
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, USA
| | - Brooke A. Fenderson
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, USA
| | - Clare M. Smith
- Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA
| | - Cecilia S. Lindestam Arlehamn
- Center for Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA
- Department of Infectious Disease Immunology, Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Galit Alter
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, USA
| | | | - Christopher M. Sassetti
- Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
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2
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Sadeghi MH, Radmehr S, Mohagheghzadeh N, Fathi J, Malekzadegan Y, Moghadam HZ. Innovative electrochemical biosensors for tuberculosis detection. Clin Chim Acta 2025; 574:120327. [PMID: 40286897 DOI: 10.1016/j.cca.2025.120327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Revised: 04/19/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
Tuberculosis (TB) continues to pose a significant global health threat, highlighting the urgent need for the development of rapid, precise, and accessible diagnostic tools to effectively manage its transmission. Conventional diagnostic techniques, such as sputum microscopy and culture-based assays, face several drawbacks, including lengthy processing times, limited sensitivity, and the requirement for specialized laboratory facilities. In this landscape, electrochemical biosensors have emerged as promising alternatives, offering improved sensitivity, specificity, and rapid detection capabilities. This review presents a thorough overview of recent advancements in the development and application of innovative electrochemical biosensors for TB detection. It explores the integration of nanomaterials such as graphene, gold nanoparticles, and carbon nanotubes, focusing on their contributions to enhanced sensor performance in terms of signal amplification and biorecognition efficacy. By synthesizing current research and technological developments, this review emphasizes the considerable potential of electrochemical biosensors to transform TB diagnostics, ultimately assisting in better disease management and control strategies worldwide.
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Affiliation(s)
- Mohammad Hassan Sadeghi
- Medical Student, School of Medicine,Zahedan University of Medical Science, Sistanbaluchestan, Iran
| | - Safa Radmehr
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Neda Mohagheghzadeh
- Department of Bacteriology & Virology, School of Medicine, Shiraz University of Medical Sciences, Iran
| | - Javad Fathi
- Department of Bacteriology & Virology, School of Medicine, Shiraz University of Medical Sciences, Iran
| | - Yalda Malekzadegan
- Department of Microbiology and Parasitology, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Hesam Zendehdel Moghadam
- Research and Technology Department, Iranian Academic Center for Education Culture and Research Kerman Branch, Iran.
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3
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Shin E, Yun JS, Lee YR, Cha HR, Kim SM, Shin SJ, Lee SW, Chung GT, Kim D, Yoo JS, Kim JS, Jeong HS. Efficacy and immunogenicity of rKVAC85B in a BCG prime-boost regimen against H37Rv and HN878 Mycobacterium tuberculosis strains. PLoS One 2025; 20:e0322147. [PMID: 40367100 PMCID: PMC12077692 DOI: 10.1371/journal.pone.0322147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 03/17/2025] [Indexed: 05/16/2025] Open
Abstract
Mycobacterium tuberculosis infection accounted for 1.3 million deaths worldwide in 2022. Bacillus Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB); however, it has limited protective efficacy in adults. In this study, we constructed a recombinant vaccinia virus expressing Ag85B from M. tuberculosis using a novel attenuated vaccinia virus (KVAC103). We then analyzed the immunogenicity of prime-boost inoculation strategies using recombinant KVAC103 expressing Ag85B (rKVAC85B) compared to BCG. In both rKVAC85B prime-boost and BCG prime-rKVAC85B boost inoculation regimens, rKVAC85B induced the generation of specific immunoglobulin G (IgG) and secretion of interferon-γ by immune cells. In vitro analysis of Mycobacterium growth inhibition revealed a comparable immune-mediated pattern of outcomes. Furthermore, bacterial loads in the lungs were significantly lower in mice inoculated with the BCG prime-rKVAC85B boost than in the BCG-only group following a rechallenge infection with both H37Rv and HN878 strains of M. tuberculosis. These findings collectively suggest that KVAC103, incorporated into a viral vector, is a promising candidate for the development of a novel TB vaccine platform that is effective against multiple M. tuberculosis strains, including H37Rv and HN878, and that rKVAC85B effectively stimulates immune responses against M. tuberculosis infection.
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Affiliation(s)
- Eunkyung Shin
- National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungbuk, Republic of Korea
| | - Jin-Seung Yun
- National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungbuk, Republic of Korea
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Young-Ran Lee
- Bio-Convergence R&D Division, Korea Institute of Ceramic Engineering and Technology, CheongJu, Chungbuk, Republic of Korea
| | - Hye-Ran Cha
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo-Min Kim
- National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungbuk, Republic of Korea
| | - Sung-Jae Shin
- Department of Microbiology, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Sang-Won Lee
- Department of Data Science, Korea Disease Control and Prevention Agency, CheongJu, Chungbuk, Republic of Korea
| | - Gyung Tae Chung
- National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungbuk, Republic of Korea
| | - Dokeun Kim
- National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungbuk, Republic of Korea
| | - Jung Sik Yoo
- National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungbuk, Republic of Korea
| | - Jong-Seok Kim
- Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea
| | - Hye-Sook Jeong
- National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungbuk, Republic of Korea
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4
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Navarrete JAY, Rodriguez D, Kanno AI, de Cerqueira Leite LC, Trentini MM. Modulation of immune responses induced by recombinant BCG expressing LTAK63 adjuvant in an immunotherapeutic model vaccine. Vaccine 2025; 57:127215. [PMID: 40359816 DOI: 10.1016/j.vaccine.2025.127215] [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: 10/23/2024] [Revised: 04/29/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025]
Abstract
Tuberculosis (TB) remains a major global health issue, with current treatments relying on prolonged multidrug regimens that can reduce patient compliance, and lead to drug resistance. Immunotherapeutic vaccines against Mycobacterium tuberculosis (Mtb) offer a novel approach. We have previously shown that the recombinant BCG expressing LTAK63 adjuvant (rBCG-LTAK63) decreases bacillary load and lung inflammation in Mtb-infected mice. In this work, we further investigated specific immune mechanism induced in mice infected with Mtb and treated with rBCG-LTAK63 in combination with conventional chemotherapy; different routes of administration of rBCG-LTAK63 were evaluated, such as SC, IN, and IV. Immunotherapy with rBCG-LTAK63 induces early innate immune cells migration (predominantly NK cells and monocytes/macrophages) to distinct sites; increased IFN-γ, TNF-α, and IL-17 T cells, FoxP3 expressing regulatory T cells correlating with reduced bacillary load, particularly with IN administration. The findings highlight the potential of rBCG-LTAK63 to complement TB treatment.
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Affiliation(s)
- Josselyn Andrea Yaguana Navarrete
- Laboratório de Desenvolvimento de Vacinas, Instituto Butantan, São Paulo, Brazil; UnivLyon, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Dunia Rodriguez
- Laboratório de Desenvolvimento de Vacinas, Instituto Butantan, São Paulo, Brazil
| | - Alex Issamu Kanno
- Laboratório de Desenvolvimento de Vacinas, Instituto Butantan, São Paulo, Brazil
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Hilligan KL, Darrah PA, Seder RA, Sher A. Deconvoluting the interplay of innate and adaptive immunity in BCG-induced nonspecific and TB-specific host resistance. J Exp Med 2025; 222:e20240496. [PMID: 40100096 PMCID: PMC11917170 DOI: 10.1084/jem.20240496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/23/2025] [Accepted: 02/27/2025] [Indexed: 03/20/2025] Open
Abstract
BCG is the oldest vaccine in continuous use. While current intradermal vaccination regimens confer limited protection outside the context of pediatric extrapulmonary tuberculosis (TB), promising new data indicate that when administered mucosally or intravenously at a higher dose, BCG can induce sterilizing immunity against pulmonary TB in nonhuman primates. BCG is also known to promote nonspecific host resistance against a variety of unrelated infections and is a standard immunotherapy for bladder cancer, suggesting that this innate immune function may contribute to its protective role against TB. Here, we propose that both the mycobacterial-specific and off-target effects of BCG depend on the interplay of adaptive and innate cells and the cytokines they produce, and that the elucidation of this interaction should be a major strategy in the development of more effective BCG-based vaccines and immunotherapies.
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Affiliation(s)
| | - Patricia A. Darrah
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Robert A. Seder
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Alan Sher
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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6
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Chen B, Wang X, Jiang B, Xin S. Advancements in the study of T lymphocytes in thoracic aortic aneurysm and aortic dissection. Tissue Cell 2025; 93:102768. [PMID: 39923647 DOI: 10.1016/j.tice.2025.102768] [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: 10/17/2024] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/11/2025]
Abstract
Thoracic aortic aneurysms and dissection (TAAD) is a critical, life-threatening cardiovascular condition characterized by immune-mediated inflammatory infiltration and structural degradation of the aorta wall, which are pivotal in its etiology. In recent years, the significance of T lymphocytes in TAAD has increasingly garnered scientific attention. TAAD is a multifaceted vascular disorder characterized by the involvement of many immune cells, with T lymphocytes playing a pivotal role, particularly in the modulation of inflammatory responses, immunological control, and tissue damage. A comprehensive understanding of the T lymphocyte activation process in TAAD is crucial for the advancement of novel preventative and therapy strategies. This article evaluates the recent research advancements on the function of T lymphocytes in TAAD, aiming to offer novel insights for the future prevention and treatment of TAAD.
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Affiliation(s)
- Baolin Chen
- Department of Vascular Surgery, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China; Key Laboratory of Pathogenesis, Prevention and Therapeutics of Aortic Aneurysm, Shenyang, Liaoning, China
| | - Xueling Wang
- Department of Vascular Surgery, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China; Key Laboratory of Pathogenesis, Prevention and Therapeutics of Aortic Aneurysm, Shenyang, Liaoning, China
| | - Bo Jiang
- Department of Vascular Surgery, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China; Key Laboratory of Pathogenesis, Prevention and Therapeutics of Aortic Aneurysm, Shenyang, Liaoning, China
| | - Shijie Xin
- Department of Vascular Surgery, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China; Key Laboratory of Pathogenesis, Prevention and Therapeutics of Aortic Aneurysm, Shenyang, Liaoning, China.
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7
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Wang Z, Sun X, Lin Y, Fu Y, Yi Z. Stealth in non-tuberculous mycobacteria: clever challengers to the immune system. Microbiol Res 2025; 292:128039. [PMID: 39752805 DOI: 10.1016/j.micres.2024.128039] [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: 08/07/2024] [Revised: 12/18/2024] [Accepted: 12/23/2024] [Indexed: 01/19/2025]
Abstract
Non-tuberculous Mycobacteria (NTM) are found extensively in various environments, yet most are non-pathogenic. Only a limited number of these organisms can cause various infections, including those affecting the lungs, skin, and central nervous system, particularly when the host's autoimmune function is compromised. Among these, Non-tuberculous Mycobacteria Pulmonary Diseases (NTM-PD) are the most prevalent. Currently, there is a lack of effective treatments and preventive measures for NTM infections. This article aims to deepen the comprehension of the pathogenic mechanisms linked to NTM and to formulate new intervention strategies by synthesizing current research and detailing the different tactics used by NTM to avoid elimination by the host's immune response. These intricate mechanisms not only affect the innate immune response but also successfully oppose the adaptive immune response, establishing persistent infections within the host. This includes effects on the functions of macrophages, neutrophils, dendritic cells, and T lymphocytes, as well as modulation of cytokine production. The article particularly emphasizes the survival strategies of NTM within macrophages, such as inhibiting phagosome maturation and acidification, resisting intracellular killing mechanisms, and interfering with autophagy and cell death pathways. This review aims to deepen the understanding of NTM's immune evasion mechanisms, thereby facilitating efforts to inhibit its proliferation and spread within the host, ultimately providing new methods and strategies for NTM-related treatments.
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Affiliation(s)
- Zhenghao Wang
- School of Clinical Medicine, Shandong Second Medical University, Weifang 261053, China
| | - Xiurong Sun
- School of Clinical Medicine, Shandong Second Medical University, Weifang 261053, China
| | - Yuli Lin
- School of Medical Laboratory, Shandong Second Medical University, Weifang 261053, China
| | - Yurong Fu
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang 261053, China.
| | - Zhengjun Yi
- School of Medical Laboratory, Shandong Second Medical University, Weifang 261053, China.
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8
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Peters JM, Irvine EB, Makatsa MS, Rosenberg JM, Wadsworth MH, Hughes TK, Sutton MS, Nyquist SK, Bromley JD, Mondal R, Roederer M, Seder RA, Darrah PA, Alter G, Seshadri C, Flynn JL, Shalek AK, Fortune SM, Bryson BD. High-dose intravenous BCG vaccination induces enhanced immune signaling in the airways. SCIENCE ADVANCES 2025; 11:eadq8229. [PMID: 39742484 PMCID: PMC11694782 DOI: 10.1126/sciadv.adq8229] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 11/20/2024] [Indexed: 01/03/2025]
Abstract
Intradermal Bacillus Calmette-Guérin (BCG) is the most widely administered vaccine, but it does not sufficiently protect adults against pulmonary tuberculosis. Recent studies in nonhuman primates show that intravenous BCG administration offers superior protection against Mycobacterium tuberculosis (Mtb). We used single-cell analysis of bronchoalveolar lavage cells from rhesus macaques vaccinated via different routes and doses of BCG to identify alterations in the immune ecosystem in the airway following vaccination. Our findings reveal that high-dose intravenous BCG induces an influx of polyfunctional T cells and macrophages in the airways, with alveolar macrophages from high-dose intravenous BCG displaying a basal activation state in the absence of purified protein derivative stimulation, defined in part by interferon signaling. Enhanced intercellular immune signaling and stronger T helper 1-T helper 17 transcriptional responses were observed following purified protein derivative stimulation. These results suggest that high-dose intravenous BCG vaccination creates a specialized immune environment that primes airway cells for effective Mtb clearance.
