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1
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Bénard A, Balboa L, Caouaille M, Ravon-Katossky L, Meunier E, Fillatreau S, Sasiain MDC, Neyrolles O, Hudrisier D. Human IL-6-Producing B Cells Promote the Differentiation of Monocytes Toward an Anti-Inflammatory CD16⁺CD163⁺CD206⁺PD-L1⁺ Phenotype in Tuberculosis. Eur J Immunol 2025; 55:e202451509. [PMID: 40252014 DOI: 10.1002/eji.202451509] [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: 09/09/2024] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 04/21/2025]
Abstract
The polarization of the monocyte/macrophage compartment toward an anti-inflammatory profile is considered detrimental in tuberculosis (TB), but the factors controlling M2 polarization in this context are still poorly understood. Here, we found that B cells promote the differentiation of human monocytes toward an M2-like activation program through a process primarily dependent on IL-6 and the activation of STAT3 signaling in monocytes. This confers monocytes with immunomodulatory properties characterized by a reduced ability to produce proinflammatory cytokines and to stimulate IFNγ secretion by allogeneic T cells. Our findings were validated using B cells from TB patients, which constitutively produce high levels of IL-6, underscoring the clinical relevance of our experimental observations. Collectively, our results indicate that human B-cell-derived IL-6 might impair TB immunity by driving monocyte polarization toward an anti-inflammatory phenotype.
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MESH Headings
- Humans
- Monocytes/immunology
- Monocytes/cytology
- Cell Differentiation/immunology
- Interleukin-6/immunology
- Interleukin-6/biosynthesis
- Interleukin-6/metabolism
- Receptors, IgG/immunology
- Receptors, IgG/metabolism
- B-Lymphocytes/immunology
- B-Lymphocytes/metabolism
- STAT3 Transcription Factor/metabolism
- STAT3 Transcription Factor/immunology
- Tuberculosis/immunology
- CD163 Antigen
- Antigens, CD/immunology
- Antigens, CD/metabolism
- B7-H1 Antigen/immunology
- B7-H1 Antigen/metabolism
- Receptors, Cell Surface/immunology
- Receptors, Cell Surface/metabolism
- Antigens, Differentiation, Myelomonocytic/immunology
- Antigens, Differentiation, Myelomonocytic/metabolism
- Interferon-gamma/immunology
- Interferon-gamma/metabolism
- Signal Transduction/immunology
- Phenotype
- Cells, Cultured
- GPI-Linked Proteins
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Affiliation(s)
- Alan Bénard
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
- Department of Surgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Luciana Balboa
- Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina, Buenos Aires, Argentina
- International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167) / International Research Project Toulouse, France, Buenos Aires, Argentina
| | - Maxime Caouaille
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Lea Ravon-Katossky
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Etienne Meunier
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Simon Fillatreau
- Institut Necker Enfants Malades (INEM), INSERM U1151/CNRS UMR 8253, Université de Paris, Paris, France
- Université Paris Cité, Faculté de Médecine, Paris, France
- AP-HP, Hôpital Necker-Enfants Malades, Paris, France
| | - Maria Del Carmen Sasiain
- Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina, Buenos Aires, Argentina
- International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167) / International Research Project Toulouse, France, Buenos Aires, Argentina
| | - Olivier Neyrolles
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
- International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167) / International Research Project Toulouse, France, Buenos Aires, Argentina
| | - Denis Hudrisier
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
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2
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Dutt TS, Choreño-Parra JA. Editorial: Tuberculosis and humoral immunity. Front Immunol 2025; 16:1562567. [PMID: 39995662 PMCID: PMC11847867 DOI: 10.3389/fimmu.2025.1562567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 01/27/2025] [Indexed: 02/26/2025] Open
Affiliation(s)
- Taru S. Dutt
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
| | - José Alberto Choreño-Parra
- Departamento de Enseñanza, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico
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3
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Miranda-Hernandez S, Kumar M, Henderson A, Graham E, Tan X, Taylor J, Meehan M, Ceja Z, Del Pozo-Ramos L, Pan Y, Tsui E, Donovan ML, Rentería ME, Flores-Valdez MA, Blumenthal A, Nguyen Q, Subbian S, Field MA, Kupz A. CD8 + T cells mediate vaccination-induced lymphatic containment of latent Mycobacterium tuberculosis infection following immunosuppression, while B cells are dispensable. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.23.634479. [PMID: 39896630 PMCID: PMC11785187 DOI: 10.1101/2025.01.23.634479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
It is estimated that two billion people are latently infected with Mycobacterium tuberculosis ( Mtb ), the causative agent of tuberculosis (TB). Latent Mtb infection (LTBI) can occur in multiple organs, including the lymphatics. The risk of LTBI reactivation increases in immunocompromised conditions, such as coinfection with human immunodeficiency virus (HIV), and during treatment of autoimmune diseases and organ transplantation. The immunological correlates of protection against TB, including against reactivation of LTBI, remain largely elusive. Here, we used a mouse model of latent lymphatic Mtb infection to dissect the immunological mechanisms underlying LTBI containment versus reactivation. We show that immunosuppression-mediated reactivation of lymphatic LTBI and the subsequent spread to non-lymphatic organs can be prevented by vaccination with multiple recombinant BCG (rBCG) strains despite the deficiency of CD4 + T cells. Using spatial transcriptomics, multi-parameter imaging, network analysis and bioinformatic integration of histopathological images, we reveal that immunosuppression is associated with a distinct repositioning of non-CD4 immune cells at the edge of TB lesions within the infection-draining cervical lymph nodes. While B cells increased in numbers, they are dispensable for the containment of LTBI. Lymphatic Mtb infection in different immune cell-deficient mouse strains, antibody-mediated cell depletion and adoptive transfer experiments into highly susceptible mice unequivocally show that vaccination-mediated prevention of LTBI reactivation is critically dependent on CD8 + T cells. These findings have profound implications for our understanding of immunity to TB and the management of LTBI.
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4
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Meade RK, Smith CM. Immunological roads diverged: mapping tuberculosis outcomes in mice. Trends Microbiol 2025; 33:15-33. [PMID: 39034171 DOI: 10.1016/j.tim.2024.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/23/2024]
Abstract
The journey from phenotypic observation to causal genetic mechanism is a long and challenging road. For pathogens like Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), host-pathogen coevolution has spanned millennia, costing millions of human lives. Mammalian models can systematically recapitulate host genetic variation, producing a spectrum of disease outcomes. Leveraging genome sequences and deep phenotyping data from infected mouse genetic reference populations (GRPs), quantitative trait locus (QTL) mapping approaches have successfully identified host genomic regions associated with TB phenotypes. Here, we review the ongoing optimization of QTL mapping study design alongside advances in mouse GRPs. These next-generation resources and approaches have enabled identification of novel host-pathogen interactions governing one of the most prevalent infectious diseases in the world today.
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Affiliation(s)
- Rachel K Meade
- Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA; University Program in Genetics and Genomics, Duke University, Durham, NC, USA
| | - Clare M Smith
- Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA; University Program in Genetics and Genomics, Duke University, Durham, NC, USA.
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5
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Szachniewicz MM, van den Eeden SJF, van Meijgaarden KE, Franken KLMC, van Veen S, Geluk A, Bouwstra JA, Ottenhoff THM. Cationic pH-sensitive liposome-based subunit tuberculosis vaccine induces protection in mice challenged with Mycobacterium tuberculosis. Eur J Pharm Biopharm 2024; 203:114437. [PMID: 39122053 DOI: 10.1016/j.ejpb.2024.114437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 07/18/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
Tuberculosis (TB) has been and still is a global emergency for centuries. Prevention of disease through vaccination would have a major impact on disease prevalence, but the only available current vaccine, BCG, has insufficient impact. In this article, a novel subunit vaccine against TB was developed, using the Ag85B-ESAT6-Rv2034 fusion antigen, two adjuvants - CpG and MPLA, and a cationic pH-sensitive liposome as a delivery system, representing a new TB vaccine delivery strategy not previously reported for TB. In vitro in human dendritic cells (DCs), the adjuvanted formulation induced a significant increase in the production of (innate) cytokines and chemokines compared to the liposome without additional adjuvants. In vivo, the new vaccine administrated subcutaneously significantly reduced Mycobacterium tuberculosis (Mtb) bacterial load in the lungs and spleens of mice, significantly outperforming results from mice vaccinated with the antigen mixed with adjuvants without liposomes. In-depth analysis underpinned the vaccine's effectiveness in terms of its capacity to induce polyfunctional CD4+ and CD8+ T-cell responses, both considered essential for controlling Mtb infection. Also noteworthy was the differential abundance of various CD69+ B-cell subpopulations, which included IL17-A-producing B-cells. The vaccine stimulated robust antigen-specific antibody titers, further extending its potential as a novel protective agent against TB.
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Affiliation(s)
- M M Szachniewicz
- Leiden University Center for Infectious Diseases, Leiden University Medical Center (LUMC), the Netherlands.
| | - S J F van den Eeden
- Leiden University Center for Infectious Diseases, Leiden University Medical Center (LUMC), the Netherlands
| | - K E van Meijgaarden
- Leiden University Center for Infectious Diseases, Leiden University Medical Center (LUMC), the Netherlands
| | - K L M C Franken
- Leiden University Center for Infectious Diseases, Leiden University Medical Center (LUMC), the Netherlands
| | - S van Veen
- Leiden University Center for Infectious Diseases, Leiden University Medical Center (LUMC), the Netherlands
| | - A Geluk
- Leiden University Center for Infectious Diseases, Leiden University Medical Center (LUMC), the Netherlands
| | - J A Bouwstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, the Netherlands
| | - T H M Ottenhoff
- Leiden University Center for Infectious Diseases, Leiden University Medical Center (LUMC), the Netherlands
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6
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Logunova N, Kapina M, Dyatlov A, Kondratieva T, Rubakova E, Majorov K, Kondratieva E, Linge I, Apt A. Polygenic TB control and the sequence of innate/adaptive immune responses to infection: MHC-II alleles determine the size of the S100A8/9-producing neutrophil population. Immunology 2024; 173:381-393. [PMID: 39003642 DOI: 10.1111/imm.13836] [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: 05/02/2024] [Accepted: 07/01/2024] [Indexed: 07/15/2024] Open
Abstract
Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2-congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC-II) region from TB-susceptible H2j mice transferred onto the genetic background of the TB-resistant C57BL/6 (H2b) strain. Susceptible B6.I-9.3 mice differ from B6 progenitors by the alleles of their only classical MHC-II H2-Aβ gene. The goals of the present study were to: (i) comprehensively characterise the differences in TB-related phenotypes between mice of the two strains and (ii) decipher interactions between the H2-Aβ and S100A8/9 genes. Here, we describe the dynamics of TB-related phenotypes differentiating B6.I-9.3 and B6 mice (colony forming units counts, histopathology, lung immune cell infiltration and cytokine profiles). We show that disproportionally diminished CD4+ T-cell population, an enlarged S100A8/9-positive neutrophil population and higher S100A8/9 serum levels in B6.I-9.3 mice collectively form the 'susceptible' phenotype before infection. An increase in IL-17 and a decrease in intrferon-gamma production by CD4+ T-cells in these mice provide a mechanistic explanation of this phenotype. Using F2 segregation analysis, we show that the number of S100A8/9-producing neutrophils in lungs and spleens and the proportion of Th17 CD4+ T-cells in lungs are significantly lower in the presence of the MHC-II dominant 'resistant' b allele compared to the recessive 'susceptible' j/j genotype. This provides direct genetic evidence that MHC-II-regulated CD4+ T-cell landscapes determine neutrophil abundance before infection, an important pathogenic factor in TB immunity.
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Affiliation(s)
- Nadezhda Logunova
- Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia
| | - Marina Kapina
- Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia
| | - Alexander Dyatlov
- Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia
| | - Tatiana Kondratieva
- Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia
| | - Elvira Rubakova
- Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia
| | - Konstantin Majorov
- Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia
| | - Elena Kondratieva
- Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia
| | - Irina Linge
- Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia
| | - Alexander Apt
- Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia
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7
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Tsai CY, Oo M, Peh JH, Yeo BCM, Aptekmann A, Lee B, Liu JJJ, Tsao WS, Dick T, Fink K, Gengenbacher M. Splenic marginal zone B cells restrict Mycobacterium tuberculosis infection by shaping the cytokine pattern and cell-mediated immunity. Cell Rep 2024; 43:114426. [PMID: 38959109 PMCID: PMC11307145 DOI: 10.1016/j.celrep.2024.114426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 04/29/2024] [Accepted: 06/17/2024] [Indexed: 07/05/2024] Open
Abstract
Understanding the role of B cells in tuberculosis (TB) is crucial for developing new TB vaccines. However, the changes in B cell immune landscapes during TB and their functional implications remain incompletely explored. Using high-dimensional flow cytometry to map the immune landscape in response to Mycobacterium tuberculosis (Mtb) infection, our results show an accumulation of marginal zone B (MZB) cells and other unconventional B cell subsets in the lungs and spleen, shaping an unconventional B cell landscape. These MZB cells exhibit activated and memory-like phenotypes, distinguishing their functional profiles from those of conventional B cells. Notably, functional studies show that MZB cells produce multiple cytokines and contribute to systemic protection against TB by shaping cytokine patterns and cell-mediated immunity. These changes in the immune landscape are reversible upon successful TB chemotherapy. Our study suggests that, beyond antibody production, targeting the regulatory function of B cells may be a valuable strategy for TB vaccine development.
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Affiliation(s)
- Chen-Yu Tsai
- Center for Discovery and Innovation (CDI), Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ 07110, USA
| | - Myo Oo
- Center for Discovery and Innovation (CDI), Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ 07110, USA
| | - Jih Hou Peh
- Biosafety Level 3 Core, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Level 15, Centre for Translational Medicine (MD6), NUS, 14 Medical Drive, Singapore 117599, Singapore
| | - Benjamin C M Yeo
- Infectious Diseases Translational Research Programme and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Level 2, Blk MD4, 5 Science Drive 2, Singapore 117545, Singapore
| | - Ariel Aptekmann
- Center for Discovery and Innovation (CDI), Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ 07110, USA
| | - Bernett Lee
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research, Biopolis, 8A Biomedical Grove, Level 3 & 4, Immunos Building, Singapore 138648, Singapore; Centre for Biomedical Informatics, Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore; A(∗)STAR Infectious Diseases Labs, Agency for Science, Technology and Research, 8A Biomedical Grove #05-13, Immunos, Singapore 138648, Singapore
| | - Joe J J Liu
- Biosafety Level 3 Core, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Level 15, Centre for Translational Medicine (MD6), NUS, 14 Medical Drive, Singapore 117599, Singapore
| | - Wen-Shan Tsao
- Center for Discovery and Innovation (CDI), Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ 07110, USA
| | - Thomas Dick
- Center for Discovery and Innovation (CDI), Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ 07110, USA; Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA
| | - Katja Fink
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research, Biopolis, 8A Biomedical Grove, Level 3 & 4, Immunos Building, Singapore 138648, Singapore
| | - Martin Gengenbacher
- Center for Discovery and Innovation (CDI), Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ 07110, USA; Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA.
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8
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Weeratunga P, Moller DR, Ho LP. Immune mechanisms of granuloma formation in sarcoidosis and tuberculosis. J Clin Invest 2024; 134:e175264. [PMID: 38165044 PMCID: PMC10760966 DOI: 10.1172/jci175264] [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] [Indexed: 01/03/2024] Open
Abstract
Sarcoidosis is a complex immune-mediated disease characterized by clusters of immune cells called granulomas. Despite major steps in understanding the cause of this disease, many questions remain. In this Review, we perform a mechanistic interrogation of the immune activities that contribute to granuloma formation in sarcoidosis and compare these processes with its closest mimic, tuberculosis, highlighting shared and divergent immune activities. We examine how Mycobacterium tuberculosis is sensed by the immune system; how the granuloma is initiated, formed, and perpetuated in tuberculosis compared with sarcoidosis; and the role of major innate and adaptive immune cells in shaping these processes. Finally, we draw these findings together around several recent high-resolution studies of the granuloma in situ that utilized the latest advances in single-cell technology combined with spatial methods to analyze plausible disease mechanisms. We conclude with an overall view of granuloma formation in sarcoidosis.
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Affiliation(s)
- Praveen Weeratunga
- MRC Translational Immunology Discovery Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | | | - Ling-Pei Ho
- MRC Translational Immunology Discovery Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
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9
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Meng X, Layhadi JA, Keane ST, Cartwright NJ, Durham SR, Shamji MH. Immunological mechanisms of tolerance: Central, peripheral and the role of T and B cells. Asia Pac Allergy 2023; 13:175-186. [PMID: 38094089 PMCID: PMC10715743 DOI: 10.5415/apallergy.0000000000000128] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 11/14/2023] [Indexed: 02/01/2025] Open
Abstract
T and B cells are key components of the adaptive immune system. Through their immune properties and their interactions with other immune cells and cytokines around them, they build a complex network to achieve immune tolerance and maintain homeostasis of the body. This is achieved through mechanisms of central and peripheral tolerance, both of which are associated with advantages and disadvantages. For this reason, the immune system is tightly regulated and their dysregulation can result in the subsequent initiation of various diseases. In this review, we will summarize the roles played by T cells and B cells within immune tolerance with specific examples in the context of different diseases that include allergic disease. In addition, we will also provide an overview on their suitability as biomarkers of allergen-specific immunotherapy.
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Affiliation(s)
- Xun Meng
- Department of National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Janice A. Layhadi
- Department of National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Sean T. Keane
- Department of National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Natanya J.K. Cartwright
- Department of National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Stephen R. Durham
- Department of National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Mohamed H. Shamji
- Department of National Heart and Lung Institute, Imperial College London, London, United Kingdom
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Roy A, Kumari Agnivesh P, Sau S, Kumar S, Pal Kalia N. Tweaking host immune responses for novel therapeutic approaches against Mycobacterium tuberculosis. Drug Discov Today 2023; 28:103693. [PMID: 37390961 DOI: 10.1016/j.drudis.2023.103693] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 06/14/2023] [Accepted: 06/22/2023] [Indexed: 07/02/2023]
Abstract
In TB, combat between the human host and Mycobacterium tuberculosis involves intricate interactions with immune cells. M. tuberculosis has evolved a complex evasion system to circumvent immune cells, leading to persistence and limiting its clearance by the host. Host-directed therapies are emerging approaches to modulate host responses, including inflammatory responses, cytokine responses, and autophagy, by using small molecules to curb mycobacterial infections. Targeting host immune pathways reduces the chances of antibiotic resistance to M. tuberculosis because, unlike antibiotics, this approach acts directly on the cells of the host. In this review, we discuss the role of immune cells during M. tuberculosis proliferation, provide a updated understanding of immunopathogenesis, and explore the range of host-modulating options for the clearance of this pathogen.