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Affiliation(s)
- Joshua M. Peters
- Department of Biological Engineering, MIT, Cambridge, MA, USA
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Edward B. Irvine
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Mohau S. Makatsa
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Jacob M. Rosenberg
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Division of Infectious Diseases, MGH, Boston, MA, USA
| | - Marc H. Wadsworth
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
| | - Travis K. Hughes
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
| | | | - Sarah K. Nyquist
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
| | - Joshua D. Bromley
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
| | - Rajib Mondal
- Research Laboratory of Electronics, Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA
| | | | | | | | - Galit Alter
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
| | - Chetan Seshadri
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - JoAnne L. Flynn
- Department of Microbiology and Molecular Genetics and Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Alex K. Shalek
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
| | - Sarah M. Fortune
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Bryan D. Bryson
- Department of Biological Engineering, MIT, Cambridge, MA, USA
- Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA, USA
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9
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Ahmed M, Farris E, Swanson RV, Das S, Yang Y, Martin T, Khader SA. Saponin TQL1055 adjuvant-containing vaccine confers protection upon Mycobacterium tuberculosis challenge in mice. Hum Vaccin Immunother 2024; 20:2302070. [PMID: 38190806 PMCID: PMC10793695 DOI: 10.1080/21645515.2024.2302070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 01/02/2024] [Indexed: 01/10/2024] Open
Abstract
Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), affects the lungs of infected individuals (pulmonary TB) but can also affect other sites (extrapulmonary TB). The only licensed vaccine Mycobacterium bovis bacillus Calmette-Guerin (BCG) protects infants and young children but exhibits variable efficacy in protecting against adult pulmonary TB. Poor compliance and prolonged treatment regimens associated with the use of chemotherapy has contributed to the development of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb. Thus, there is an urgent need for the design of more effective vaccines against TB. The development of safe and novel adjuvants for human use is critical. In this study, we demonstrate that saponin-based TQL1055 adjuvant when formulated with a TLR4 agonist (PHAD) and Mtb specific immunodominant antigens (ESAT-6 and Ag85B) and delivered intramuscularly in mice, the SA-TB vaccine induced potent lung immune responses. Additionally, the SA-TB vaccine conferred significant protection against Mtb infection, comparable with levels induced by BCG. These findings support the development of a SA-TB vaccine comprising TQL1055, as a novel, safe and effective TB vaccine for potential use in humans.
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Affiliation(s)
- Mushtaq Ahmed
- Department of Microbiology, University of Chicago, Chicago, IL, USA
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA
| | - Eric Farris
- Adjuvance Technologies Inc, Lincoln, NE, USA
| | - Rosemary V. Swanson
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA
| | - Shibali Das
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA
| | - Yan Yang
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA
| | | | - Shabaana A. Khader
- Department of Microbiology, University of Chicago, Chicago, IL, USA
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA
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10
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Rungelrath V, Ahmed M, Hicks L, Miller SM, Ryter KT, Montgomery K, Ettenger G, Riffey A, Abdelwahab WM, Khader SA, Evans JT. Vaccination with Mincle agonist UM-1098 and mycobacterial antigens induces protective Th1 and Th17 responses. NPJ Vaccines 2024; 9:100. [PMID: 38844494 PMCID: PMC11156909 DOI: 10.1038/s41541-024-00897-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/28/2024] [Indexed: 06/09/2024] Open
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the top infectious killers in the world. The only licensed vaccine against TB, Bacille Calmette-Guérin (BCG), provides variable protection against pulmonary TB, especially in adults. Hence, novel TB vaccine approaches are urgently needed. Both Th1 and Th17 responses are necessary for protection against TB, yet effective adjuvants and vaccine delivery systems for inducing robust Th1 and Th17 immunity are lacking. Herein we describe a synthetic Mincle agonist, UM-1098, and a silica nanoparticle delivery system that drives Th1/Th17 responses to Mtb antigens. Stimulation of human peripheral blood mononuclear cells (hPBMCs) with UM-1098 induced high levels of Th17 polarizing cytokines IL-6, IL-1β, IL-23 as well as IL-12p70, IL-4 and TNF-α in vitro. PBMCs from both C57BL/6 and BALB/c mice responded with a similar cytokine pattern in vitro and in vivo. Importantly, intramuscular (I.M.) vaccination with UM-1098-adjuvanted TB antigen M72 resulted in significantly higher antigen-specific IFN-γ and IL-17A levels in C57BL/6 wt mice than Mincle KO mice. Vaccination of C57BL/6 wt mice with immunodominant Mtb antigens ESAT6/Ag85B or M72 resulted in predominantly Th1 and Th17 responses and induced antigen-specific serum antibodies. Notably, in a virulent Mtb challenge model, vaccination with UM-1098 adjuvanted ESAT6/Ag85B or M72 significantly reduced lung bacterial burden when compared with unvaccinated mice and protection occurred in the absence of pulmonary inflammation. These data demonstrate that the synthetic Mincle agonist UM-1098 induces strong Th1 and Th17 immunity after vaccination with Mtb antigens and provides protection against Mtb infection in mice.
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Affiliation(s)
- Viktoria Rungelrath
- Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA
- Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Mushtaq Ahmed
- Department of Microbiology, University of Chicago, 920 E. 58th St., Chicago, IL, 60637, USA
| | - Linda Hicks
- Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA
- Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Shannon M Miller
- Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA
- Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Kendal T Ryter
- Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA
- Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Kyle Montgomery
- Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA
- Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - George Ettenger
- Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA
- Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Alexander Riffey
- Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA
- Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Walid M Abdelwahab
- Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA
- Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Shabaana Abdul Khader
- Department of Microbiology, University of Chicago, 920 E. 58th St., Chicago, IL, 60637, USA
| | - Jay T Evans
- Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA.
- Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA.
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11
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Ogongo P, Tran A, Marzan F, Gingrich D, Krone M, Aweeka F, Lindestam Arlehamn CS, Martin JN, Deeks SG, Hunt PW, Ernst JD. High-parameter phenotypic characterization reveals a subset of human Th17 cells that preferentially produce IL-17 against M. tuberculosis antigen. Front Immunol 2024; 15:1378040. [PMID: 38698866 PMCID: PMC11064812 DOI: 10.3389/fimmu.2024.1378040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 03/28/2024] [Indexed: 05/05/2024] Open
Abstract
Background Interleukin-17-producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with human immunodeficiency virus (HIV) disproportionately affects distinct Th17-cell subsets that respond to Mtb is incompletely defined. Methods We performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by liquid chromatography-mass spectrometry (LC/MS) on plasma and tested the hypothesis that tryptophan catabolism influences Th17-cell frequencies in this context. Results We identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3-cells of which subset 1 was significantly reduced in latent tuberculosis infection (LTBI) with HIV-ART, yet Mtb-responsive IL-17-producing CD4 T cells were preserved; we found that IL-17-producing CD4 T cells dominate the response to Mtb antigen but not cytomegalovirus (CMV) antigen or staphylococcal enterotoxin B (SEB), and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17-cell frequencies. Conclusions We found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL-17-producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.
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Affiliation(s)
- Paul Ogongo
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA, United States
- Department of Tropical and Infectious Diseases, Institute of Primate Research, Nairobi, Kenya
| | - Anthony Tran
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Florence Marzan
- Drug Research Unit, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, San Francisco, CA, United States
| | - David Gingrich
- Drug Research Unit, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, San Francisco, CA, United States
| | - Melissa Krone
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
| | - Francesca Aweeka
- Drug Research Unit, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, San Francisco, CA, United States
| | | | - Jeffrey N. Martin
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
| | - Steven G. Deeks
- Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Peter W. Hunt
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Joel D. Ernst
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA, United States
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12
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Zeng L, Ma X, Qu M, Tang M, Li H, Lei C, Ji J, Li H. Immunogenicity and protective efficacy of Ag85A and truncation of PstS1 fusion protein vaccines against tuberculosis. Heliyon 2024; 10:e27034. [PMID: 38463854 PMCID: PMC10920368 DOI: 10.1016/j.heliyon.2024.e27034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/12/2024] Open
Abstract
Tuberculosis (TB) is an important public health problem, and the One Health approach is essential for controlling zoonotic tuberculosis. Therefore, a rationally designed and more effective TB vaccine is urgently needed. To enhance vaccine efficacy, it is important to design vaccine candidates that stimulate both cellular and humoral immunity against TB. In this study, we fused the secreted protein Ag85A as the T cell antigen with truncated forms of the mycobacterial cell wall protein PstS1 with B cell epitopes to generate vaccine candidates, Ag85A-tnPstS1 (AP1, AP2, and AP3), and tested their immunogenicity and protective efficacy in mice. The three vaccine candidates induced a significant increase in the levels of T cell-related cytokines such as IFN-γ and IL-17, and AP1 and AP2 can induce more balanced Th1/Th2 responses than AP3. Strong humoral immune responses were also observed in which the production of IgG antibodies including its subclasses IgG1, IgG2c, and IgG3 was tremendously stimulated. AP1 and AP2 induced early antibody responses and more IgG3 isotype antibodies than AP3. Importantly, the mice immunised with the subunit vaccine candidates, particularly AP1 and AP2, had lower bacterial burdens than the control mice. Moreover, the serum from immunised mice can enhance phagocytosis and phagosome-lysosome fusion in macrophages, which can help to eradicate intracellular bacteria. These results indicate that the subunit vaccines Ag85A-tnPstS1 can be promising vaccine candidates for tuberculosis prevention.
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Affiliation(s)
- Lingyuan Zeng
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Xiuling Ma
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Mengjin Qu
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Minghui Tang
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Huoming Li
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Chengrui Lei
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Jiahong Ji
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Hao Li
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
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13
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Bradford SD, Ryan KJ, Divens AM, Povroznik JM, Bonigala S, Robinson CM. IL-27 alters inflammatory cytokine expression and limits protective immunity against Mycobacterium tuberculosis in a neonatal BCG vaccination model. Front Immunol 2024; 15:1217098. [PMID: 38390338 PMCID: PMC10881868 DOI: 10.3389/fimmu.2024.1217098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 01/19/2024] [Indexed: 02/24/2024] Open
Abstract
Background Efforts to control tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), have been hampered by the immense variability in protection from BCG vaccination. While BCG protects young children from some forms of TB disease, long-term protection against pulmonary disease is more limited, suggesting a poor memory response. New vaccines or vaccination strategies are required to have a realistic chance of eliminating TB disease. In TB endemic areas, routine immunization occurs during the neonatal period and as such, we hypothesized that inadequate protective immunity elicited by BCG vaccination could be the result of the unique early-life immune landscape. Interleukin (IL)-27 is a heterodimeric cytokine with immune suppressive activity that is elevated in the neonatal period. Objective We investigated the impact of IL-27 on regulation of immune responses during neonatal BCG vaccination and protection against Mtb. Methods Here, we used a novel model of neonatal vaccination and adult aerosol challenge that models the human timeline of vaccine delivery and disease transmission. Results Overall, we observed improved control of Mtb in mice unresponsive to IL-27 (IL-27Rα-/-) that was consistent with altered expression patterns of IFN-γ and IL-17 in the lungs. The balance of these cytokines with TNF-α expression may be key to effective bacterial clearance. Conclusions Our findings suggest the importance of evaluating new vaccines and approaches to combat TB in the neonatal population most likely to receive them as part of global vaccination campaigns. They further indicate that temporal strategies to antagonize IL-27 during early life vaccination may improve protection.
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Affiliation(s)
- Shelby D. Bradford
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
| | - Kenneth J. Ryan
- Department of Statistics, West Virginia University, Morgantown, WV, United States
| | - Ashley M. Divens
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Jessica M. Povroznik
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
| | - Sunilkanth Bonigala
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Cory M. Robinson
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
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14
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Zhen L, Chen Y, Gao J, Li B, Jia Y. MicroRNA-99b Regulates Bacillus Calmette-Guerin-Infected Immature Dendritic Cell-Induced CD4+ T Cell Differentiation by Targeting mTOR Signaling. Crit Rev Immunol 2024; 44:35-47. [PMID: 38305335 DOI: 10.1615/critrevimmunol.2023050312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
This study aimed to elucidate the mechanisms by which microRNA-99b (miR-99b) regulates CD4+ T cell differentiation induced by Bacillus Calmette-Guerin (BCG)-infected immature dendritic cells (imDCs). Levels of miR-99b, interferon-gamma (IFN-γ), Foxp3, interleukin (IL)-10, IL-17, IL-23, and ROR-γt were assessed. Effects of miR-99b inhibition and mechanistic target of rapamycin (mTOR) agonist on Th17/Treg cell ratio and cytokine levels (IL-6, IL-17, IL-23) were studied. Expression of mTOR, S6K1, and 4E-BP1 related to miR-99b was analyzed. BCG-infected imDCs led to CD4+ T cell differentiation and altered levels of IFN-γ, Foxp3, IL-10, miR-99b, IL-17, IL-23, and ROR-γt. Inhibition of miR-99b increased the Th17/Treg cell ratio in CD4+ T cells co-cultured with BCG-infected imDCs, and this effect was further enhanced by the mTOR agonist. Additionally, the miR-99b inhibitor elevated the levels of IL-6, IL-17, and IL-23 when CD4+ T cells were co-cultured with BCG-infected imDCs, and the mTOR agonist further amplified this increase. Notably, miR-99b negatively regulated mTOR signaling, as the miR-99b inhibitor upregulated the expression levels of mTOR, S6K1, and 4E-BP1 while decreasing miR-99b. It was concluded that miR-99b modulates CD4+ T cell differentiation via mTOR pathway in response to BCG-infected im-DCs. Inhibiting miR-99b affects Th17/Treg ratio and pro-inflammatory cytokines, potentially impacting tuberculosis immunotherapies.