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Affiliation(s)
- Arnab Roy
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500 037, India
| | - Puja Kumari Agnivesh
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500 037, India
| | - Shashikanta Sau
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500 037, India
| | - Sunil Kumar
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500 037, India
| | - Nitin Pal Kalia
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500 037, India.
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11
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Warner S, Blaxland A, Counoupas C, Verstraete J, Zampoli M, Marais BJ, Fitzgerald DA, Robinson PD, Triccas JA. Clinical and Experimental Determination of Protection Afforded by BCG Vaccination against Infection with Non-Tuberculous Mycobacteria: A Role in Cystic Fibrosis? Vaccines (Basel) 2023; 11:1313. [PMID: 37631881 PMCID: PMC10459431 DOI: 10.3390/vaccines11081313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individuals with obstructive lung diseases such as cystic fibrosis (CF). Treatment requires multiple drugs and is characterised by high rates of relapse; thus, new strategies to limit infection are urgently required. This study sought to determine how Bacille Calmette-Guérin (BCG) vaccination may impact NTM infection, using a murine model of Mycobacterium abscessus infection and observational data from a non-BCG vaccinated CF cohort in Sydney, Australia and a BCG-vaccinated CF cohort in Cape Town, South Africa. In mice, BCG vaccination induced multifunctional antigen-specific CD4+ T cells circulating in the blood and was protective against dissemination of bacteria to the spleen. Prior infection with M. abscessus afforded the highest level of protection against M. abscessus challenge in the lung, and immunity was characterised by a greater frequency of pulmonary cytokine-secreting CD4+ T cells compared to BCG vaccination. In the clinical CF cohorts, the overall rates of NTM sampling during a three-year period were equivalent; however, rates of NTM colonisation were significantly lower in the BCG-vaccinated (Cape Town) cohort, which was most apparent for M. abscessus. This study provides evidence that routine BCG vaccination may reduce M. abscessus colonisation in individuals with CF, which correlates with the ability of BCG to induce multifunctional CD4+ T cells recognising M. abscessus in a murine model. Further research is needed to determine the optimal strategies for limiting NTM infections in individuals with CF.
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Affiliation(s)
- Sherridan Warner
- Sydney Infectious Diseases Institute, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; (S.W.); (C.C.); (B.J.M.)
- School of Medical Sciences and Charles Perkins Centre, The University of Sydney, Camperdown, NSW 2050, Australia
| | - Anneliese Blaxland
- Department of Respiratory Medicine, The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia; (A.B.); (D.A.F.)
| | - Claudio Counoupas
- Sydney Infectious Diseases Institute, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; (S.W.); (C.C.); (B.J.M.)
- School of Medical Sciences and Charles Perkins Centre, The University of Sydney, Camperdown, NSW 2050, Australia
- Tuberculosis Research Program, Centenary Institute, Camperdown, NSW 2050, Australia
| | - Janine Verstraete
- Department of Paediatrics and Child Health, Faculty of Health Science, University of Cape Town, Cape Town 7700, South Africa; (J.V.); (M.Z.)
- Red Cross War Memorial Children’s Hospital, South Africa, Rondebosch, Cape Town 7700, South Africa
| | - Marco Zampoli
- Department of Paediatrics and Child Health, Faculty of Health Science, University of Cape Town, Cape Town 7700, South Africa; (J.V.); (M.Z.)
- Red Cross War Memorial Children’s Hospital, South Africa, Rondebosch, Cape Town 7700, South Africa
| | - Ben J. Marais
- Sydney Infectious Diseases Institute, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; (S.W.); (C.C.); (B.J.M.)
- Department of Infectious Diseases, The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia
- Discipline of Paediatrics and Child Health, University of Sydney, Camperdown, NSW 2050, Australia
| | - Dominic A. Fitzgerald
- Department of Respiratory Medicine, The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia; (A.B.); (D.A.F.)
- Discipline of Paediatrics and Child Health, University of Sydney, Camperdown, NSW 2050, Australia
| | - Paul D. Robinson
- Department of Respiratory Medicine, The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia; (A.B.); (D.A.F.)
- Discipline of Paediatrics and Child Health, University of Sydney, Camperdown, NSW 2050, Australia
- Children’s Health and Environment Program, Child Health Research Centre, University of Queensland, St Lucia, QLD 4072, Australia
| | - James A. Triccas
- Sydney Infectious Diseases Institute, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; (S.W.); (C.C.); (B.J.M.)
- School of Medical Sciences and Charles Perkins Centre, The University of Sydney, Camperdown, NSW 2050, Australia
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12
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Logunova N, Kapina M, Kondratieva E, Apt A. The H2-A Class II molecule α/β-chain cis-mismatch severely affects cell surface expression, selection of conventional CD4 + T cells and protection against TB infection. Front Immunol 2023; 14:1183614. [PMID: 37426653 PMCID: PMC10324577 DOI: 10.3389/fimmu.2023.1183614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/31/2023] [Indexed: 07/11/2023] Open
Abstract
Introduction To dissect the role of the part of the H2 complex comprised of the MHC-II genes in the control of tuberculosis (TB) infection, we previously established a panel of recombinant congenic mouse strains bearing different segments of the H2 j haplotype on the B6 (H2 b) genetic background. Fine genetic mapping, gene sequencing and assessment of TB phenotypes resulted in identification of the H2-Ab gene as a major factor of TB control. Methods We further narrowed the MHC-II H2 j interval by spotting a new recombination event, sequencing newly established DNA configuration and establishing a mouse strain B6.I-103 in which j/b recombination occurred within the coding sequence of the H2-Ab gene. Results Unexpectedly, a novel H2-Aα b/AβjE0 haplotype provided exclusively high susceptibility to TB challenge. Immunologic analysis revealed an altered CD4+ T-cell selection and maintenance in B6.I-103 mice, as well as seriously impaired expression of the H2-Aαb/Aβj molecule on the surface of antigen presenting cells. Unlike previously reported cases of Class II malfunctioning, the defective phenotype arose not from strong structural mutations, but from regular recombination events within the MHC-II recombination hot spot region. Discussion Our findings provide evidence that Class II α/β-chain cis-allelic mismatches created by regular genetic recombination may severely affect immune system functioning. This issue is discussed in the context of the MHC evolution.
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13
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Abstract
A body of evidence has re-energized the interest on the role neutrophils in inflammatory and autoimmune conditions. For decades, neutrophils have been considered a homogenous population. Nevertheless, accumulating evidence suggests that neutrophils are more versatile and heterogeneous than initially considered. The notion of neutrophil heterogeneity has been supported by the identification of low-density granulocytes (LDGs) in systemic lupus erythematosus (SLE) and other systemic autoimmune and autoinflammatory conditions. Transcriptomic, epigenetic, proteomic, and functional analyses support that LDGs are a distinct subset of proinflammatory neutrophils implicated in the pathogenesis of SLE and other autoimmune diseases. Importantly, it remains incompletely characterized whether LDGs detected in other inflammatory/autoimmune conditions display the same phenotype that those present in SLE. A shared feature of LDGs across diseases is their association with vascular damage, an important contributor to morbidity and mortality in chronic inflammatory conditions. Additionally, the lack of specific markers to identify LDGs in circulation or in tissue, makes it a challenge to elucidate their role in the pathogenesis of inflammatory and autoimmune conditions. In this review, we aim to examine the evidence on the biology and the putative pathogenic role of LDGs in systemic autoimmune diseases.
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Affiliation(s)
- Carmelo Carmona-Rivera
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mariana J. Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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14
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B cells promote granulomatous inflammation during chronic Mycobacterium tuberculosis infection in mice. PLoS Pathog 2023; 19:e1011187. [PMID: 36888692 PMCID: PMC9994760 DOI: 10.1371/journal.ppat.1011187] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 02/05/2023] [Indexed: 03/09/2023] Open
Abstract
The current study reveals that in chronic TB, the B cell-deficient μMT strain, relative to wild-type (WT) C57BL/6 mice, displays in the lungs lower levels of inflammation that are associated with decreased CD4+ T cell proliferation, diminished Th1 response, and enhanced levels of interleukin (IL)-10. The latter result raises the possibility that B cells may restrict lung expression of IL-10 in chronic TB. These observations are recapitulated in WT mice depleted for B cells using anti-CD20 antibodies. IL-10 receptor (IL-10R) blockade reverses the phenotypes of decreased inflammation and attenuated CD4+ T cell responses in B cell-depleted mice. Together, these results suggest that in chronic murine TB, B cells, by virtue of their capacity to restrict expression of the anti-inflammatory and immunosuppressive IL-10 in the lungs, promote the development of a robust protective Th1 response, thereby optimizing anti-TB immunity. This vigorous Th1 immunity and restricted IL-10 expression may, however, allow the development of inflammation to a level that can be detrimental to the host. Indeed, decreased lung inflammation observed in chronically infected B cell-deficient mice, which exhibit augmented lung IL-10 levels, is associated with a survival advantage relative to WT animals. Collectively, the results reveal that in chronic murine TB, B cells play a role in modulating the protective Th1 immunity and the anti-inflammatory IL-10 response, which results in augmentation of lung inflammation that can be host-detrimental. Intriguingly, in tuberculous human lungs, conspicuous B cell aggregates are present in close proximity to tissue-damaging lesions manifesting necrosis and cavitation, suggesting the possibility that in human TB, B cells may contribute to the development of exacerbated pathology that is known to promote transmission. Since transmission is a major hindrance to TB control, investigating into whether B cells can shape the development of severe pulmonic pathological responses in tuberculous individuals is warranted.
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15
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Talreja J, Peng C, Nguyen TM, Draghici S, Samavati L. Discovery of Novel Transketolase Epitopes and the Development of IgG-Based Tuberculosis Serodiagnostics. Microbiol Spectr 2023; 11:e0337722. [PMID: 36651770 PMCID: PMC9927582 DOI: 10.1128/spectrum.03377-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 12/19/2022] [Indexed: 01/19/2023] Open
Abstract
Despite advances in rapid molecular techniques for tuberculosis (TB) diagnostics, there is an unmet need for a point-of-care, nonsputum-based test. Previously, through a T7 phage antigen display platform and immunoscreening, we identified that the serum IgGs of active TB patients differentially bind to several antigen-clones and that this immunoreactivity discriminates TB from other respiratory diseases. One of these high-performance clones has some homology to the transketolase of Mycobacterium tuberculosis (M.tb TKT). In this study, we developed a direct enzyme-linked immunosorbent assay (ELISA) detecting IgG against the TKT antigen-clone (TKTμ). Through sequence alignment and in silico analysis, we designed two more peptides with potential antigenicity that correspond to M.tb-specific transketolase (M.tb TKT1 and M.tb TKT3) epitopes. After the development and standardization of a direct peptide ELISA for three peptides, we tested 292 subjects, including TB (n = 101), latent tuberculosis infection (LTBI) (n = 49), healthy controls (n = 66), and sarcoidosis (n = 76). We randomly assigned 60% of the subjects to a training set to create optimal models to distinguish positive TB samples, and the remaining 40% were used to validate the diagnostic power of the IgG-based assays that were developed in the training set. Antibodies against M.tb TKT3 yielded the highest sensitivity (0.845), and these were followed by TKTμ (0.817) and M.tb TKT1 (0.732). The specificities obtained by TKTμ, M.tb TKT3, and M.tb TKT1 on the test sets were 1, 0.95, and 0.875, respectively. The model using TKTμ obtained a perfect positive predictive value (PPV) of 1, and this was followed by M.tb TKT3 (0.968) and M.tb TKT1 (0.912). These results show that IgG antibodies against transketolase can discriminate active TB against LTBI, sarcoidosis, and controls. IMPORTANCE There is an unmet need for a point-of-care, nonsputum-based TB test. Through the immunoscreening of a novel T7 phage library, we identified classifiers that specifically bind to IgGs in active TB sera. We discovered that one of these clones is aligned with Mycobacterium tuberculosis transketolase (TKT). TKT is an essential enzyme for Mycobacterium tuberculosis growth. We designed three TKT epitopes (TKTμ, TKT1, and TKT3) to detect TKT-specific IgGs. After the development and standardization of three different ELISA-utilizing TKT peptides, we tested 292 subjects, including active TB, LTBI, healthy controls, and sarcoidosis. Rigorous statistical analyses using training and validation sets showed that ELISA-based detections of specific IgGs against TKT3 and TKTμ have the greatest sensitivity, specificity, and accuracy to distinguish active TB subjects from others, even LTBI. Our work provides a novel scientific platform from which to further develop a point-of-care test, thereby aiding in faster TB diagnoses.
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Affiliation(s)
- Jaya Talreja
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan, USA
| | - Changya Peng
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan, USA
| | - Tuan-Minh Nguyen
- Department of Computer Science, Wayne State University, Detroit, Michigan, USA
| | - Sorin Draghici
- Department of Computer Science, Wayne State University, Detroit, Michigan, USA
| | - Lobelia Samavati
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, Michigan, USA
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA
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16
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Prolonged B-Lymphocyte-Mediated Immune and Inflammatory Responses to Tuberculosis Infection in the Lungs of TB-Resistant Mice. Int J Mol Sci 2023; 24:ijms24021140. [PMID: 36674664 PMCID: PMC9861759 DOI: 10.3390/ijms24021140] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/25/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
During tuberculosis (TB) infection, B-lymphocytes migrate to the lungs and form B-cell follicles (BCFs) in the vicinity of TB granulomata. B-cell-lacking mice display enhanced susceptibility to TB infection, and early B-cell depletion in infected non-human primates alters T-lymphocyte cytokine responses and increases bacterial burdens in the lungs. However, the role of B cells during late TB stages remained unaddressed. Here, we demonstrate that B cells and BCFs persist up to weeks 25-45 post-challenge in the lungs of TB-resistant C57BL/6 (B6) mice. In hyper-susceptible I/St mice, B-cell content markedly drops between weeks 12-16 post-infection, paralleled by diffuse lung tissue inflammation and elevated gene expression levels for pro-inflammatory cytokines IL-1, IL-11, IL-17a, and TNF-α. To check whether B-cells/BCFs control TB infection at advanced stages, we specifically depleted B-cells from B6 mice by administrating anti-CD20 mAbs at week 16 post-infection. This resulted in more rapid cachexia, a shortened lifespan of the infected animals, an increase in (i) lung-infiltrating CD8+ T cells, (ii) IL-6 production by F4/80+ macrophages, (iii) expression levels of genes for neutrophil-attracting factors CXCL1 and IL-17, and tissue-damaging factors MMP8, MMP9, and S100A8. Taken together, our results suggest that lung B cells and BCFs are moderately protective against chronic TB infection.
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17
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Dutt TS, Karger BR, Fox A, Youssef N, Dadhwal R, Ali MZ, Patterson J, Creissen E, Rampacci E, Cooper SK, Podell BK, Gonzalez-Juarrero M, Obregon-Henao A, Henao-Tamayo M. Mucosal exposure to non-tuberculous mycobacteria elicits B cell-mediated immunity against pulmonary tuberculosis. Cell Rep 2022; 41:111783. [PMID: 36516760 DOI: 10.1016/j.celrep.2022.111783] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/09/2022] [Accepted: 11/15/2022] [Indexed: 12/15/2022] Open
Abstract
Bacille Calmette-Guerin (BCG) is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) disease. However, BCG has limited efficacy, necessitating the development of better vaccines. Non-tuberculous mycobacteria (NTMs) are opportunistic pathogens present ubiquitously in the environment. TB endemic countries experience higher exposure to NTMs, but previous studies have not elucidated the relationship between NTM exposure and BCG efficacy against TB. Therefore, we develop a mouse model (BCG + NTM) to simulate human BCG immunization regime and continuous NTM exposure. BCG + NTM mice exhibit superior and prolonged protection against pulmonary TB, with increased B cell influx and anti-Mtb antibodies in serum and airways, compared with BCG alone. Notably, spatial transcriptomics and immunohistochemistry reveal that BCG + NTM mice formed B cell aggregates with features of germinal center development, which correlate with reduced Mtb burden. Our studies suggest a direct relationship between NTM exposure and TB protection, with B cells playing a crucial role.
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Affiliation(s)
- Taru S Dutt
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA.
| | | | - Amy Fox
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA
| | | | - Rhythm Dadhwal
- College of Business, Colorado State University, Fort Collins, CO, USA
| | - Malik Zohaib Ali
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA; Cell and Molecular Biology, Colorado State University, Fort Collins, CO, USA
| | - Johnathan Patterson
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA
| | - Elizabeth Creissen
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA
| | - Elisa Rampacci
- Department of Veterinary Medicine, University of Perugia, Perugia, Italy
| | - Sarah K Cooper
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA
| | - Brendan K Podell
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA
| | - Mercedes Gonzalez-Juarrero
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA
| | - Andres Obregon-Henao
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA
| | - Marcela Henao-Tamayo
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523, USA.