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Affiliation(s)
- Libo Zhen
- Department of Tuberculosis, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou 310030, China
| | - Yuanyuan Chen
- Tuberculosis Laboratory, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou 310030, China
| | - Juwei Gao
- Department of Oncology, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310061, China
| | - Boying Li
- Department of Tuberculosis, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou 310030, China
| | - Yangmin Jia
- Department of Occupational Medicine, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou 310030, China
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15
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Nakken O, Vaage AM, Stigum H, Heldal E, Meyer HE, Holmøy T. Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk. Brain Behav Immun Health 2023; 34:100704. [PMID: 38033614 PMCID: PMC10681879 DOI: 10.1016/j.bbih.2023.100704] [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: 10/31/2023] [Accepted: 11/05/2023] [Indexed: 12/02/2023] Open
Abstract
Background T cell infiltration around dying motor neurons is a hallmark of amyotrophic lateral sclerosis (ALS). It is not known if this immune response represents a cause or a consequence of the disease. We aimed to establish whether individual variation in regulation of a T cell driven immune response is associated with long-term ALS risk. Methods Tuberculin skin test (TST) following BCG vaccination represents a standardized measure of a secondary T cell driven immune response. During a Norwegian tuberculosis screening program (1963-1975) Norwegian citizens born from 1910 to 1955 underwent TST. In those previously BCG vaccinated (median 7 years prior to TST), we related tuberculin skin tests to later ALS disease identified through validated Norwegian health registers. We fitted Cox proportional hazard models to investigate the association between tuberculin reactivity and ALS risk. Results Among 324,629 participants (52 % women) with median age 22 (IQR 10) years at tuberculosis screening, 496 (50 % women) later developed ALS. Hazard ratio for ALS was 0.74 (95% CI 0.57-0.95) for those who remained TST negative compared to those who mounted a positive TST. The association was strongest when time between BCG immunization and TST was short. The associations observed persisted for more than four decades after TST measurement. Conclusions Negative TST responses after BCG vaccination is associated with decreased long-term risk for ALS development, supporting a primary role for adaptive immunity in ALS development.
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Affiliation(s)
- Ola Nakken
- Department of Neurology, Akershus University Hospital, Lørenskog, Norway
| | - Anders Myhre Vaage
- Department of Neurology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Hein Stigum
- Norwegian Institute of Public Health, Oslo, Norway
- Department of Community Medicine and Global Health, University of Oslo, Oslo, Norway
| | - Einar Heldal
- Norwegian Institute of Public Health, Oslo, Norway
| | - Haakon E. Meyer
- Norwegian Institute of Public Health, Oslo, Norway
- Department of Community Medicine and Global Health, University of Oslo, Oslo, Norway
| | - Trygve Holmøy
- Department of Neurology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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16
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Ouaked N, Demoitié MA, Godfroid F, Mortier MC, Vanloubbeeck Y, Temmerman ST. Non-clinical evaluation of local and systemic immunity induced by different vaccination strategies of the candidate tuberculosis vaccine M72/AS01. Tuberculosis (Edinb) 2023; 143:102425. [PMID: 38180028 DOI: 10.1016/j.tube.2023.102425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 10/11/2023] [Accepted: 10/22/2023] [Indexed: 01/06/2024]
Abstract
A new efficacious tuberculosis vaccine targeting adolescents/adults represents an urgent medical need. The M72/AS01E vaccine candidate protected half of the latently-infected adults against progression to pulmonary tuberculosis in a Phase IIb trial (NCT01755598). We report that three immunizations of mice, two weeks apart, with AS01-adjuvanted M72 induced polyfunctional, Th1-cytokine-expressing M72-specific CD4+/CD8+ T cells in blood and lungs, with the highest frequencies in lungs. Antigen-dose reductions across the three vaccinations skewed pulmonary CD4+ T-cell profiles towards IL-17 expression. In blood, reducing antigen and adjuvant doses of only the third injection (to 1/5th or 1/25th of those of the first injections) did not significantly alter CD4+ T-cell/antibody responses; applying a 10-week delay for the fractional third dose enhanced antibody titers. Delaying a full-dose booster enhanced systemic CD4+ T-cell and antibody responses. Cross-reactivity with PPE and non-PPE proteins was assessed, as Mycobacterium tuberculosis (Mtb) virulence factors and evasion mechanisms are often associated with PE/PPE proteins, to which Mtb39a (contained in M72) belongs. In silico/in vivo analyses revealed that M72/AS01 induced cross-reactive systemic CD4+ T-cell responses to epitopes in a non-vaccine antigen (putative latency-associated Mtb protein PPE24/Rv1753c). These preclinical data describing novel mechanisms of M72/AS01-induced immunity could guide future clinical development of the vaccine.
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Affiliation(s)
- Nadia Ouaked
- GSK, Rue de l'Institut 89, 1330, Rixensart, Belgium
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17
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Rojewski S, Westberg M, Nordsletten L, Meyer HE, Holvik K, Furnes O, Fenstad AM, Dahl J. Postvaccination immune responses and risk of primary total hip arthroplasty-A population-based cohort study. Osteoarthritis Cartilage 2023; 31:1249-1256. [PMID: 37236299 DOI: 10.1016/j.joca.2023.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 04/23/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023]
Abstract
OBJECTIVE To investigate the relationship between individual postvaccination immune responses and subsequent risk of total hip arthroplasty (THA) due to idiopathic osteoarthritis (OA) or rheumatoid arthritis (RA). METHOD Results of tuberculin skin tests (TSTs) following the Bacille Calmette-Guerin (BCG) vaccination were used as a marker of individual immune responses. TST results from the mandatory mass tuberculosis screening program 1948-1975 (n = 236 770) were linked with information on subsequent THA during 1987-2020 from the Norwegian Arthroplasty Register. The multivariable Cox proportional hazard regression was performed. RESULTS A total of 10 698 individuals received a THA during follow-up. In men, there was no association between TST and risk of THA due to OA (Hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.92-1.12 for positive versus negative TST and HR 1.06, 95% CI 0.95-1.18 for strong positive vs negative TST), while the risk estimates increased with increasingly restrictive sensitivity analyses. In women, there was no association with THA due to OA for positive versus negative TST (HR 0.98, 95% CI 0.92-1.05), while a strong positive TST was associated with reduced risk of THA (HR 0.90, 95% CI 0.84-0.97). No significant associations were observed in the sensitivity analysis for women or for THA due to RA. CONCLUSION Our results suggest that an increased postvaccination immune response is associated with a nonsignificant trend of increased risk of THA among men and a decreased risk among women, although risk estimates were small.
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Affiliation(s)
- Sonia Rojewski
- Division of Orthopaedic Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Physical Health and Ageing, Norwegian Institute of Public Health, Oslo, Norway.
| | - Marianne Westberg
- Division of Orthopaedic Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Lars Nordsletten
- Division of Orthopaedic Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Haakon E Meyer
- Department of Physical Health and Ageing, Norwegian Institute of Public Health, Oslo, Norway; Department of Community Medicine and Global Health, University of Oslo, Oslo, Norway.
| | - Kristin Holvik
- Department of Physical Health and Ageing, Norwegian Institute of Public Health, Oslo, Norway.
| | - Ove Furnes
- Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway; Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway.
| | - Anne Marie Fenstad
- Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway.
| | - Jesper Dahl
- Department of Physical Health and Ageing, Norwegian Institute of Public Health, Oslo, Norway.
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Peters JM, Irvine EB, Rosenberg JM, Wadsworth MH, Hughes TK, Sutton M, Nyquist SK, Bromley JD, Mondal R, Roederer M, Seder RA, Darrah PA, Alter G, Flynn JL, Shalek AK, Fortune SM, Bryson BD. Protective intravenous BCG vaccination induces enhanced immune signaling in the airways. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.16.549208. [PMID: 37502895 PMCID: PMC10370046 DOI: 10.1101/2023.07.16.549208] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Intradermal (ID) Bacillus Calmette-Guérin (BCG) is the most widely administered vaccine in the world. However, ID-BCG fails to achieve the level of protection needed in adults to alter the course of the tuberculosis epidemic. Recent studies in non-human primates have demonstrated high levels of protection against Mycobacterium tuberculosis ( Mtb ) following intravenous (IV) administration of BCG. However, the protective immune features that emerge following IV BCG vaccination remain incompletely defined. Here we used single-cell RNA-sequencing (scRNAseq) to transcriptionally profile 157,114 unstimulated and purified protein derivative (PPD)-stimulated bronchoalveolar lavage (BAL) cells from 29 rhesus macaques immunized with BCG across routes of administration and doses to uncover cell composition-, gene expression-, and biological network-level signatures associated with IV BCG-mediated protection. Our analyses revealed that high-dose IV BCG drove an influx of polyfunctional T cells and macrophages into the airways. These macrophages exhibited a basal activation phenotype even in the absence of PPD-stimulation, defined in part by IFN and TNF-α signaling up to 6 months following BCG immunization. Furthermore, intercellular immune signaling pathways between key myeloid and T cell subsets were enhanced following PPD-stimulation in high-dose IV BCG-vaccinated macaques. High-dose IV BCG also engendered quantitatively and qualitatively stronger transcriptional responses to PPD-stimulation, with a robust Th1-Th17 transcriptional phenotype in T cells, and augmented transcriptional signatures of reactive oxygen species production, hypoxia, and IFN-γ response within alveolar macrophages. Collectively, this work supports that IV BCG immunization creates a unique cellular ecosystem in the airways, which primes and enables local myeloid cells to effectively clear Mtb upon challenge.
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Gu Y, Yang J, He C, Zhao T, Lu R, Liu J, Mo X, Wen F, Shi H. Incorporation of a Toll-like receptor 2/6 agonist potentiates mRNA vaccines against cancer and infectious diseases. Signal Transduct Target Ther 2023; 8:273. [PMID: 37455272 DOI: 10.1038/s41392-023-01479-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 04/12/2023] [Accepted: 04/27/2023] [Indexed: 07/18/2023] Open
Abstract
mRNA vaccines have emerged rapidly in recent years as a prophylactic and therapeutic agent against various diseases including cancer and infectious diseases. Improvements of mRNA vaccines have been underway, among which boosting of efficacy is of great importance. Pam2Cys, a simple synthetic metabolizable lipoamino acid that signals through Toll-like receptor (TLR) 2/6 pathway, eliciting both humoral and cellular adaptive immune responses, is an interesting candidate adjuvant. To investigate the enhancement of the efficacies of mRNA vaccines by Pam2Cys, the adjuvant was incorporated into mRNA-lipid nanoparticles (LNPs) to achieve co-delivery with mRNA. Immunization with the resulting mRNA-LNPs (Pam2Cys) shaped up the immune milieu in the draining lymph nodes (dLNs) through the induction of IL-12 and IL-17, among other cytokines. Antigen presentation was carried out mainly by migratory and dLN-resident conventional type 2 DCs (cDC2s) and significantly more potent antitumor responses were triggered in both prophylactic and therapeutic tumor models in a CD4+ and CD8+ T cell-dependent fashion. Accompanying memory antitumor immunity was also established. Moreover, the vaccine also stimulated much more robust humoral and cellular immunity in a surrogate COVID-19 prophylactic model. Last but not the least, the new vaccines exhibited good preliminary safety profiles in murine models. These facts warrant future development of Pam2Cys-incorporated mRNA vaccines or relevant mRNA therapeutics for clinical application.
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Affiliation(s)
- Yangzhuo Gu
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China.
- Division of Pulmonary Diseases, State Key Laboratory of Biotherapy and Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
| | - Jingyun Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China
| | - Cai He
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China
| | - Tingmei Zhao
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China
| | - Ran Lu
- Laboratory of Stem Cell Biology and Department of Pediatric Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China
| | - Jian Liu
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China
| | - Xianming Mo
- Laboratory of Stem Cell Biology and Department of Pediatric Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China
| | - Fuqiang Wen
- Division of Pulmonary Diseases, State Key Laboratory of Biotherapy and Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Huashan Shi
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China.
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20
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Yamashita Y, Yasuda I, Tanaka T, Ikeda T, Terada M, Takaki M, Tsuchihashi Y, Asoh N, Ohara Y, Enany S, Kobayashi H, Matsumoto S, Morimoto K. Antigen-specific cytokine profiles for pulmonary Mycobacterium avium complex disease stage diagnosis. Front Immunol 2023; 14:1222428. [PMID: 37520555 PMCID: PMC10380938 DOI: 10.3389/fimmu.2023.1222428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 06/23/2023] [Indexed: 08/01/2023] Open
Abstract
Introduction Controlling pulmonary Mycobacterium avium complex (MAC) disease is difficult because there is no way to know the clinical stage accurately. There have been few attempts to use cell-mediated immunity for diagnosing the stage. The objective of this study was to characterize cytokine profiles of CD4+T and CD19+B cells that recognize various Mycobacterium avium-associated antigens in different clinical stages of MAC. Methods A total of 47 MAC patients at different stages based on clinical information (14 before-treatment, 16 on-treatment, and 17 after-treatment) and 17 healthy controls were recruited. Peripheral blood mononuclear cells were cultured with specific antigens (MAV0968, 1160, 1276, and 4925), and the cytokine profiles (IFN-γ, TNF-α, IL-2, IL-10, IL-13, and IL-17) of CD4+/CD3+ and CD19+ cells were analyzed by flow cytometry. Results The response of Th1 cytokines such as IFN-γ and TNF-α against various antigens was significantly higher in both the on-treatment and after-treatment groups than in the before-treatment group and control (P < 0.01-0.0001 and P < 0.05-0.0001). An analysis of polyfunctional T cells suggested that the presence of IL-2 is closely related to the stage after the start of treatment (P = 0.0309-P < 0.0001) and is involved in memory function. Non-Th1 cytokines, such as IL-10 and IL-17, showed significantly higher responses in the before-treatment group (P < 0.0001 and P < 0.01-0.0001). These responses were not observed with purified protein derivative (PPD). CD19+B cells showed a response similar to that of CD4+T cells. Conclusion There is a characteristic cytokine profile at each clinical stage of MAC.