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18
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Immune cell interactions in tuberculosis. Cell 2022; 185:4682-4702. [PMID: 36493751 DOI: 10.1016/j.cell.2022.10.025] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [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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19
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Daniel L, Bhattacharyya ND, Counoupas C, Cai Y, Chen X, Triccas JA, Britton WJ, Feng CG. Stromal structure remodeling by B lymphocytes limits T cell activation in lymph nodes of Mycobacterium tuberculosis-infected mice. J Clin Invest 2022; 132:157873. [PMID: 36317628 PMCID: PMC9621141 DOI: 10.1172/jci157873] [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: 12/22/2021] [Accepted: 09/08/2022] [Indexed: 11/06/2022] Open
Abstract
An effective adaptive immune response depends on the organized architecture of secondary lymphoid organs, including the lymph nodes (LNs). While the cellular composition and microanatomy of LNs under steady state are well defined, the impact of chronic tissue inflammation on the structure and function of draining LNs is incompletely understood. Here we showed that Mycobacterium tuberculosis infection remodeled LN architecture by increasing the number and paracortical translocation of B cells. The formation of paracortical B lymphocyte and CD35+ follicular dendritic cell clusters dispersed CCL21-producing fibroblastic reticular cells and segregated pathogen-containing myeloid cells from antigen-specific CD4+ T cells. Depletion of B cells restored the chemokine and lymphoid structure and reduced bacterial burdens in LNs of the chronically infected mice. Importantly, this remodeling process impaired activation of naive CD4+ T cells in response to mycobacterial and unrelated antigens during chronic tuberculosis infection. Our studies reveal a mechanism in the regulation of LN microanatomy during inflammation and identify B cells as a critical element limiting the T cell response to persistent intracellular infection in LNs.
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Affiliation(s)
- Lina Daniel
- Immunology and Host Defence Group, School of Medical Sciences, Faculty of Medicine and Health.,Centenary Institute.,Charles Perkins Centre, and
| | - Nayan D Bhattacharyya
- Immunology and Host Defence Group, School of Medical Sciences, Faculty of Medicine and Health.,Centenary Institute.,Charles Perkins Centre, and
| | - Claudio Counoupas
- Centenary Institute.,Charles Perkins Centre, and.,Microbial Pathogenesis and Immunity Group, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Yi Cai
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xinchun Chen
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China
| | - James A Triccas
- Centenary Institute.,Charles Perkins Centre, and.,Microbial Pathogenesis and Immunity Group, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,The University of Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, New South Wales, Australia
| | - Warwick J Britton
- Centenary Institute.,The University of Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, New South Wales, Australia.,Department of Clinical Immunology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - Carl G Feng
- Immunology and Host Defence Group, School of Medical Sciences, Faculty of Medicine and Health.,Centenary Institute.,Charles Perkins Centre, and.,The University of Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, New South Wales, Australia
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20
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Effects of oral wound on the neutrophil lineage in murine bone-marrow: Modulation mechanism hindered by chlorhexidine. Int Immunopharmacol 2022; 105:108544. [DOI: 10.1016/j.intimp.2022.108544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 11/18/2022]
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21
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Tangie E, Walters A, Hsu NJ, Fisher M, Magez S, Jacobs M, Keeton R. BCG-mediated protection against M. tuberculosis is sustained post-malaria infection independent of parasite virulence. Immunology 2021; 165:219-233. [PMID: 34775598 DOI: 10.1111/imm.13431] [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: 07/24/2021] [Revised: 09/15/2021] [Accepted: 09/28/2021] [Indexed: 11/28/2022] Open
Abstract
Tuberculosis (TB) and malaria remain serious threats to global health. Bacillus Calmette-Guerin (BCG), the only licensed vaccine against TB protects against severe disseminated forms of TB in infants but shows poor efficacy against pulmonary TB in adults. Co-infections have been reported as one of the factors implicated in vaccine inefficacy. Given the geographical overlap of malaria and TB in areas where BCG vaccination is routinely administered, we hypothesized that virulence-dependent co-infection with Plasmodium species could alter the BCG-specific immune responses thus resulting in failure to protect against Mycobacterium tuberculosis. We compared virulent Plasmodium berghei and non-virulent Plasmodium chabaudi, their effects on B cells, effector and memory T cells, and the outcome on BCG-induced efficacy against M. tuberculosis infection. We demonstrate that malaria co-infection modulates both B- and T-cell immune responses but does not significantly alter the ability of the BCG vaccine to inhibit the growth of M. tuberculosis irrespective of parasite virulence. This malaria-driven immune regulation may have serious consequences in the early clinical trials of novel vaccines, which rely on vaccine-specific T-cell responses to screen novel vaccines for progression to the more costly vaccine efficacy trials.
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Affiliation(s)
- Emily Tangie
- Division of Immunology, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town, Observatory, South Africa
| | - Avril Walters
- Division of Immunology, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town, Observatory, South Africa
| | - Nai-Jen Hsu
- Division of Immunology, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town, Observatory, South Africa
| | - Michelle Fisher
- South African Tuberculosis Vaccine Initiative, University of Cape Town, Observatory, South Africa
| | - Stefan Magez
- Laboratory for Cellular and Molecular Immunology (CMIM), Department of Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium.,Department of Biochemistry and Microbiology, Ghent University, Gent, Belgium.,Laboratory for Biomedical Research, Department of Molecular Biotechnology, Environment Technology and Food Technology, Ghent University Global Campus, Incheon, Korea
| | - Muazzam Jacobs
- Division of Immunology, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town, Observatory, South Africa.,National Health Laboratory Service, Cape Town, South Africa.,Infectious Disease Research Unit, University of Cape Town, Observatory, South Africa
| | - Roanne Keeton
- Division of Immunology, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town, Observatory, South Africa
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22
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Bhatt K, Bhagavathula M, Verma S, Timmins GS, Deretic VP, Ellner JJ, Salgame P. Rapamycin modulates pulmonary pathology in a murine model of Mycobacterium tuberculosis infection. Dis Model Mech 2021; 14:dmm049018. [PMID: 34486033 PMCID: PMC8560501 DOI: 10.1242/dmm.049018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 09/01/2021] [Indexed: 12/14/2022] Open
Abstract
Tuberculosis (TB) treatment regimens are lengthy, causing non-adherence to treatment. Inadequate treatment can lead to relapse and the development of drug resistance TB. Furthermore, patients often exhibit residual lung damage even after cure, increasing the risk for relapse and development of other chronic respiratory illnesses. Host-directed therapeutics are emerging as an attractive means to augment the success of TB treatment. In this study, we used C3HeB/FeJ mice as an experimental model to investigate the potential role of rapamycin, a mammalian target of rapamycin inhibitor, as an adjunctive therapy candidate during the treatment of Mycobacterium tuberculosis infection with moxifloxacin. We report that administration of rapamycin with or without moxifloxacin reduced infection-induced lung inflammation, and the number and size of caseating necrotic granulomas. Results from this study strengthen the potential use of rapamycin and its analogs as adjunct TB therapy, and importantly underscore the utility of the C3HeB/FeJ mouse model as a preclinical tool for evaluating host-directed therapy candidates for the treatment of TB.
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Affiliation(s)
- Kamlesh Bhatt
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Madhuri Bhagavathula
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Sheetal Verma
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Graham S. Timmins
- Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA
| | - Vojo P. Deretic
- Autophagy Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Jerrold J. Ellner
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Padmini Salgame
- Center for Emerging Pathogens, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
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23
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Munir H, Lu TT. T2B or not to B: Calming neutrophils offshore. J Exp Med 2021; 218:e20211407. [PMID: 34374712 PMCID: PMC8357534 DOI: 10.1084/jem.20211407] [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] [Indexed: 11/04/2022] Open
Abstract
In this issue of JEM, Podstawka et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210409) show that B cells can limit neutrophil responses within the lung microvasculature by marginating and acting on marginated neutrophils. This study provides a new view of B cells and reveals a novel mechanism of cell-mediated intravascular regulation.
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Affiliation(s)
- Hafsa Munir
- Hospital for Special Surgery Research Institute, New York, NY
- Weill Cornell Medicine, New York, NY
| | - Theresa T. Lu
- Hospital for Special Surgery Research Institute, New York, NY
- Weill Cornell Medicine, New York, NY
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24
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Podstawka J, Sinha S, Hiroki CH, Sarden N, Granton E, Labit E, Kim JH, Andonegui G, Lou Y, Snarr BD, Sheppard DC, Rosin NL, Biernaskie J, Yipp BG. Marginating transitional B cells modulate neutrophils in the lung during inflammation and pneumonia. J Exp Med 2021; 218:e20210409. [PMID: 34313733 PMCID: PMC8318832 DOI: 10.1084/jem.20210409] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/04/2021] [Accepted: 07/06/2021] [Indexed: 12/25/2022] Open
Abstract
Pulmonary innate immunity is required for host defense; however, excessive neutrophil inflammation can cause life-threatening acute lung injury. B lymphocytes can be regulatory, yet little is known about peripheral transitional IgM+ B cells in terms of regulatory properties. Using single-cell RNA sequencing, we discovered eight IgM+ B cell subsets with unique gene regulatory networks in the lung circulation dominated by transitional type 1 B and type 2 B (T2B) cells. Lung intravital confocal microscopy revealed that T2B cells marginate in the pulmonary capillaries via CD49e and require CXCL13 and CXCR5. During lung inflammation, marginated T2B cells dampened excessive neutrophil vascular inflammation via the specialized proresolving molecule lipoxin A4 (LXA4). Exogenous CXCL13 dampened excessive neutrophilic inflammation by increasing marginated B cells, and LXA4 recapitulated neutrophil regulation in B cell-deficient mice during inflammation and fungal pneumonia. Thus, the lung microvasculature is enriched in multiple IgM+ B cell subsets with marginating capillary T2B cells that dampen neutrophil responses.
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Affiliation(s)
- John Podstawka
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sarthak Sinha
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Carlos H. Hiroki
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Nicole Sarden
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Elise Granton
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Elodie Labit
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jung Hwan Kim
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Graciela Andonegui
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Yuefei Lou
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Brendan D. Snarr
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
| | - Donald C. Sheppard
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
- Division of Infectious Diseases, McGill University Health Centre, Montreal, Quebec, Canada
- Department of Medical Microbiology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Nicole L. Rosin
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jeff Biernaskie
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Bryan G. Yipp
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Luo Y, Xue Y, Tang G, Cai Y, Yuan X, Lin Q, Song H, Liu W, Mao L, Zhou Y, Chen Z, Zhu Y, Liu W, Wu S, Wang F, Sun Z. Lymphocyte-Related Immunological Indicators for Stratifying Mycobacterium tuberculosis Infection. Front Immunol 2021; 12:658843. [PMID: 34276653 PMCID: PMC8278865 DOI: 10.3389/fimmu.2021.658843] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 06/10/2021] [Indexed: 12/16/2022] Open
Abstract
Background Easily accessible tools that reliably stratify Mycobacterium tuberculosis (MTB) infection are needed to facilitate the improvement of clinical management. The current study attempts to reveal lymphocyte-related immune characteristics of active tuberculosis (ATB) patients and establish immunodiagnostic model for discriminating ATB from latent tuberculosis infection (LTBI) and healthy controls (HC). Methods A total of 171 subjects consisted of 54 ATB, 57 LTBI, and 60 HC were consecutively recruited at Tongji hospital from January 2019 to January 2021. All participants were tested for lymphocyte subsets, phenotype, and function. Other examination including T-SPOT and microbiological detection for MTB were performed simultaneously. Results Compared with LTBI and HC, ATB patients exhibited significantly lower number and function of lymphocytes including CD4+ T cells, CD8+ T cells and NK cells, and significantly higher T cell activation represented by HLA-DR and proportion of immunosuppressive cells represented by Treg. An immunodiagnostic model based on the combination of NK cell number, HLA-DR+CD3+ T cells, Treg, CD4+ T cell function, and NK cell function was built using logistic regression. Based on receiver operating characteristic curve analysis, the area under the curve (AUC) of the diagnostic model was 0.920 (95% CI, 0.867-0.973) in distinguishing ATB from LTBI, while the cut-off value of 0.676 produced a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and specificity of 91.23% (95% CI, 81.06%-96.20%). Meanwhile, AUC analysis between ATB and HC according to the diagnostic model was 0.911 (95% CI, 0.855-0.967), with a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and a specificity of 90.00% (95% CI, 79.85%-95.34%). Conclusions Our study demonstrated that the immunodiagnostic model established by the combination of lymphocyte-related indicators could facilitate the status differentiation of MTB infection.
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Affiliation(s)
- Ying Luo
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Xue
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guoxing Tang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yimin Cai
- Department of Epidemiology and Biostatistics, Key Laboratory of Environmental Health of Ministry of Education, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xu Yuan
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qun Lin
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huijuan Song
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Liu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liyan Mao
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Zhou
- Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Zhongju Chen
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaowu Zhu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weiyong Liu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiji Wu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Wang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ziyong Sun
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Parihar SP, Ozturk M, Höft MA, Chia JE, Guler R, Keeton R, van Rensburg IC, Loxton AG, Brombacher F. IL-4-Responsive B Cells Are Detrimental During Chronic Tuberculosis Infection in Mice. Front Immunol 2021; 12:611673. [PMID: 34220793 PMCID: PMC8243286 DOI: 10.3389/fimmu.2021.611673] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 05/25/2021] [Indexed: 12/02/2022] Open
Abstract
In tuberculosis, T cell-mediated immunity is extensively studied whilst B cells received limited attention in human and mice. Of interest, Mycobacterium tuberculosis (Mtb) does increase IL-4 Receptor-alpha (IL4Rα) expression in murine B cells. To better understand the role of IL4Rα signalling in B cells, we compared wild type mice with B cell-specific IL4Rα deficient mice (mb1creIL-4Rα-/lox mice). Chronic Mtb aerosol infection in mb1creIL-4Rα-/lox mice reduced lung and spleen bacterial burdens, compared to littermate (IL-4Rα-/lox) control animals. Consequently, lung pathology, inflammation and inducible nitric oxide synthase (iNOS) expression were reduced in the lungs of mb1creIL-4Rα-/lox mice, which was also accompanied by increased lung IgA and decreased IgG1 levels. Furthermore, intratracheal adoptive transfer of wild-type B cells into B cell-specific IL4Rα deficient mice reversed the protective phenotype. Moreover, constitutively mCherry expressing Mtb showed decreased association with B cells from mb1creIL-4Rα-/lox mice ex vivo. In addition, supernatants from Mtb-exposed B cells of mb1creIL-4Rα-/lox mice also increased the ability of macrophages to produce nitric oxide, IL-1β, IL-6 and TNF. Together, this demonstrates that IL-4-responsive B cells are detrimental during the chronic phase of tuberculosis in mice with perturbed antibody profiles, inflammatory cytokines and tnf and stat1 levels in the lungs.
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Affiliation(s)
- Suraj P. Parihar
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Division of Medical Microbiology, Department of Pathology, Faculty of Health Sciences, Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Mumin Ozturk
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Maxine A. Höft
- AFGrica Medical Mycology Research Unit, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Julius E. Chia
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Reto Guler
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Department of Pathology, Faculty of Health Sciences, Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Roanne Keeton
- Division of Medical Virology, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Ilana C. van Rensburg
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Andre G. Loxton
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Frank Brombacher
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Department of Pathology, Faculty of Health Sciences, Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
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Duan LY, Liang Y, Gong WP, Xue Y, Mi J, Wang J, Wang L, Jia ZX, Lei H, Liang YM, Liu J, Zheng Y, Wu XQ. Comparative study on the antituberculous effect and mechanism of the traditional Chinese medicines NiuBeiXiaoHe extract and JieHeWan. Mil Med Res 2021; 8:34. [PMID: 34074345 PMCID: PMC8170785 DOI: 10.1186/s40779-021-00324-5] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 04/26/2021] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The traditional Chinese medicine NiuBeiXiaoHe (NBXH) extract and Chinese medicine preparation JieHeWan (JHW) exhibit anti-tuberculosis effects. The anti- tuberculosis effect of NBXH was compared with that of JHW to elucidate the mechanism of action of NBXH. METHODS BALB/c mice aged 6-8 weeks were randomly divided into a normal control group, Tuberculosis (TB) model group, JHW treatment group, and NBXH treatment group. After 3 and 13 weeks of treatment, the therapeutic effect in each group was evaluated by comparing lung histopathology, lung and liver colony counts, the number of spots representing effector T cells secreting IFN-γ in an ELISPOT, and the levels of Th1, Th2, and Th17 cytokines, which were measured by a cytometric bead array (CBA). Mouse RNA samples were subjected to transcriptome sequencing. RESULTS After 13 weeks of treatment, the mean histopathological lesion area of the NBXH group was significantly smaller than that of the TB model group (P < 0.05). Compared with those in the TB model group, the lung colony counts in the JHW and NBXH groups were significantly decreased (P < 0.05), and the IL-2 and IL-4 levels in the NBXH group were significantly increased (P < 0.05). NBXH partly restored significant changes in gene expression caused by Mycobacterium tuberculosis (M. tuberculosis) infection. According to GO and KEGG analyses, the changes in biological process (BP), cell composition (CC) and molecular function (MF) terms and in signaling pathways caused by NBXH and JHW treatment were not completely consistent, but they were mainly related to the immune response and inflammatory response in the mouse TB model. CONCLUSIONS NBXH had therapeutic effects similar to those of JHW in improving lung histopathology, reducing lung colony counts, and regulating the levels of cytokines. NBXH restored significant changes in gene expression and repaired cell damage caused by M. tuberculosis infection by regulating immune-related pathways, which clarified the mechanism of action of NBXH.
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Affiliation(s)
- Li-Yao Duan
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
- HeBei North University, Zhangjiakou, 075000 China
| | - Yan Liang
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
| | - Wen-Ping Gong
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
| | - Yong Xue
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
| | - Jie Mi
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
| | - Jie Wang
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
| | - Lan Wang
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
| | - Zai-Xing Jia
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
- HeBei North University, Zhangjiakou, 075000 China
| | - Hong Lei
- Clinical Laboratory, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
| | - Yu-Mei Liang
- Pathology Department, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
| | - Jun Liu
- Guangdong Qifang Pharmaceutical Co., Ltd, Guangzhou, 510075 China
| | - Yue Zheng
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
- HeBei North University, Zhangjiakou, 075000 China
| | - Xue-Qiong Wu
- Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Tuberculosis Research Institute, the 8th Medical Center, Chinese PLA General Hospital, Beijing, 100091 China
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Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense. Int J Mol Sci 2021; 22:ijms22094801. [PMID: 33946542 PMCID: PMC8125784 DOI: 10.3390/ijms22094801] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/28/2021] [Accepted: 04/28/2021] [Indexed: 12/20/2022] Open
Abstract
Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of Mtb–neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb, including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis.