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Affiliation(s)
- Yoshiro Yamashita
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Nagasaki, Japan
- Department of Respiratory Medicine, Shunkaikai Inoue Hospital, Nagasaki, Nagasaki, Japan
| | - Ikkoh Yasuda
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Nagasaki, Japan
- Department of General Internal Medicine and Clinical Infectious Diseases, Fukushima Medical University, Fukushima, Fukushima, Japan
| | - Takeshi Tanaka
- Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Nagasaki, Japan
| | - Toru Ikeda
- Department of Respiratory Medicine, Nagasaki Rosai Hospital, Sasebo, Nagasaki, Japan
| | - Mayumi Terada
- Department of Internal Medicine, Koseikai Nijigaoka Hospital, Nagasaki, Nagasaki, Japan
| | - Masahiro Takaki
- Department of Respiratory Medicine, Shunkaikai Inoue Hospital, Nagasaki, Nagasaki, Japan
| | - Yoshiko Tsuchihashi
- Department of Respiratory Medicine, Juzenkai Hospital, Nagasaki, Nagasaki, Japan
| | - Norichika Asoh
- Department of Respiratory Medicine, Juzenkai Hospital, Nagasaki, Nagasaki, Japan
| | - Yukiko Ohara
- Department of Bacteriology, Niigata University Graduate School of Medicine, Niigata, Niigata, Japan
| | - Shymaa Enany
- Department of Microbiology and Immunology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
- Biomedical Research Department, Armed Force College of Medicine, Cairo, Egypt
| | - Haruka Kobayashi
- Department of Bacteriology, Niigata University Graduate School of Medicine, Niigata, Niigata, Japan
| | - Sohkichi Matsumoto
- Department of Bacteriology, Niigata University Graduate School of Medicine, Niigata, Niigata, Japan
| | - Konosuke Morimoto
- Department of Internal Medicine, Koseikai Nijigaoka Hospital, Nagasaki, Nagasaki, Japan
- Department of Respiratory Infectious Disease, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Nagasaki, Japan
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21
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Corripio-Miyar Y, MacLeod CL, Mair I, Mellanby RJ, Moore BD, McNeilly TN. Self-Adjuvanting Calcium-Phosphate-Coated Microcrystal-Based Vaccines Induce Pyroptosis in Human and Livestock Immune Cells. Vaccines (Basel) 2023; 11:1229. [PMID: 37515044 PMCID: PMC10385459 DOI: 10.3390/vaccines11071229] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/05/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
Successful vaccines require adjuvants able to activate the innate immune system, eliciting antigen-specific immune responses and B-cell-mediated antibody production. However, unwanted secondary effects and the lack of effectiveness of traditional adjuvants has prompted investigation into novel adjuvants in recent years. Protein-coated microcrystals modified with calcium phosphate (CaP-PCMCs) in which vaccine antigens are co-immobilised within amino acid crystals represent one of these promising self-adjuvanting vaccine delivery systems. CaP-PCMCs has been shown to enhance antigen-specific IgG responses in mouse models; however, the exact mechanism of action of these microcrystals is currently unclear. Here, we set out to investigate this mechanism by studying the interaction between CaP-PCMCs and mammalian immune cells in an in vitro system. Incubation of cells with CaP-PCMCs induced rapid pyroptosis of peripheral blood mononuclear cells and monocyte-derived dendritic cells from cattle, sheep and humans, which was accompanied by the release of interleukin-1β and the activation of Caspase-1. We show that this pyroptotic event was cell-CaP-PCMCs contact dependent, and neither soluble calcium nor microcrystals without CaP (soluble PCMCs) induced pyroptosis. Our results corroborate CaP-PCMCs as a promising delivery system for vaccine antigens, showing great potential for subunit vaccines where the enhancement or find tuning of adaptive immunity is required.
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Affiliation(s)
| | - Clair Lyle MacLeod
- Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XQ, UK
| | - Iris Mair
- The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Midlothian EH25 9RG, UK
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK
| | - Richard J Mellanby
- The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Midlothian EH25 9RG, UK
| | - Barry D Moore
- Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XQ, UK
| | - Tom N McNeilly
- Moredun Research Institute, Pentlands Science Park, Penicuik EH26 0PZ, UK
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22
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Shey MS, Balfour A, Masina N, Bekiswa A, Schutz C, Goliath R, Dielle R, Katoto PDMC, Wilkinson KA, Lewinsohn D, Lewinsohn DA, Meintjes G. Mycobacterial-specific secretion of cytokines and chemokines in healthcare workers with apparent resistance to infection with Mycobacterium tuberculosis. Front Immunol 2023; 14:1176615. [PMID: 37275871 PMCID: PMC10233115 DOI: 10.3389/fimmu.2023.1176615] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/08/2023] [Indexed: 06/07/2023] Open
Abstract
Background Currently, diagnosis of latent TB infection (LTBI) is based on the secretion of IFN-γ in response to Mycobacterium tuberculosis (Mtb) antigens, the absence of which is regarded as no infection. Some individuals appear to resist Mtb infection despite sustained exposure (resisters). In this study, we aimed to assess cytokines, chemokines and antibodies that may be associated with resistance to Mtb infection. We hypothesized that there may be an alternative immune response to Mtb exposure in the absence of IFN-γ in resisters. Methods We enrolled HIV-uninfected healthcare workers who had worked in high TB-exposure environments for 5 years or longer. We screened them for LTBI using the tuberculin skin test and the QuantiFERON-TB Gold Plus assay. We performed multiplex Luminex to measure concentrations of T cell-associated cytokines and chemokines as well as total antibodies in plasma collected from unstimulated fresh whole blood and supernatants from QuantiFERON-TB Gold Plus tubes following incubation of whole blood for 16-24 hours with ESAT6/CFP10 peptides. Results Samples from 78 individuals were analyzed: 33 resisters (TST<10mm; IGRA<0.35 IU/mL), 33 with LTBI (TST≥10mm and IGRA≥0.35 IU/mL) and 12 discordant (TST=0mm; IGRA≥1.0 IU/mL). There were no differences in concentrations of cytokines and chemokines in plasma between the different groups. Resisters had significantly lower concentrations of IFN-γ, IL-2, TNF-α, MIP-1α, MIP-1β, ITAC, IL-13 and GM-CSF in supernatants compared with LTBI group. There were no significant differences in the concentrations in supernatants of IL-10, IL-1β, IL-17A, IL-21, IL-23, MIP-3α, IL-4, IL-5, IL-6, IL-7, IL-8, Fractalkine and IL-12p70 between the groups. We observed that resisters had similar concentrations of total antibodies (IgG1, IgG2, IgG3, IgG4, IgA, and IgM) in plasma and supernatants compared to the LTBI and discordant groups. Conclusion Resistance to Mtb infection despite sustained exposure is associated with lower Mtb-specific secretion of Th1-associated cytokines and chemokines. However, resisters showed secreted concentrations after Mtb stimulation of total antibodies and cytokines/chemokines associated with innate and Th17 immune responses similar to those with Mtb infection. This suggests an ability to mount non-IFN-γ immune responses to Mtb in apparent resisters.
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Affiliation(s)
- Muki Shehu Shey
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Avuyonke Balfour
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Nomawethu Masina
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Abulele Bekiswa
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Charlotte Schutz
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Rene Goliath
- Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Rachel Dielle
- Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Patrick DMC. Katoto
- Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa
- Centre for General Medicine and Global Health, Department of Medicine, University of Cape Town, Cape Town, South Africa
- Centre for Tropical Diseases and Global Health and Department of Internal Medicine , Catholic University of Bukavu, Bukavu, Democratic Republic of Congo
| | - Katalin Andrea Wilkinson
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Tuberculosis Laboratory, The Francis Crick Institute, London, United Kingdom
| | - David Lewinsohn
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, OR, United States
| | - Deborah Anne Lewinsohn
- Division of Infectious Diseases, Department of Paediatrics, Oregon Health and Science University, Portland, OR, United States
| | - Graeme Meintjes
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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23
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A MAPS Vaccine Induces Multipronged Systemic and Tissue-Resident Cellular Responses and Protects Mice against Mycobacterium tuberculosis. mBio 2023; 14:e0361122. [PMID: 36749098 PMCID: PMC9973048 DOI: 10.1128/mbio.03611-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. To date, the mainstay of vaccination involves the use of Mycobacterium bovis bacillus Calmette-Guérin (BCG), a live-attenuated vaccine that confers protection against extrapulmonary disease in infants and children but not against lung disease. Thus, there is an urgent need for novel vaccines. Here, we show that a multicomponent acellular vaccine (TB-MAPS) induces robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4+ and CD8+ T cells, and promotes trained innate immunity mediated by γδT and NKT cells in mice. When tested in a mouse aerosol infection model, TB-MAPS significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate. IMPORTANCE Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. Here, we evaluate a novel vaccine which induces a broad immune response to Mycobacterium tuberculosis including robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4+ and CD8+ T cells. When tested in a mouse aerosol infection model, this vaccine significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate.
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24
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Schick J, Altunay M, Lacorcia M, Marschner N, Westermann S, Schluckebier J, Schubart C, Bodendorfer B, Christensen D, Alexander C, Wirtz S, Voehringer D, da Costa CP, Lang R. IL-4 and helminth infection downregulate MINCLE-dependent macrophage response to mycobacteria and Th17 adjuvanticity. eLife 2023; 12:72923. [PMID: 36753434 PMCID: PMC9908076 DOI: 10.7554/elife.72923] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 01/30/2023] [Indexed: 02/09/2023] Open
Abstract
The myeloid C-type lectin receptor (CLR) MINCLE senses the mycobacterial cell wall component trehalose-6,6'-dimycolate (TDM). Recently, we found that IL-4 downregulates MINCLE expression in macrophages. IL-4 is a hallmark cytokine in helminth infections, which appear to increase the risk for mycobacterial infection and active tuberculosis. Here, we investigated functional consequences of IL-4 and helminth infection on MINCLE-driven macrophage activation and Th1/Th17 adjuvanticity. IL-4 inhibited MINCLE and cytokine induction after macrophage infection with Mycobacterium bovis bacille Calmette-Guerin (BCG). Infection of mice with BCG upregulated MINCLE on myeloid cells, which was inhibited by IL-4 plasmid injection and by infection with the nematode Nippostrongylus brasiliensis in monocytes. To determine the impact of helminth infection on MINCLE-dependent immune responses, we vaccinated mice with a recombinant protein together with the MINCLE ligand trehalose-6,6-dibehenate (TDB) as adjuvant. Concurrent infection with N. brasiliensis or with Schistosoma mansoni promoted T cell-derived IL-4 production and suppressed Th1/Th17 differentiation in the spleen. In contrast, helminth infection did not reduce Th1/Th17 induction by TDB in draining peripheral lymph nodes, where IL-4 levels were unaltered. Upon use of the TLR4-dependent adjuvant G3D6A, N. brasiliensis infection impaired selectively the induction of splenic antigen-specific Th1 but not of Th17 cells. Inhibition of MINCLE-dependent Th1/Th17 responses in mice infected with N. brasiliensis was dependent on IL-4/IL-13. Thus, helminth infection attenuated the Th17 response to MINCLE-dependent immunization in an organ- and adjuvant-specific manner via the Th2 cytokines IL-4/IL-13. Taken together, our results demonstrate downregulation of MINCLE expression on monocytes and macrophages by IL-4 as a possible mechanism of thwarted Th17 vaccination responses by underlying helminth infection.
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Affiliation(s)
- Judith Schick
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
| | - Meltem Altunay
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
| | - Matthew Lacorcia
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Center for Global Health, Technische Universität MünchenMunichGermany,Center for Global Health, Technical University MunichMunichGermany
| | - Nathalie Marschner
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
| | - Stefanie Westermann
- Infektionsbiologische Abteilung, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
| | - Julia Schluckebier
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Center for Global Health, Technische Universität MünchenMunichGermany,Center for Global Health, Technical University MunichMunichGermany
| | - Christoph Schubart
- Infektionsbiologische Abteilung, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
| | - Barbara Bodendorfer
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
| | - Dennis Christensen
- Adjuvant Research, Department of Infectious Disease Immunology, Statens Serum InstitutCopenhagenDenmark
| | - Christian Alexander
- Cellular Microbiology, Forschungszentrum Borstel, Leibniz Lung Center BorstelBorstelGermany
| | - Stefan Wirtz
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
| | - David Voehringer
- Infektionsbiologische Abteilung, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
| | - Clarissa Prazeres da Costa
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Center for Global Health, Technische Universität MünchenMunichGermany,Center for Global Health, Technical University MunichMunichGermany
| | - Roland Lang
- Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-NürnbergErlangenGermany
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25
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Flynn JL, Chan J. Immune cell interactions in tuberculosis. Cell 2022; 185:4682-4702. [PMID: 36493751 PMCID: PMC12162144 DOI: 10.1016/j.cell.2022.10.025] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/15/2022] [Accepted: 10/26/2022] [Indexed: 12/13/2022]
Abstract
Despite having been identified as the organism that causes tuberculosis in 1882, Mycobacterium tuberculosis has managed to still evade our understanding of the protective immune response against it, defying the development of an effective vaccine. Technology and novel experimental models have revealed much new knowledge, particularly with respect to the heterogeneity of the bacillus and the host response. This review focuses on certain immunological elements that have recently yielded exciting data and highlights the importance of taking a holistic approach to understanding the interaction of M. tuberculosis with the many host cells that contribute to the development of protective immunity.
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Affiliation(s)
- JoAnne L Flynn
- Department of Microbiology and Molecular Genetics and the Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - John Chan
- Department of Medicine, Center for Emerging Pathogens, Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
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26
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Lee JM, Park J, Reed SG, Coler RN, Hong JJ, Kim LH, Lee W, Kwon KW, Shin SJ. Vaccination inducing durable and robust antigen-specific Th1/Th17 immune responses contributes to prophylactic protection against Mycobacterium avium infection but is ineffective as an adjunct to antibiotic treatment in chronic disease. Virulence 2022; 13:808-832. [PMID: 35499090 PMCID: PMC9067471 DOI: 10.1080/21505594.2022.2068489] [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: 01/03/2022] [Revised: 04/01/2022] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
Mycobacterium avium complex (MAC) causing pulmonary disease in humanshas emerged worldwide. Thus, effective strategies simultaneously aiming to prevent MAC infection and accelerate therapeutic efficacy are required. To this end, subunit vaccine-induced protection against a well-defined virulent Mycobacterium avium (Mav) isolate was assessed as a preventative and therapeutic modality in murine models. Mav-derived culture filtrate antigen (CFA) was used as a vaccine antigen with glucopyranosyl lipid A stable emulsion (GLA-SE) or GLA-SE plus cyclic-di-GMP (GLA-SE/CDG), and we compared the immunogenicities, protective efficacies and immune correlates. Interestingly, CFA+GLA-SE/CDG immunization induced greater CFA-specific Th1/Th17 responses in both the lung and spleen than among the tested groups. Consequently, protective efficacy was optimally achieved with CFA+GLA-SE/CDG by significantly reducing bacterial loads along with long-lasting maintenance of antigen-specific Th1/Th17 cytokine-producing multifunctional T cell responses and relevant cytokine productions. Thus, we employed this subunit vaccine as an adjunct to antibiotic treatment. However, this vaccine was ineffective in further reducing bacterial loads. Collectively, our study demonstrates that strong Mav CFA-specific Th1/Th17 responses are critical for preventative protection against Mav infection but may be ineffective or even detrimental in an established and progressive chronic disease, indicating that different approaches to combating Mav infection are necessary according to vaccination purposes.