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Abstract
Tuberculosis (TB) remains an infectious disease of global significance and a
leading cause of death in low- and middle-income countries. Significant effort
has been directed towards understanding Mycobacterium
tuberculosis genomics, virulence, and pathophysiology within the
framework of Koch postulates. More recently, the advent of “-omics” approaches
has broadened our appreciation of how “commensal” microbes have coevolved with
their host and have a central role in shaping health and susceptibility to
disease. It is now clear that there is a diverse repertoire of interactions
between the microbiota and host immune responses that can either sustain or
disrupt homeostasis. In the context of the global efforts to combatting TB, such
findings and knowledge have raised important questions: Does microbiome
composition indicate or determine susceptibility or resistance to
M. tuberculosis infection? Is the
development of active disease or latent infection upon M.
tuberculosis exposure influenced by the microbiome? Does
microbiome composition influence TB therapy outcome and risk of reinfection with
M. tuberculosis? Can the microbiome be
actively managed to reduce risk of M.
tuberculosis infection or recurrence of TB? Here, we
explore these questions with a particular focus on microbiome-immune
interactions that may affect TB susceptibility, manifestation and progression,
the long-term implications of anti-TB therapy, as well as the potential of the
host microbiome as target for clinical manipulation.
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Affiliation(s)
- Giorgia Mori
- The University of Queensland Diamantina Institute, Faculty
of Medicine, The University of Queensland, Brisbane, Australia
| | - Mark Morrison
- The University of Queensland Diamantina Institute, Faculty
of Medicine, The University of Queensland, Brisbane, Australia
| | - Antje Blumenthal
- The University of Queensland Diamantina Institute, Faculty
of Medicine, The University of Queensland, Brisbane, Australia
- * E-mail:
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30
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Rijnink WF, Ottenhoff THM, Joosten SA. B-Cells and Antibodies as Contributors to Effector Immune Responses in Tuberculosis. Front Immunol 2021; 12:640168. [PMID: 33679802 PMCID: PMC7930078 DOI: 10.3389/fimmu.2021.640168] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 01/29/2021] [Indexed: 12/19/2022] Open
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is still a major threat to mankind, urgently requiring improved vaccination and therapeutic strategies to reduce TB-disease burden. Most present vaccination strategies mainly aim to induce cell-mediated immunity (CMI), yet a series of independent studies has shown that B-cells and antibodies (Abs) may contribute significantly to reduce the mycobacterial burden. Although early studies using B-cell knock out animals did not support a major role for B-cells, more recent studies have provided new evidence that B-cells and Abs can contribute significantly to host defense against Mtb. B-cells and Abs exist in many different functional subsets, each equipped with unique functional properties. In this review, we will summarize current evidence on the contribution of B-cells and Abs to immunity toward Mtb, their potential utility as biomarkers, and their functional contribution to Mtb control.
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Affiliation(s)
- Willemijn F Rijnink
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
| | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
| | - Simone A Joosten
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
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31
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The double-sided effects of Mycobacterium Bovis bacillus Calmette-Guérin vaccine. NPJ Vaccines 2021; 6:14. [PMID: 33495451 PMCID: PMC7835355 DOI: 10.1038/s41541-020-00278-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 12/14/2020] [Indexed: 01/30/2023] Open
Abstract
Bacillus Calmette-Guérin (BCG), the only vaccine proven to be effective against tuberculosis (TB), is the most commonly used vaccine globally. In addition to its effects on mycobacterial diseases, an increasing amount of epidemiological and experimental evidence accumulated since its introduction in 1921 has shown that BCG also exerts non-specific effects against a number of diseases, such as non-mycobacterial infections, allergies and certain malignancies. Recent Corona Virus Disease 2019 (COVID-19) outbreak has put BCG, a classic vaccine with significant non-specific protection, into the spotlight again. This literature review briefly covers the diverse facets of BCG vaccine, providing new perspectives in terms of specific and non-specific protection mechanisms of this old, multifaceted, and controversial vaccine.
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32
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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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Hazlewood JE, Dumenil T, Le TT, Slonchak A, Kazakoff SH, Patch AM, Gray LA, Howley PM, Liu L, Hayball JD, Yan K, Rawle DJ, Prow NA, Suhrbier A. Injection site vaccinology of a recombinant vaccinia-based vector reveals diverse innate immune signatures. PLoS Pathog 2021; 17:e1009215. [PMID: 33439897 PMCID: PMC7837487 DOI: 10.1371/journal.ppat.1009215] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/26/2021] [Accepted: 12/04/2020] [Indexed: 02/07/2023] Open
Abstract
Poxvirus systems have been extensively used as vaccine vectors. Herein a RNA-Seq analysis of intramuscular injection sites provided detailed insights into host innate immune responses, as well as expression of vector and recombinant immunogen genes, after vaccination with a new multiplication defective, vaccinia-based vector, Sementis Copenhagen Vector. Chikungunya and Zika virus immunogen mRNA and protein expression was associated with necrosing skeletal muscle cells surrounded by mixed cellular infiltrates. The multiple adjuvant signatures at 12 hours post-vaccination were dominated by TLR3, 4 and 9, STING, MAVS, PKR and the inflammasome. Th1 cytokine signatures were dominated by IFNγ, TNF and IL1β, and chemokine signatures by CCL5 and CXCL12. Multiple signatures associated with dendritic cell stimulation were evident. By day seven, vaccine transcripts were absent, and cell death, neutrophil, macrophage and inflammation annotations had abated. No compelling arthritis signatures were identified. Such injection site vaccinology approaches should inform refinements in poxvirus-based vector design. Poxvirus vector systems have been widely developed for vaccine applications. Despite considerable progress, so far only one recombinant poxvirus vectored vaccine has to date been licensed for human use, with ongoing efforts seeking to enhance immunogenicity whilst minimizing reactogenicity. The latter two characteristics are often determined by early post-vaccination events at the injection site. We therefore undertook an injection site vaccinology approach to analyzing gene expression at the vaccination site after intramuscular inoculation with a recombinant, multiplication defective, vaccinia-based vaccine. This provided detailed insights into inter alia expression of vector-encoded immunoregulatory genes, as well as host innate and adaptive immune responses. We propose that such injection site vaccinology can inform rational vaccine vector design, and we discuss how the information and approach elucidated herein might be used to improve immunogenicity and limit reactogenicity of poxvirus-based vaccine vector systems.
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Affiliation(s)
- Jessamine E. Hazlewood
- Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Troy Dumenil
- Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Thuy T. Le
- Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Andrii Slonchak
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Australia
| | - Stephen H. Kazakoff
- Clinical Genomics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Ann-Marie Patch
- Clinical Genomics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Lesley-Ann Gray
- Australian Genome Research Facility Ltd., Melbourne, Australia
| | | | - Liang Liu
- Experimental Therapeutics Laboratory, University of South Australia Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - John D. Hayball
- Sementis Ltd., Hackney, Australia
- Experimental Therapeutics Laboratory, University of South Australia Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - Kexin Yan
- Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Daniel J. Rawle
- Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Natalie A. Prow
- Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Experimental Therapeutics Laboratory, University of South Australia Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - Andreas Suhrbier
- Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Australian Infectious Disease Research Centre, Brisbane, Australia
- * E-mail:
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Moulson AJ, Av-Gay Y. BCG immunomodulation: From the 'hygiene hypothesis' to COVID-19. Immunobiology 2021; 226:152052. [PMID: 33418320 PMCID: PMC7833102 DOI: 10.1016/j.imbio.2020.152052] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/07/2020] [Accepted: 12/17/2020] [Indexed: 12/23/2022]
Abstract
The century-old tuberculosis vaccine BCG has been the focus of renewed interest due to its well-documented ability to protect against various non-TB pathogens. Much of these broad spectrum protective effects are attributed to trained immunity, the epigenetic and metabolic reprogramming of innate immune cells. As BCG vaccine is safe, cheap, widely available, amendable to use as a recombinant vector, and immunogenic, it has immense potential for use as an immunotherapeutic agent for various conditions including autoimmune, allergic, neurodegenerative, and neoplastic diseases as well as a preventive measure against infectious agents. Of particular interest is the use of BCG vaccination to counteract the increasing prevalence of autoimmune and allergic conditions in industrialized countries attributable to reduced infectious burden as described by the 'hygiene hypothesis.' Furthermore, BCG vaccination has been proposed as a potential therapy to mitigate spread and disease burden of COVID-19 as a bridge to development of a specific vaccine and recombinant BCG expression vectors may prove useful for the introduction of SARS-CoV-2 antigens (rBCG-SARS-CoV-2) to induce long-term immunity. Understanding the immunomodulatory effects of BCG vaccine in these disease contexts is therefore critical. To that end, we review here BCG-induced immunomodulation focusing specifically on BCG-induced trained immunity and how it relates to the 'hygiene hypothesis' and COVID-19.