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Affiliation(s)
- Ju Mi Lee
- Department of Microbiology, Institute for Immunology and Immunological Disease, Graduate School of Medical science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Jiyun Park
- Department of Microbiology, Institute for Immunology and Immunological Disease, Graduate School of Medical science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | | | - Rhea N Coler
- Seattle Children’s Research Institute, Center for Global Infectious Disease Research, Seattle, WA, USA
- Department of Global Health, University of Washington, Seattle, WA, USA
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
| | - Jung Joo Hong
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, South Korea
| | - Lee-Han Kim
- Department of Microbiology, Institute for Immunology and Immunological Disease, Graduate School of Medical science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Wonsik Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Kee Woong Kwon
- Department of Microbiology, Institute for Immunology and Immunological Disease, Graduate School of Medical science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Sung Jae Shin
- Department of Microbiology, Institute for Immunology and Immunological Disease, Graduate School of Medical science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
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27
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Singh S, Saavedra-Avila NA, Tiwari S, Porcelli SA. A century of BCG vaccination: Immune mechanisms, animal models, non-traditional routes and implications for COVID-19. Front Immunol 2022; 13:959656. [PMID: 36091032 PMCID: PMC9459386 DOI: 10.3389/fimmu.2022.959656] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/01/2022] [Indexed: 11/21/2022] Open
Abstract
Bacillus Calmette-Guerin (BCG) has been used as a vaccine against tuberculosis since 1921 and remains the only currently approved vaccine for this infection. The recent discovery that BCG protects against initial infection, and not just against progression from latent to active disease, has significant implications for ongoing research into the immune mechanisms that are relevant to generate a solid host defense against Mycobacterium tuberculosis (Mtb). In this review, we first explore the different components of immunity that are augmented after BCG vaccination. Next, we summarize current efforts to improve the efficacy of BCG through the development of recombinant strains, heterologous prime-boost approaches and the deployment of non-traditional routes. These efforts have included the development of new recombinant BCG strains, and various strategies for expression of important antigens such as those deleted during the M. bovis attenuation process or antigens that are present only in Mtb. BCG is typically administered via the intradermal route, raising questions about whether this could account for its apparent failure to generate long-lasting immunological memory in the lungs and the inconsistent level of protection against pulmonary tuberculosis in adults. Recent years have seen a resurgence of interest in the mucosal and intravenous delivery routes as they have been shown to induce a better immune response both in the systemic and mucosal compartments. Finally, we discuss the potential benefits of the ability of BCG to confer trained immunity in a non-specific manner by broadly stimulating a host immunity resulting in a generalized survival benefit in neonates and the elderly, while potentially offering benefits for the control of new and emerging infectious diseases such as COVID-19. Given that BCG will likely continue to be widely used well into the future, it remains of critical importance to better understand the immune responses driven by it and how to leverage these for the design of improved vaccination strategies against tuberculosis.
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Affiliation(s)
- Shivani Singh
- Department of Medicine, New York University School of Medicine, New York, NY, United States
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, United States
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, United States
- *Correspondence: Shivani Singh,
| | | | - Sangeeta Tiwari
- Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, Texas, United States
| | - Steven A. Porcelli
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, United States
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, United States
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28
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Mycobacterium intracellulare induces a Th17 immune response via M1-like macrophage polarization in canine peripheral blood mononuclear cells. Sci Rep 2022; 12:11818. [PMID: 35821058 PMCID: PMC9276657 DOI: 10.1038/s41598-022-16117-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 07/05/2022] [Indexed: 11/11/2022] Open
Abstract
Mycobacterium avium-intracellulare complex (MAC) is one of the most prevalent pathogenic nontuberculous mycobacteria that cause chronic pulmonary disease. The prevalence of MAC infection has been rising globally in a wide range of hosts, including companion animals. MAC infection has been reported in dogs; however, little is known about interaction between MAC and dogs, especially in immune response. In this study, we investigated the host immune response driven by M. intracellulare using the co-culture system of canine T helper cells and autologous monocyte-derived macrophages (MDMs). Transcriptomic analysis revealed that canine MDMs differentiated into M1-like macrophages after M. intracellulare infection and the macrophages secreted molecules that induced Th1/Th17 cell polarization. Furthermore, canine lymphocytes co-cultured with M. intracellulare-infected macrophages induced the adaptive Th17 responses after 5 days. Taken together, our results indicate that M. intracellulare elicits a Th17 response through macrophage activation in this system. Those findings might help the understanding of the canine immune response to MAC infection and diminishing the potential zoonotic risk in One Health aspect.
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Akter S, Chauhan KS, Dunlap MD, Choreño-Parra JA, Lu L, Esaulova E, Zúñiga J, Artyomov MN, Kaushal D, Khader SA. Mycobacterium tuberculosis infection drives a type I IFN signature in lung lymphocytes. Cell Rep 2022; 39:110983. [PMID: 35732116 PMCID: PMC9616001 DOI: 10.1016/j.celrep.2022.110983] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 04/20/2022] [Accepted: 05/27/2022] [Indexed: 11/16/2022] Open
Abstract
Mycobacterium tuberculosis (Mtb) infects 25% of the world's population and causes tuberculosis (TB), which is a leading cause of death globally. A clear understanding of the dynamics of immune response at the cellular level is crucial to design better strategies to control TB. We use the single-cell RNA sequencing approach on lung lymphocytes derived from healthy and Mtb-infected mice. Our results show the enrichment of the type I IFN signature among the lymphoid cell clusters, as well as heat shock responses in natural killer (NK) cells from Mtb-infected mice lungs. We identify Ly6A as a lymphoid cell activation marker and validate its upregulation in activated lymphoid cells following infection. The cross-analysis of the type I IFN signature in human TB-infected peripheral blood samples further validates our results. These findings contribute toward understanding and characterizing the transcriptional parameters at a single-cell depth in a highly relevant and reproducible mouse model of TB.
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Affiliation(s)
- Sadia Akter
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA,These authors contributed equally
| | - Kuldeep S. Chauhan
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA,These authors contributed equally
| | - Micah D. Dunlap
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - José Alberto Choreño-Parra
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA,Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City 14080, Mexico,Laboratorio de Inmunoquímica I, Posgrado en Ciencias Quimicobiológicas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 07320, Mexico
| | - Lan Lu
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ekaterina Esaulova
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Joaquin Zúñiga
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City 14080, Mexico,Laboratorio de Inmunoquímica I, Posgrado en Ciencias Quimicobiológicas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 07320, Mexico
| | - Maxim N. Artyomov
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Deepak Kaushal
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
| | - Shabaana A. Khader
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA,Lead contact,Correspondence: (D.K.), (S.A.K.) https://doi.org/10.1016/j.celrep.2022.110983
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30
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Nakken O, Holmøy T, Stigum H, Myhr KM, Dahl J, Heldal E, Meyer HE. Strong tuberculin response after BCG vaccination is associated with low multiple sclerosis risk: a population-based cohort study. Int J Epidemiol 2022; 51:1637-1644. [PMID: 35278068 PMCID: PMC9557857 DOI: 10.1093/ije/dyac039] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 02/18/2022] [Indexed: 12/14/2022] Open
Abstract
Abstract
Background
Multiple sclerosis (MS) is characterized by inflammatory lesions in the central nervous system involving pro-inflammatory T-cells. Immune dysregulation is well described in prevalent disease, but it is not known whether this precedes disease development. Bacillus Calmette–Guérin (BCG) vaccination ameliorates MS-like disease in mice. In people vaccinated with BCG, the tuberculin skin test (TST) offers a standardized measure of a T-cell-mediated immune response. We therefore hypothesized that the strength of the TST response after BCG vaccination is associated with subsequent MS risk.
Methods
Using data from a Norwegian tuberculosis screening programme (1963–1975), we designed a population-based cohort study and related the size of TST reactions in individuals previously vaccinated with BCG to later MS disease identified through the Norwegian MS registry. We fitted Cox proportional hazard models and flexible parametric survival models to investigate the association between TST reactivity, MS risk and its temporal relationship.
Results
Among 279 891 participants (52% females), 679 (69% females) later developed MS. Larger TST reactivity was associated with decreased MS risk. The hazard ratio for MS per every 4-mm increase in skin induration size was 0.86 (95% confidence interval 0.76–0.96) and similar between sexes. The strength of the association persisted for >30 years after the TST.
Conclusion
A strong in vivo vaccine response to BCG is associated with reduced MS risk >30 years later. The immunological mechanisms determining TST reactivity suggest that skewed T-cell-mediated immunity precedes MS onset by many decades.
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Affiliation(s)
- Ola Nakken
- Department of Neurology, Akershus University Hospital, Lørenskog, Norway
| | - Trygve Holmøy
- Department of Neurology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Hein Stigum
- Department of Physical Health and Ageing, Norwegian Institute of Public Health, Oslo, Norway
- Department of Community Medicine and Global Health, University of Oslo, Oslo, Norway
| | - Kjell-Morten Myhr
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Jesper Dahl
- Department of Physical Health and Ageing, Norwegian Institute of Public Health, Oslo, Norway
| | - Einar Heldal
- Department of Physical Health and Ageing, Norwegian Institute of Public Health, Oslo, Norway
| | - Haakon E Meyer
- Department of Physical Health and Ageing, Norwegian Institute of Public Health, Oslo, Norway
- Department of Community Medicine and Global Health, University of Oslo, Oslo, Norway
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31
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Smith CM, Baker RE, Proulx MK, Mishra BB, Long JE, Park SW, Lee HN, Kiritsy MC, Bellerose MM, Olive AJ, Murphy KC, Papavinasasundaram K, Boehm FJ, Reames CJ, Meade RK, Hampton BK, Linnertz CL, Shaw GD, Hock P, Bell TA, Ehrt S, Schnappinger D, Pardo-Manuel de Villena F, Ferris MT, Ioerger TR, Sassetti CM. Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice. eLife 2022; 11:74419. [PMID: 35112666 PMCID: PMC8846590 DOI: 10.7554/elife.74419] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 01/27/2022] [Indexed: 11/21/2022] Open
Abstract
The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen’s ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of Mtb transposon mutant fitness (TnSeq) across the CC panel revealed that many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen’s genome that has been maintained to ensure fitness in a diverse population. Both immunological and bacterial traits can be associated with genetic variants distributed across the mouse genome, making the CC a unique population for identifying specific host-pathogen genetic interactions that influence pathogenesis.
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Affiliation(s)
- Clare M Smith
- Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
| | - Richard E Baker
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Megan K Proulx
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Bibhuti B Mishra
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Jarukit E Long
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Sae Woong Park
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
| | - Ha-Na Lee
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
| | - Michael C Kiritsy
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Michelle M Bellerose
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Andrew J Olive
- Microbiology and Molecular Genetics, Michigan State University, East Lansing, United States
| | - Kenan C Murphy
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Kadamba Papavinasasundaram
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Frederick J Boehm
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Charlotte J Reames
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
| | - Rachel K Meade
- Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
| | - Brea K Hampton
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Colton L Linnertz
- Department of Genetics, University of North Carolina at Chapel Hill, Morrisville, United States
| | - Ginger D Shaw
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Pablo Hock
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Timothy A Bell
- Department of Genetics,, University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Sabine Ehrt
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
| | - Dirk Schnappinger
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
| | | | - Martin T Ferris
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Thomas R Ioerger
- Department of Computer Science and Engineering, Texas A&M University, College Station, United States
| | - Christopher M Sassetti
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
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32
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Gomez M, Ahmed M, Das S, McCollum J, Mellett L, Swanson R, Gupta A, Carrigy NB, Wang H, Barona D, Bachchhav S, Gerhardt A, Press C, Archer MC, Liang H, Seydoux E, Kramer RM, Kuehl PJ, Vehring R, Khader SA, Fox CB. Development and Testing of a Spray-Dried Tuberculosis Vaccine Candidate in a Mouse Model. Front Pharmacol 2022; 12:799034. [PMID: 35126135 PMCID: PMC8814656 DOI: 10.3389/fphar.2021.799034] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/27/2021] [Indexed: 11/15/2022] Open
Abstract
Converting a vaccine into a thermostable dry powder is advantageous as it reduces the resource burden linked with the cold chain and provides flexibility in dosage and administration through different routes. Such a dry powder presentation may be especially useful in the development of a vaccine towards the respiratory infectious disease tuberculosis (TB). This study assesses the immunogenicity and protective efficacy of spray-dried ID93+GLA-SE, a promising TB vaccine candidate, against Mycobacterium tuberculosis (Mtb) in a murine model when administered via different routes. Four administration routes for the spray-dried ID93+GLA-SE were evaluated along with relevant controls—1) reconstitution and intramuscular injection, 2) reconstitution and intranasal delivery, 3) nasal dry powder delivery via inhalation, and 4) pulmonary dry powder delivery via inhalation. Dry powder intranasal and pulmonary delivery was achieved using a custom nose-only inhalation device, and optimization using representative vaccine-free powder demonstrated that approximately 10 and 44% of the maximum possible delivered dose would be delivered for intranasal delivery and pulmonary delivery, respectively. Spray-dried powder was engineered according to the different administration routes including maintaining approximately equivalent delivered doses of ID93 and GLA. Vaccine properties of the different spray-dried lots were assessed for quality control in terms of nanoemulsion droplet diameter, polydispersity index, adjuvant content, and antigen content. Our results using the Mtb mouse challenge model show that both intranasal reconstituted vaccine delivery as well as pulmonary dry powder vaccine delivery resulted in Mtb control in infected mice comparable to traditional intramuscular delivery. Improved protection in these two vaccinated groups over their respective control groups coincided with the presence of cytokine-producing T cell responses. In summary, our results provide novel vaccine formulations and delivery routes that can be harnessed to provide protection against Mtb infection.
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Affiliation(s)
- Mellissa Gomez
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Mushtaq Ahmed
- Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
| | - Shibali Das
- Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
| | - Joseph McCollum
- Infectious Disease Research Institute, Seattle, WA, United States
| | - Leah Mellett
- Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
| | - Rosemary Swanson
- Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
| | - Ananya Gupta
- Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
| | - Nicholas B. Carrigy
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Hui Wang
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - David Barona
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Shital Bachchhav
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Alana Gerhardt
- Infectious Disease Research Institute, Seattle, WA, United States
| | - Chris Press
- Infectious Disease Research Institute, Seattle, WA, United States
| | | | - Hong Liang
- Infectious Disease Research Institute, Seattle, WA, United States
| | - Emilie Seydoux
- Infectious Disease Research Institute, Seattle, WA, United States
| | - Ryan M. Kramer
- Infectious Disease Research Institute, Seattle, WA, United States
| | | | - Reinhard Vehring
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Shabaana A. Khader
- Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
- *Correspondence: Shabaana A. Khader, ; Christopher B. Fox,
| | - Christopher B. Fox
- Infectious Disease Research Institute, Seattle, WA, United States
- Department of Global Health, University of Washington, Seattle, WA, United States
- *Correspondence: Shabaana A. Khader, ; Christopher B. Fox,
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33
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Ahmad F, Umar MS, Khan N, Jamal F, Gupta P, Zubair S, Gupta UD, Owais M. Immunotherapy With 5, 15-DPP Mediates Macrophage M1 Polarization and Modulates Subsequent Mycobacterium tuberculosis Infectivity in rBCG30 Immunized Mice. Front Immunol 2021; 12:706727. [PMID: 34777338 PMCID: PMC8586420 DOI: 10.3389/fimmu.2021.706727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 10/04/2021] [Indexed: 11/13/2022] Open
Abstract
Tuberculosis (TB) is a significant and continuing problem worldwide, with a death toll of around 1.5 million human lives annually. BCG, the only vaccine against TB, offers a varied degree of protection among human subjects in different regions and races of the world. The majority of the population living near the tropics carries a varying degree of tolerance against BCG due to the widespread prevalence of non-tuberculous mycobacteria (NTM). Interestingly, ≈90% of the Mycobacterium tuberculosis (Mtb) infected population restrain the bacilli on its own, which strengthens the notion of empowering the host immune system to advance the protective efficacy of existing mycobacterial vaccines. In general, Mtb modulates IL-10/STAT3 signaling to skew host mononuclear phagocytes toward an alternatively activated, anti-inflammatory state that helps it thrive against hostile immune advances. We hypothesized that modulating the IL-10/STAT3 driven anti-inflammatory effects in mononuclear cells may improve the prophylactic ability of TB vaccines. This study investigated the immunotherapeutic ability of a porphyrin based small molecule inhibitor of IL-10/STAT3 axis, 5, 15-diphenyl porphyrin (DPP), in improving anti-TB immunity offered by second generation recombinant BCG30 (rBCG30-ARMF-II®) vaccine in mice. The DPP therapy potentiated vaccine induced anti-TB immunity by down-modulating anti-inflammatory responses, while simultaneously up-regulating pro-inflammatory immune effector responses in the immunized host. The employed DPP based immunotherapy led to the predominant activation/proliferation of pro-inflammatory monocytes/macrophages/DCs, the concerted expansion of CD4+/CD8+ effector and central memory T cells, alongside balanced Th17 and Treg cell amplification, and conferred augmented resistance to aerosol Mtb challenge in rBCG30 immunized BALB/c mice.
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Affiliation(s)
- Faraz Ahmad
- Molecular Immunology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
| | - Mohd Saad Umar
- Molecular Immunology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
| | - Nazoora Khan
- Molecular Immunology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
| | - Fauzia Jamal
- Molecular Immunology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
| | - Pushpa Gupta
- Bio-Safety Level (BSL)-3 Animal Experimentation Facility, Indian Council of Medical Research (ICMR)-National Japanese Leprosy Mission for Asia (JALMA) Institute for Leprosy and Other Mycobacterial Diseases, Agra, India
| | - Swaleha Zubair
- Department of Computer Science, Aligarh Muslim University, Aligarh, India
| | - Umesh Datta Gupta
- Bio-Safety Level (BSL)-3 Animal Experimentation Facility, Indian Council of Medical Research (ICMR)-National Japanese Leprosy Mission for Asia (JALMA) Institute for Leprosy and Other Mycobacterial Diseases, Agra, India
| | - Mohammad Owais
- Molecular Immunology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
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34
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Ritter K, Behrends J, Erdmann H, Rousseau J, Hölscher A, Volz J, Prinz I, Lindenstrøm T, Hölscher C. Interleukin-23 instructs protective multifunctional CD4 T cell responses after immunization with the Mycobacterium tuberculosis subunit vaccine H1 DDA/TDB independently of interleukin-17A. J Mol Med (Berl) 2021; 99:1585-1602. [PMID: 34351501 PMCID: PMC8541990 DOI: 10.1007/s00109-021-02100-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 06/01/2021] [Accepted: 06/07/2021] [Indexed: 01/01/2023]
Abstract
Interleukin (IL)-17A-producing T helper (Th)17 cells are increasingly being acknowledged to be associated with protective immunity to Mycobacterium tuberculosis (Mtb). Subunit vaccines potently promote protective immune responses against Mtb infection that correlate with an expansion of IL-23-dependent Th17 cells. Previous studies revealed that after vaccination, IL-23 is required for protection against challenge with Mtb but the underlying IL-23-dependent-and possibly IL-17A-mediated-mechanisms remain elusive. Therefore, we here analyzed the early outcome of Mtb infection in C57BL/6, IL-23p19-deficient (-/-), and IL-17A-/- mice after vaccination with the subunit vaccine H1-DDA/TDB to investigate the role of the IL-23-Th17 immune axis for the instruction of vaccine-induced protection. While in IL-23p19-/- mice the protective effect was reduced, protection after vaccination was maintained in IL-17A-/- animals for the course of infection of 6 weeks, indicating that after vaccination with H1-DDA/TDB early protection against Mtb is-although dependent on IL-23-not mediated by IL-17A. In contrast, IL-17A deficiency appears to have an impact on maintaining long-term protection. In fact, IL-23 instructed the vaccine-induced memory immunity in the lung, in particular the sustained expansion of tumor necrosis factor (TNF)+IL-2+ multifunctional T cells, independently of IL-17A. Altogether, a targeted induction of IL-23 during vaccination against Mtb might improve the magnitude and quality of vaccine-induced memory immune responses. KEY MESSAGES: After subunit Mtb vaccination with H1-DDA/TDB, IL-23 but not IL-17A contributes to vaccine-induced early protection against infection with Mtb. IL-17F does not compensate for IL-17A deficiency in terms of H1-DDA/TDB-induced protection against Mtb infection. IL 23 promotes the H1-DDA/TDB-induced accumulation of effector memory T cells independently of IL 17A. IL-23 arbitrates the induction of H1-specific IFN-γ-TNF+IL-2+ double-positive multifunctional CD4 T cells after subunit Mtb vaccination in an IL-17A-independent manner.
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Affiliation(s)
- Kristina Ritter
- Infection Immunology, Research Center Borstel, Borstel, Germany
| | - Jochen Behrends
- Fluorescence Cytometry Core Unit, Research Center Borstel, Borstel, Germany
| | - Hanna Erdmann
- Infection Immunology, Research Center Borstel, Borstel, Germany
| | - Jasmin Rousseau
- Infection Immunology, Research Center Borstel, Borstel, Germany
| | | | - Johanna Volz
- Infection Immunology, Research Center Borstel, Borstel, Germany
| | - Immo Prinz
- Institute of Immunology, Hannover Medical School, Hannover, Germany
- Center for Molecular Neurobiology Hamburg, Eppendorf University Medical Center, Hamburg, Germany
| | - Thomas Lindenstrøm
- Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark
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35
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Bunjun R, Omondi FMA, Makatsa MS, Keeton R, Wendoh JM, Müller TL, Prentice CSL, Wilkinson RJ, Riou C, Burgers WA. Th22 Cells Are a Major Contributor to the Mycobacterial CD4 + T Cell Response and Are Depleted During HIV Infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:1239-1249. [PMID: 34389623 PMCID: PMC8387408 DOI: 10.4049/jimmunol.1900984] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 07/03/2021] [Indexed: 12/13/2022]
Abstract
HIV-1 infection substantially increases the risk of developing tuberculosis (TB). Mechanisms such as defects in the Th1 response to Mycobacterium tuberculosis in HIV-infected persons have been widely reported. However, Th1-independent mechanisms also contribute to protection against TB. To identify a broader spectrum of defects in TB immunity during HIV infection, we examined IL-17A and IL-22 production in response to mycobacterial Ags in peripheral blood of persons with latent TB infection and HIV coinfection. Upon stimulating with mycobacterial Ags, we observed a distinct CD4+ Th lineage producing IL-22 in the absence of IL-17A and IFN-γ. Mycobacteria-specific Th22 cells were present at high frequencies in blood and contributed up to 50% to the CD4+ T cell response to mycobacteria, comparable in magnitude to the IFN-γ Th1 response (median 0.91% and 0.55%, respectively). Phenotypic characterization of Th22 cells revealed that their memory differentiation was similar to M. tuberculosis-specific Th1 cells (i.e., predominantly early differentiated CD45RO+CD27+ phenotype). Moreover, CCR6 and CXCR3 expression profiles of Th22 cells were similar to Th17 cells, whereas their CCR4 and CCR10 expression patterns displayed an intermediate phenotype between Th1 and Th17 cells. Strikingly, mycobacterial IL-22 responses were 3-fold lower in HIV-infected persons compared with uninfected persons, and the magnitude of responses correlated inversely with HIV viral load. These data provide important insights into mycobacteria-specific Th subsets in humans and suggest a potential role for IL-22 in protection against TB during HIV infection. Further studies are needed to fully elucidate the role of IL-22 in protective TB immunity.
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Affiliation(s)
- Rubina Bunjun
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Fidilia M A Omondi
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Mohau S Makatsa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Roanne Keeton
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Jerome M Wendoh
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Tracey L Müller
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Caryn S L Prentice
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Robert J Wilkinson
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
- Department of Medicine, University of Cape Town, Cape Town, South Africa
- Department of Medicine, Imperial College London, London, United Kingdom; and
- The Francis Crick Institute, London, United Kingdom
| | - Catherine Riou
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Pathology, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
| | - Wendy A Burgers
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa;
- Department of Pathology, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa
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36
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Park HS, Choi S, Back YW, Lee KI, Choi HG, Kim HJ. Mycobacterium tuberculosis RpfE-Induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation. Int J Mol Sci 2021; 22:ijms22147535. [PMID: 34299161 PMCID: PMC8304802 DOI: 10.3390/ijms22147535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/05/2021] [Accepted: 07/11/2021] [Indexed: 01/13/2023] Open
Abstract
Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.
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Lung Epithelial Signaling Mediates Early Vaccine-Induced CD4 + T Cell Activation and Mycobacterium tuberculosis Control. mBio 2021; 12:e0146821. [PMID: 34253059 PMCID: PMC8406195 DOI: 10.1128/mbio.01468-21] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Tuberculosis (TB) is one of the leading causes of death due to a single infectious agent. The development of a TB vaccine that induces durable and effective immunity to Mycobacterium tuberculosis (Mtb) infection is urgently needed. Early and superior Mtb control can be induced in M. bovis Bacillus Calmette-Guérin (BCG)-vaccinated hosts when the innate immune response is targeted to generate effective vaccine-induced immunity. In the present study, we show that innate activation of DCs is critical for mucosal localization of clonally activated vaccine-induced CD4+ T cells in the lung and superior early Mtb control. In addition, our study reveals that Th1/Th17 cytokine axis play an important role in superior vaccine-induced immunity. Our studies also show that activation of the nuclear factor kappa-light-chain enhancer of activated B cell (NF-κβ) pathway in lung epithelial cells is critical for the mucosal localization of activated vaccine-induced CD4+ T cells for rapid Mtb control. Thus, our study provides novel insights into the immune mechanisms that can overcome TB vaccine bottlenecks and provide early rapid Mtb control.
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Tomioka H, Tatano Y, Shimizu T, Sano C. Immunoadjunctive Therapy against Bacterial Infections Using Herbal Medicines Based on Th17 Cell-mediated Protective Immunity. Curr Pharm Des 2021; 27:3949-3962. [PMID: 34102961 DOI: 10.2174/1381612827666210608143449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 04/27/2021] [Indexed: 11/22/2022]
Abstract
One of the major health concerns in the world is the global increase in intractable bacterial infectious diseases due to the emergence of multi- and extensively drug-resistant bacterial pathogens as well as an increase in compromised hosts around the world. Particularly, in the case of mycobacteriosis, the high incidence of tuberculosis in developing countries, resurgence of tuberculosis in industrialized countries, and increase in the prevalence of Mycobacterium avium complex infections are important worldwide health concerns. However, the development of novel antimycobacterial drugs is currently making slow progress. Therefore, it is considered that devising improved administration protocols for clinical treatment against refractory mycobacteriosis using existing chemotherapeutics is more practical than awaiting the development of new antimycobacterial drugs. The regulation of host immune responses using immunoadjunctive agents may increase the efficacy of antimicrobial treatment against mycobacteriosis. The same situations also exist in cases of intractable infectious diseases due to common bacteria other than mycobacteria. The mild and long-term up-regulation of host immune reactions in hosts with intractable chronic bacterial infections, using herbal medicines and medicinal plants, may be beneficial for such immunoadjunctive therapy. This review describes the current status regarding basic and clinical studies on therapeutic regimens using herbal medicines, useful for the clinical treatment of patients with intractable bacterial infections. In particular, we focus on immunoadjunctive effects of herbal medicines on the establishment and manifestation of host antibacterial immunity related to the immunological roles of Th17 cell lineages.
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Affiliation(s)
- Haruaki Tomioka
- Department of Basic Medical Science for Nursing, Department of Contemporary Psychology, Yasuda Women's University, Hiroshima, Japan
| | - Yutaka Tatano
- Department of Pharmaceutical Sciences, International University of Health and Welfare, Fukuoka, Japan
| | - Toshiaki Shimizu
- Department of Nutrition Administration, Yasuda Women's University, Hiroshima,, Japan
| | - Chiaki Sano
- Department of Community Medicine Management, Shimane University School of Medicine, Izumo, Japan
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HaileMariam M, Yu Y, Singh H, Teklu T, Wondale B, Worku A, Zewude A, Mounaud S, Tsitrin T, Legesse M, Gobena A, Pieper R. Protein and Microbial Biomarkers in Sputum Discern Acute and Latent Tuberculosis in Investigation of Pastoral Ethiopian Cohort. Front Cell Infect Microbiol 2021; 11:595554. [PMID: 34150670 PMCID: PMC8212885 DOI: 10.3389/fcimb.2021.595554] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 03/22/2021] [Indexed: 01/01/2023] Open
Abstract
Differential diagnosis of tuberculosis (TB) and latent TB infection (LTBI) remains a public health priority in high TB burden countries. Pulmonary TB is diagnosed by sputum smear microscopy, chest X-rays, and PCR tests for distinct Mycobacterium tuberculosis (Mtb) genes. Clinical tests to diagnose LTBI rely on immune cell stimulation in blood plasma with TB-specific antigens followed by measurements of interferon-γ concentrations. The latter is an important cytokine for cellular immune responses against Mtb in infected lung tissues. Sputum smear microscopy and chest X-rays are not sufficiently sensitive while both PCR and interferon-γ release assays are expensive. Alternative biomarkers for the development of diagnostic tests to discern TB disease states are desirable. This study's objective was to discover sputum diagnostic biomarker candidates from the analysis of samples from 161 human subjects including TB patients, individuals with LTBI, negative community controls (NCC) from the province South Omo, a pastoral region in Ethiopia. We analyzed 16S rRNA gene-based bacterial taxonomies and proteomic profiles. The sputum microbiota did not reveal statistically significant differences in α-diversity comparing the cohorts. The genus Mycobacterium, representing Mtb, was only identified for the TB group which also featured reduced abundance of the genus Rothia in comparison with the LTBI and NCC groups. Rothia is a respiratory tract commensal and may be sensitive to the inflammatory milieu generated by infection with Mtb. Proteomic data supported innate immune responses against the pathogen in subjects with pulmonary TB. Ferritin, an iron storage protein released by damaged host cells, was markedly increased in abundance in TB sputum compared to the LTBI and NCC groups, along with the α-1-acid glycoproteins ORM1 and ORM2. These proteins are acute phase reactants and inhibit excessive neutrophil activation. Proteomic data highlight the effector roles of neutrophils in the anti-Mtb response which was not observed for LTBI cases. Less abundant in the sputum of the LTBI group, compared to the NCC group, were two immunomodulatory proteins, mitochondrial TSPO and the extracellular ribonuclease T2. If validated, these proteins are of interest as new biomarkers for diagnosis of LTBI.
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Affiliation(s)
- Milkessa HaileMariam
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
| | - Yanbao Yu
- J. Craig Venter Institute, Rockville, MD, United States
| | - Harinder Singh
- J. Craig Venter Institute, Rockville, MD, United States
| | - Takele Teklu
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
- Department of Immunology and Molecular Biology, University of Gondar, Gondar, Ethiopia
| | - Biniam Wondale
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
- Department of Biology, Arba Minch University, Arba Minch, Ethiopia
| | - Adane Worku
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
| | - Aboma Zewude
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
| | | | - Tamara Tsitrin
- J. Craig Venter Institute, Rockville, MD, United States
| | - Mengistu Legesse
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
| | - Ameni Gobena
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
| | - Rembert Pieper
- J. Craig Venter Institute, Rockville, MD, United States
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Stabel JR, Bannantine JP. Reduced tissue colonization of Mycobacterium avium subsp. paratuberculosis in neonatal calves vaccinated with a cocktail of recombinant proteins. Vaccine 2021; 39:3131-3140. [PMID: 33966908 DOI: 10.1016/j.vaccine.2021.04.051] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 04/20/2021] [Accepted: 04/24/2021] [Indexed: 02/06/2023]
Abstract
An increasing prevalence of paratuberculosis supports the need for new efficacious vaccines as an essential management tool. Two separate studies were performed in neonatal calves to evaluate the effectiveness of pooled recombinant Mycobacterium avium subsp. paratuberculosis (MAP) proteins (MAP1087, MAP1204, MAP1272c, MAP2077c) as a potential vaccine. In the first study vaccinated calves were immunized with 400 µg protein cocktail per dose, whereas the second study compared doses of 400 µg and 800 µg of protein cocktail, followed by challenge with live MAP for both vaccinated and nonvaccinated control calves 28 days post-vaccination. At the end of 12 months, tissue colonization with MAP was significantly reduced for the vaccinated calves compared to control animals. A higher dose of vaccine improved protection, with further reductions of MAP burden. Antigen-specific IFN-γ responses and serum antibody responses were similar regardless of vaccination, indicating exposure to MAP invoked conventional host immune responses. Host immunity differed due to vaccination, resulting in increased percentages of CD4+ T cells and B cells after stimulation of PBMCs with antigen. Interestingly, gene expression in PBMCs was similar for both control and vaccinated calves except for significant increases in IFN-γ, IL-12, and IL-17 expression observed in vaccinated calves. Vaccination with a cocktail of immunogenic recombinant MAP proteins was efficacious in reducing the level of infection and fecal shedding of neonatal calves and may be a potential tool for curtailing the spread of Johne's disease.
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Affiliation(s)
- J R Stabel
- USDA-ARS, National Animal Disease Center, Ames, IA 50010, United States.
| | - J P Bannantine
- USDA-ARS, National Animal Disease Center, Ames, IA 50010, United States
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41
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Khanna M, Rady H, Dai G, Ramsay AJ. Intranasal boosting with MVA encoding secreted mycobacterial proteins Ag85A and ESAT-6 generates strong pulmonary immune responses and protection against M. tuberculosis in mice given BCG as neonates. Vaccine 2021; 39:1780-1787. [PMID: 33632562 PMCID: PMC7990059 DOI: 10.1016/j.vaccine.2021.01.071] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 01/02/2023]
Abstract
Bacille-Calmette-Guerin (BCG) has variable efficacy as an adult tuberculosis (TB) vaccine but can reduce the incidence and severity of TB infection in humans. We have engineered modified vaccinia Ankara (MVA) strain vaccine constructs to express the secreted mycobacterial proteins Ag85A and ESAT-6 (MVA-AE) and evaluated their immunogenicity and protective efficacy as mucosal booster vaccines for BCG given subcutaneously in early life. Intranasal delivery of MVA-AE to young adult mice induced CD4+ and CD8+ T cell responses to both Ag85A and ESAT-6 in lung mucosae. These responses were markedly enhanced in mice that had been primed neonatally with BCG prior to intranasal MVA-AE immunization (BCG/MVA-AE), as evidenced by numbers of pulmonary Ag85A-, ESAT-6-, and PPD-specific CD4+ and CD8+ T cells and by their capacity to secrete multiple antimicrobial factors, including IFNγ, IL-2 and IL-17. Moreover, MVA-AE boosting generated multifunctional lung CD4+ T cells responding to ESAT-6, which were not, as expected, detected in control mice given BCG, and elevated Ag85A-specific circulating antibody responses. After aerosol challenge with M. tuberculosis H37Rv (Mtb), the BCG/MVA-AE group had significantly reduced mycobacterial burden in the lungs, compared with either BCG primed mice boosted with control MVA or mice given only BCG. These data indicate that intranasal delivery of MVA-AE can boost BCG-induced Th1 and Th17-based immunity locally in the lungs and improve the protective efficacy of neonatally-administered BCG against M. tuberculosis infection.
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Affiliation(s)
- Mayank Khanna
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, and the Louisiana Vaccine Center, New Orleans, LA 70112, USA
| | - Hamada Rady
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, and the Louisiana Vaccine Center, New Orleans, LA 70112, USA
| | - Guixiang Dai
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, and the Louisiana Vaccine Center, New Orleans, LA 70112, USA
| | - Alistair J Ramsay
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, and the Louisiana Vaccine Center, New Orleans, LA 70112, USA.
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42
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Kim S, Park HE, Park WB, Kim SY, Park HT, Yoo HS. Mycobacterium avium Modulates the Protective Immune Response in Canine Peripheral Blood Mononuclear Cells. Front Cell Infect Microbiol 2021; 10:609712. [PMID: 33520738 PMCID: PMC7840563 DOI: 10.3389/fcimb.2020.609712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 11/30/2020] [Indexed: 12/31/2022] Open
Abstract
Mycobacterium avium, an opportunistic intracellular pathogen, is a member of the non-tuberculous mycobacteria species. M. avium causes respiratory disease in immunosuppressed individuals and a wide range of animals, including companion dogs and cats. In particular, the number of infected companion dogs has increased, although the underlying mechanism of M. avium pathogenesis in dogs has not been studied. Therefore, in the present study, the host immune response against M. avium in dogs was investigated by transcriptome analysis of canine peripheral blood mononuclear cells. M. avium was shown to induce different immune responses in canine peripheral blood mononuclear cells at different time points after infection. The expression of Th1-associated genes occurred early during M. avium infection, while that of Th17-associated genes increased after 12 h. In addition, the expression of apoptosis-related genes decreased and the abundance of intracellular M. avium increased in monocyte-derived macrophages after infection for 24 h. These results reveal the M. avium induces Th17 immune response and avoids apoptosis in infected canine cells. As the number of M. avium infection cases increases, the results of the present study will contribute to a better understanding of host immune responses to M. avium infection in companion dogs.
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Affiliation(s)
- Suji Kim
- Department of Infectious Diseases, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, Seoul National University, Seoul, South Korea
| | - Hyun-Eui Park
- Department of Microbiology, College of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Woo Bin Park
- Department of Infectious Diseases, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Seo Yihl Kim
- Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Hong-Tae Park
- Department of Infectious Diseases, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Han Sang Yoo
- Department of Infectious Diseases, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, Seoul National University, Seoul, South Korea
- Bio-MAX/N-Bio Institute, Seoul National University, Seoul, South Korea
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43
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Jones CI, Rose SL, Shutt A, Cairo C, Bourgeois NM, Charurat M, Sodora DL, Wood MP. Maternal HIV status skews transcriptomic response in infant cord blood monocytes exposed to Bacillus Calmette--Guerín. AIDS 2021; 35:23-32. [PMID: 33048873 PMCID: PMC7718394 DOI: 10.1097/qad.0000000000002706] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES HIV-exposed uninfected (HEU) infants exhibit altered vaccine responses and an increased mortality compared with HIV-unexposed infants. Here, vaccine responses in HEU and HIV-unexposed cord blood monocytes (CBMs) were assessed following Bacillus Calmette--Guerín (BCG) treatment. DESIGN Innate responses to in-vitro BCG treatment were assessed through transcriptional profiling using CBMs obtained from a Nigerian cohort of HIV-infected and uninfected women. METHODS HIV-unexposed (n = 9) and HEU (n = 10) infant CBMs were treated with BCG and transcriptionally profiled with the Nanostring nCounter platform. Differential expression and pathway enrichment analyses were performed, and transcripts were identified with enhanced or dampened BCG responses. RESULTS Following BCG stimulation, several pathways associated with inflammatory gene expression were upregulated irrespective of HIV exposure status. Both HIV-unexposed and HEU monocytes increased expression of several cytokines characteristic of innate BCG responses, including IL1β, TNFα, and IL-6. Using differential expression analysis, we identified genes significantly upregulated in HEU compared with HIV-unexposed monocytes including monocyte chemokine CCL7 and anti-inflammatory cytokine TNFAIP6. In contrast, genes significantly upregulated in HIV-unexposed compared with HEU monocytes include chemokine CCL3 and cytokine IL23A, both of which influence anti-mycobacterial T-cell responses. Finally, two genes, which regulate prostaglandin production, CSF2 and PTGS2, were also more significantly upregulated in the HIV-unexposed cord blood indicating that inflammatory mediators are suppressed in the HEU infants. CONCLUSION HEU monocytes exhibit altered induction of several key innate immune responses, providing mechanistic insights into dysregulated innate response pathways that can be therapeutically targeted to improve vaccine responses in HEU infants.
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Affiliation(s)
- Chloe I Jones
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington
| | - Suzanne L Rose
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington
| | - Ashley Shutt
- Institute for Human Virology, University of Maryland, Baltimore, Maryland, USA
| | - Cristiana Cairo
- Institute for Human Virology, University of Maryland, Baltimore, Maryland, USA
| | - Natasha M Bourgeois
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington
| | - Manhattan Charurat
- Institute for Human Virology, University of Maryland, Baltimore, Maryland, USA
| | - Donald L Sodora
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington
| | - Matthew P Wood
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington
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44
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Martinot AJ, Blass E, Yu J, Aid M, Mahrokhian SH, Cohen SB, Plumlee CR, Larocca RA, Siddiqi N, Wakabayashi S, Gardner M, Audette R, Devorak A, Urdahl KB, Rubin EJ, Barouch DH. Protective efficacy of an attenuated Mtb ΔLprG vaccine in mice. PLoS Pathog 2020; 16:e1009096. [PMID: 33315936 PMCID: PMC7769599 DOI: 10.1371/journal.ppat.1009096] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 12/28/2020] [Accepted: 10/26/2020] [Indexed: 01/14/2023] Open
Abstract
Bacille Calmette-Guerin (BCG), an attenuated whole cell vaccine based on Mycobacterium bovis, is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), but its efficacy is suboptimal and it fails to protect against pulmonary tuberculosis. We previously reported that Mtb lacking the virulence genes lprG and rv1410c (ΔLprG) was highly attenuated in immune deficient mice. In this study, we show that attenuated ΔLprG Mtb protects C57BL/6J, Balb/cJ, and C3HeB/FeJ mice against Mtb challenge and is as attenuated as BCG in SCID mice. In C3HeB/FeJ mice, ΔLprG vaccination resulted in innate peripheral cytokine production and induced high polyclonal PPD-specific cytokine-secreting CD4+ T lymphocytes in peripheral blood. The ΔLprG vaccine afforded protective efficacy in the lungs of C3H/FeJ mice following both H37Rv and Erdman aerosolized Mtb challenges. Vaccine efficacy correlated with antigen-specific PD-1-negative CD4+ T lymphocytes as well as with serum IL-17 levels after vaccination. We hypothesize that induction of Th17 cells in lung is critical for vaccine protection, and we show a serum cytokine biomarker for IL-17 shortly after vaccination may predict protective efficacy. Many successful vaccines are based on attenuated human pathogens. The only licensed tuberculosis vaccine, BCG, is based on an attenuated version of live whole cell Mycobacterium bovis, the causative agent of tuberculosis (TB) in cattle. Advantages to using attenuated pathogens as vaccines include a broad antigen composition including proteins, lipids, carbohydrates and other molecules that can induce durable immune responses sometimes lasting decades. Here we test an attenuated Mycobacterium tuberculosis (Mtb), the causative agent of human TB, that lacks a key virulence factor as an alternative whole cell vaccine in mice. Attenuated Mtb lacking a key virulence protein, LprG, is immunogenic and protects mice against Mtb challenge. The LprG whole cell vaccine is protective in mice that develop lung pathology more similar to what is described in human TB and the LprG vaccine induces a key cytokine, IL-17, thought to be important for vaccine protection, in the peripheral blood early after vaccination. Together these data support the continued development of attenuated TB as a potential vaccine candidate. Furthermore our data suggests that serum IL-17 should be explored as a potential biomarker for vaccine efficacy in preclinical animal models.
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Affiliation(s)
- Amanda J. Martinot
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Infectious Diseases and Global Health, Tufts University Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America
| | - Eryn Blass
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Jingyou Yu
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Malika Aid
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Shant H. Mahrokhian
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Sara B. Cohen
- Department of Immunology, Seattle Children’s Research Institute, Seattle, Washington, United States of America
| | - Courtney R. Plumlee
- Department of Immunology, Seattle Children’s Research Institute, Seattle, Washington, United States of America
| | - Rafael A. Larocca
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Noman Siddiqi
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America
| | - Shoko Wakabayashi
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America
| | - Michelle Gardner
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America
| | - Rebecca Audette
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America
| | - Anne Devorak
- Department of Infectious Diseases and Global Health, Tufts University Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America
| | - Kevin B. Urdahl
- Department of Immunology, Seattle Children’s Research Institute, Seattle, Washington, United States of America
- Departments of Pediatrics and Immunology, University of Washington, Seattle, Washington, United States of America
| | - Eric J. Rubin
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America
| | - Dan H. Barouch
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, United States of America
- * E-mail:
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45
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Epithelial processed Mycobacterium avium subsp. paratuberculosis induced prolonged Th17 response and suppression of phagocytic maturation in bovine peripheral blood mononuclear cells. Sci Rep 2020; 10:21048. [PMID: 33273606 PMCID: PMC7713309 DOI: 10.1038/s41598-020-78113-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023] Open
Abstract
Johne’s disease (JD) caused by Mycobacterium avium subsp. paratuberculosis (MAP) is a chronic, wasting infectious disease in ruminants that causes enormous economic losses to the dairy and beef cattle industries. Understanding the mechanism of persistency of MAP is key to produce novel ideas for the development of new diagnostic methods or prevention techniques. We sought interactions between the host and MAP using epithelial passage model, which mimic initial stage of infection. From the transcriptomic analysis of bovine immune cells (PBMCs), it was suggested that infection through the epithelial cells elicited prolonged Th17-derived immune response, as indicated by upregulation of IL-17A, IL-17F and RORC until 120 h p.i., compared to directly infected PBMCs. Global downregulation of gene expression was observed after 72 h p.i., especially for genes encoding cell surface receptors of phagocytic cells, such as Toll-like receptors and MHC class II molecules. In addition, the cholesterol efflux transporters ABCA1, ABCG1, and APOE, which are regulated by the LXR/RXR pathway, were downregulated. In summary, it would be suggested that the host initiate immune response to activate Th17-derived cytokines, and MAP survives persistently by altering the host adaptive immune response by suppressing surface receptors and manipulating lipid metabolism in phagocytic cells.
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46
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Dahl J, Holvik K, Heldal E, Grimnes G, Hoff M, Finnes TE, Apalset EM, Meyer HE. Individual Variation in Adaptive Immune Responses and Risk of Hip Fracture-A NOREPOS Population-Based Cohort Study. J Bone Miner Res 2020; 35:2327-2334. [PMID: 32697001 DOI: 10.1002/jbmr.4135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 06/25/2020] [Accepted: 07/14/2020] [Indexed: 11/06/2022]
Abstract
Immune-mediated bone loss significantly impacts fracture risk in patients with autoimmune disease, but to what extent individual variations in immune responses affect fracture risk on a population level is unknown. To examine how immune responses relate to risk of hip fracture, we looked at the individual variation in a post-vaccination skin test response that involves some of the immune pathways that also drive bone loss. From 1963 to 1975, the vast majority of the Norwegian adult population was examined as part of the compulsory nationwide Norwegian mass tuberculosis screening. These examinations included standardized tuberculin skin tests (TSTs). Our study population included young individuals (born 1940 to 1960 and aged 14 to 30 years at examination) who had all received Bacille Calmette-Guerin (BCG) vaccination after a negative TST at least 1 year prior and had no signs of tuberculosis upon clinical examination. The study population ultimately included 244,607 individuals, whose data were linked with a national database of all hospitalized hip fractures in Norway from 1994 to 2013. There were 3517 incident hip fractures during follow-up. Using a predefined Cox model, we found that men with a positive or a strong positive TST result had a 20% (hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01-1.44) and 24% (HR = 1.24, 95% CI 1.03-1.49) increased risk of hip fracture, respectively, compared with men with a negative TST. This association was strengthened in sensitivity analyses. Total hip bone mineral density (BMD) was available for a limited subsample and similarly revealed a non-significantly reduced BMD among men with a positive TST. Interestingly, no such clear association was observed in women. An increased immune response after vaccination is associated with an increased risk of hip fracture decades later among men, possibly because of increased immune-mediated bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Jesper Dahl
- Norwegian Institute of Public Health, Oslo, Norway
| | | | - Einar Heldal
- Norwegian Institute of Public Health, Oslo, Norway
| | - Guri Grimnes
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.,Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Mari Hoff
- Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Rheumatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Trine E Finnes
- Department of Internal Medicine, Innlandet Hospital Trust, Hamar, Norway
| | - Ellen M Apalset
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.,Bergen Group of Epidemiology and Biomarkers in Rheumatic Disease, Department of Rheumatology, Haukeland University Hospital, Bergen, Norway
| | - Haakon E Meyer
- Norwegian Institute of Public Health, Oslo, Norway.,Department of Community Medicine and Global Health, University of Oslo, Oslo, Norway
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Bruno M, Zweijpfenning SMH, Verhoeven J, Boeree MJ, Netea MG, van de Veerdonk FL, van Ingen J, Hoefsloot W. Subtle immunodeficiencies in nodular-bronchiectatic Mycobacterium avium complex lung disease. ERJ Open Res 2020; 6:00548-2020. [PMID: 33123562 PMCID: PMC7569207 DOI: 10.1183/23120541.00548-2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 08/03/2020] [Indexed: 11/05/2022] Open
Abstract
Patients with nodular-bronchiectatic MAC lung disease have dysregulated adaptive immunity with defective IL-17 and IFN-γ production, and IL-10 overproduction. This suggests a role for adjunctive immunomodulatory treatments. https://bit.ly/33AALwx.
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Affiliation(s)
- Mariolina Bruno
- Dept of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sanne M H Zweijpfenning
- Radboudumc Center for Infectious Diseases, Dept of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeske Verhoeven
- Radboudumc Center for Infectious Diseases, Dept of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martin J Boeree
- Radboudumc Center for Infectious Diseases, Dept of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mihai G Netea
- Dept of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.,Dept for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Frank L van de Veerdonk
- Dept of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jakko van Ingen
- Radboudumc Center for Infectious Diseases, Dept of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Wouter Hoefsloot
- Radboudumc Center for Infectious Diseases, Dept of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
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48
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Saralahti AK, Uusi-Mäkelä MIE, Niskanen MT, Rämet M. Integrating fish models in tuberculosis vaccine development. Dis Model Mech 2020; 13:13/8/dmm045716. [PMID: 32859577 PMCID: PMC7473647 DOI: 10.1242/dmm.045716] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Tuberculosis is a chronic infection by Mycobacterium tuberculosis that results in over 1.5 million deaths worldwide each year. Currently, there is only one vaccine against tuberculosis, the Bacillus Calmette–Guérin (BCG) vaccine. Despite widespread vaccination programmes, over 10 million new M. tuberculosis infections are diagnosed yearly, with almost half a million cases caused by antibiotic-resistant strains. Novel vaccination strategies concentrate mainly on replacing BCG or boosting its efficacy and depend on animal models that accurately recapitulate the human disease. However, efforts to produce new vaccines against an M. tuberculosis infection have encountered several challenges, including the complexity of M. tuberculosis pathogenesis and limited knowledge of the protective immune responses. The preclinical evaluation of novel tuberculosis vaccine candidates is also hampered by the lack of an appropriate animal model that could accurately predict the protective effect of vaccines in humans. Here, we review the role of zebrafish (Danio rerio) and other fish models in the development of novel vaccines against tuberculosis and discuss how these models complement the more traditional mammalian models of tuberculosis. Summary: In this Review, we discuss how zebrafish (Danio rerio) and other fish models can complement the more traditional mammalian models in the development of novel vaccines against tuberculosis.
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Affiliation(s)
- Anni K Saralahti
- Laboratory of Experimental Immunology, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere FI-33014, Finland
| | - Meri I E Uusi-Mäkelä
- Laboratory of Experimental Immunology, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere FI-33014, Finland
| | - Mirja T Niskanen
- Laboratory of Experimental Immunology, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere FI-33014, Finland
| | - Mika Rämet
- Laboratory of Experimental Immunology, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere FI-33014, Finland .,Vaccine Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere FI-33014, Finland.,PEDEGO Research Unit, Medical Research Center, University of Oulu, Oulu FI-90014, Finland.,Department of Children and Adolescents, Oulu University Hospital, Oulu FI-90029, Finland
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49
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Nemes E, Khader SA, Swanson RV, Hanekom WA. Targeting Unconventional Host Components for Vaccination-Induced Protection Against TB. Front Immunol 2020; 11:1452. [PMID: 32793199 PMCID: PMC7393005 DOI: 10.3389/fimmu.2020.01452] [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: 04/06/2020] [Accepted: 06/04/2020] [Indexed: 12/28/2022] Open
Abstract
The current tuberculosis (TB) vaccine, Bacille Calmette-Guerin (BCG), is effective in preventing TB in young children but was developed without a basic understanding of human immunology. Most modern TB vaccine candidates have targeted CD4+ T cell responses, thought to be important for protection against TB disease, but not known to be sufficient or critical for protection. Advances in knowledge of host responses to TB afford opportunities for developing TB vaccines that target immune components not conventionally considered. Here, we describe the potential of targeting NK cells, innate immune training, B cells and antibodies, and Th17 cells in novel TB vaccine development. We also discuss attempts to target vaccine immunity specifically to the lung, the primary disease site in humans.
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Affiliation(s)
- Elisa Nemes
- South African Tuberculosis Vaccine Initiative, Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Shabaana A Khader
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
| | - Rosemary V Swanson
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
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50
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do Carmo Gonçalves A, Hungria EM, Freitas AA, Sékula-Bührer S, Gomes CM, Coelho AC, Nascimento LB, de Araújo Stefani MM. Leprosy surveillance study in a highly endemic Brazilian area using leprosy specific serologic tests and IFNγ whole blood assay. Eur J Clin Microbiol Infect Dis 2020; 39:2345-2360. [PMID: 32666479 DOI: 10.1007/s10096-020-03979-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/02/2020] [Indexed: 01/22/2023]
Abstract
This surveillance study evaluated leprosy-serologic tests and the IFNγ whole-blood-assay/WBA as adjunct diagnostic tools. Previously diagnosed leprosy index cases, intradomiciliary, peridomiciliary contacts from a Brazilian endemic area were enrolled during domiciliary visits. Physical evaluation was performed by trained nurses and leprosy diagnosis confirmed by expert dermatologist. ELISA detected IgM anti-PGL-I, IgG anti-LID-1, and IgM/IgG anti-ND-O-LID antibodies. Heparinized WBA plasma stimulated with LID-1, 46f + LID-1, ML0276 + LID-1 (24 h, 37 °C, 5% CO2) was tested for human IFNγ (QuantiFERON®-TB Gold/QFT-G; Qiagen). The survey included 1731 participants: 44 leprosy index cases, 64 intradomiciliary, 1623 peridomiciliary contacts. Women represented 57.7%, median age was 32 years, 72.2% had BCG scar. Leprosy prevalence was higher in intradomiciliary (8.57%) versus peridomiciliary contacts (0.67%), p < 0.001. Among 23 suspects, five leprosy cases were confirmed: 4 multibacillary/MB and 1 paucibacillary/PB. Leprosy incidence was 0.30%: 1.56% in intradomiciliary versus 0.25% in peridomiciliary (p = 0.028). Seropositivity rates were 1.9% to PGL-I, 4.9% to LID-1, and 1.0% to ND-O-LID. LID-1 positivity was higher in all groups; incident cases were LID-1 seropositive. ND-O-LID positivity was higher in intra- versus peridomiciliary contacts (p = 0.022). IFNγ WBA (40 index cases, 19 suspects, 35 intradomiciliary, 74 peridomiciliary contacts) showed higher LID-1/WBA positivity in peridomiciliary contacts (p > 0.05); significant differences among groups were seen with 46f + LID-1 but 0276 + LID-1 induced higher IFNγ levels. Incident cases were LID-1 seropositive, while IFNγ-WBA had marginal diagnostic application. As seropositivity indicates exposed individuals at higher risk of disease development, the utility of serologic screening for surveillance and prophylactic measures remains to be demonstrated.
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Affiliation(s)
- Aline do Carmo Gonçalves
- Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Emerith Mayra Hungria
- Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Aline Araújo Freitas
- Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Samira Sékula-Bührer
- Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiânia, Goiás, Brazil
| | | | - Ana Cecília Coelho
- Superintendência de Vigilância em Saúde, Secretaria Municipal de Saúde de Goiânia, Goiânia, Goiás, Brazil
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