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Affiliation(s)
- Aaron J Moulson
- Faculty of Medicine, University of British Columbia, Vancouver, Canada.
| | - Yossef Av-Gay
- Faculty of Medicine, University of British Columbia, Vancouver, Canada; Division of Infectious Disease, University of British Columbia, Vancouver, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
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Sharma D, Sharma S, Sharma J. Potential strategies for the management of drug-resistant tuberculosis. J Glob Antimicrob Resist 2020; 22:210-214. [PMID: 32169684 DOI: 10.1016/j.jgar.2020.02.029] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 12/18/2019] [Accepted: 02/26/2020] [Indexed: 12/30/2022] Open
Abstract
In the current scenario, the emergence of drug resistance in Mycobacterium tuberculosis is the consequence of the failure of conventional diagnostic and treatment approaches. To combat this global emergence of drug resistance, alternative approaches such as pathogen-centric (use of repurposed drugs, novel analogues of existing anti-TB drugs and novel compounds with a different mechanism of action), host-centric (immunomodulatory agents, therapeutic vaccines, immune and cellular therapies) and nano-based drug/vaccine delivery should be used singly or in combination. Diverse types of nano-carriers have assessed as auspicious diagnostic and drug delivery systems. In this focused review, we have suggested a long-term solution for combating antimicrobial resistance and also an attractive means to increase patient compliance and reduce treatment duration.
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Affiliation(s)
- Divakar Sharma
- Department of Biochemistry, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra 282004, India.
| | - Sandeep Sharma
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medical Laboratory Sciences, Division of Research and Development, Lovely Professional University, Phagwara, Punjab 144411, India
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Bright MR, Curtis N, Messina NL. The role of antibodies in Bacille Calmette Guérin-mediated immune responses and protection against tuberculosis in humans: A systematic review. Tuberculosis (Edinb) 2020; 131:101947. [PMID: 33691988 DOI: 10.1016/j.tube.2020.101947] [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: 01/05/2020] [Revised: 05/02/2020] [Accepted: 05/11/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND The mechanisms underlying Bacille Calmette-Guérin (BCG) vaccine's protective effects against tuberculosis (TB) are incompletely understood but are proposed to involve a predominantly cell-mediated process. However, there is increasing evidence for the involvement of antibodies in the control of Mycobacteria tuberculosis and in the immune response to BCG. METHODS We did a systematic review of studies investigating anti-BCG antibodies in individuals with active or latent TB, and in the response to BCG vaccination. RESULTS Of 1417 articles screened, 70 were relevant, comprising 52 investigating anti-BCG antibodies in TB and 18 investigating the anti-BCG antibody response to BCG-vaccination. Individuals with active TB have higher levels of anti-BCG antibodies compared with individuals with latent TB or healthy individuals. Antibodies to BCG are present after BCG vaccination. There is some evidence for the in utero transfer of maternal anti-BCG antibodies to infants. CONCLUSIONS BCG vaccination induces a humoral response. Antibodies targeted against BCG and its antigens may play a role in protection against active TB.
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Affiliation(s)
- Matthew R Bright
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
| | - Nigel Curtis
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Murdoch Children's Research Institute, Parkville, Victoria, Australia; Infectious Diseases Unit, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
| | - Nicole L Messina
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Murdoch Children's Research Institute, Parkville, Victoria, Australia.
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Abstract
Mycobacterium tuberculosis remains the leading cause of death attributed to a single infectious organism. Bacillus Calmette-Guerin (BCG), the standard vaccine against M. tuberculosis, is thought to prevent only 5% of all vaccine-preventable deaths due to tuberculosis, thus an alternative vaccine is required. One of the principal barriers to vaccine development against M. tuberculosis is the complexity of the immune response to infection, with uncertainty as to what constitutes an immunological correlate of protection. In this paper, we seek to give an overview of the immunology of M. tuberculosis infection, and by doing so, investigate possible targets of vaccine development. This encompasses the innate, adaptive, mucosal and humoral immune systems. Though MVA85A did not improve protection compared with BCG alone in a large-scale clinical trial, the correlates of protection this has revealed, in addition to promising results from candidate such as VPM1002, M72/ASO1E and H56:IC31 point to a brighter future in the field of TB vaccine development.
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Affiliation(s)
- Benedict Brazier
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ UK
| | - Helen McShane
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ UK
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Chai Q, Lu Z, Liu CH. Host defense mechanisms against Mycobacterium tuberculosis. Cell Mol Life Sci 2020; 77:1859-1878. [PMID: 31720742 PMCID: PMC11104961 DOI: 10.1007/s00018-019-03353-5] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/30/2019] [Accepted: 10/21/2019] [Indexed: 12/19/2022]
Abstract
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death worldwide from a single infectious pathogen. Mtb is a paradigmatic intracellular pathogen that primarily invades the lungs after host inhalation of bacteria-containing droplets via the airway. However, the majority of Mtb-exposed individuals can spontaneously control the infection by virtue of a robust immune defense system. The mucosal barriers of the respiratory tract shape the first-line defense against Mtb through various mucosal immune responses. After arriving at the alveoli, the surviving mycobacteria further encounter a set of host innate immune cells that exert multiple cellular bactericidal functions. Adaptive immunity, predominantly mediated by a range of different T cell and B cell subsets, is subsequently activated and participates in host anti-mycobacterial defense. During Mtb infection, host bactericidal immune responses are exquisitely adjusted and balanced by multifaceted mechanisms, including genetic and epigenetic regulation, metabolic regulation and neuroendocrine regulation, which are indispensable for maintaining host immune efficiency and avoiding excessive tissue injury. A better understanding of the integrated and equilibrated host immune defense system against Mtb will contribute to the development of rational TB treatment regimens especially novel host-directed therapeutics.
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Affiliation(s)
- Qiyao Chai
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Zhe Lu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Cui Hua Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
- Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
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Abstract
Tuberculosis (TB) is a serious global public health challenge that results in significant morbidity and mortality worldwide. TB is caused by infection with the bacilli Mycobacterium tuberculosis (M. tuberculosis), which has evolved a wide variety of strategies in order to thrive within its host. Understanding the complex interactions between M. tuberculosis and host immunity can inform the rational design of better TB vaccines and therapeutics. This chapter covers innate and adaptive immunity against M. tuberculosis infection, including insights on bacterial immune evasion and subversion garnered from animal models of infection and human studies. In addition, this chapter discusses the immunology of the TB granuloma, TB diagnostics, and TB comorbidities. Finally, this chapter provides a broad overview of the current TB vaccine pipeline.
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40
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RNA Sensing of Mycobacterium tuberculosis and Its Impact on TB Vaccination Strategies. Vaccines (Basel) 2020; 8:vaccines8010067. [PMID: 32033104 PMCID: PMC7158685 DOI: 10.3390/vaccines8010067] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/01/2020] [Accepted: 02/01/2020] [Indexed: 02/07/2023] Open
Abstract
Tuberculosis (TB) is still an important global threat and although the causing organism has been discovered long ago, effective prevention strategies are lacking. Mycobacterium tuberculosis (MTB) is a unique pathogen with a complex host interaction. Understanding the immune responses upon infection with MTB is crucial for the development of new vaccination strategies and therapeutic targets for TB. Recently, it has been proposed that sensing bacterial nucleic acid in antigen-presenting cells via intracellular pattern recognition receptors (PRRs) is a central mechanism for initiating an effective host immune response. Here, we summarize key findings of the impact of mycobacterial RNA sensing for innate and adaptive host immunity after MTB infection, with emphasis on endosomal toll-like receptors (TLRs) and cytosolic sensors such as NLRP3 and RLRs, modulating T-cell differentiation through IL-12, IL-21, and type I interferons. Ultimately, these immunological pathways may impact immune memory and TB vaccine efficacy. The novel findings described here may change our current understanding of the host response to MTB and potentially impact clinical research, as well as future vaccination design. In this review, the current state of the art is summarized, and an outlook is given on how progress can be made.
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Mourik BC, de Steenwinkel JEM, de Knegt GJ, Huizinga R, Verbon A, Ottenhoff THM, van Soolingen D, Leenen PJM. Mycobacterium tuberculosis clinical isolates of the Beijing and East-African Indian lineage induce fundamentally different host responses in mice compared to H37Rv. Sci Rep 2019; 9:19922. [PMID: 31882653 PMCID: PMC6934500 DOI: 10.1038/s41598-019-56300-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/14/2019] [Indexed: 11/15/2022] Open
Abstract
Substantial differences exist in virulence among Mycobacterium tuberculosis strains in preclinical TB models. In this study we show how virulence affects host responses in mice during the first four weeks of infection with a mycobacterial strain belonging to the Beijing, East-African-Indian or Euro-American lineage. BALB/c mice were infected with clinical isolates of the Beijing-1585 strain or the East-African Indian (EAI)-1627 strain and host responses were compared to mice infected with the non-clinical H37Rv strain of the Euro-American lineage. We found that H37Rv induced a ‘classical’ T-cell influx with high IFN-γ levels, while Beijing-1585 and EAI-1627 induced an influx of B-cells into the lungs together with elevated pulmonary IL-4 protein levels. Myeloid cells in the lungs appeared functionally impaired upon infection with Beijing-1585 and EAI-1627 with reduced iNOS and IL-12 expression levels compared to H37Rv infection. This impairment might be related to significantly reduced expression in the bone marrow of IFN-γ, TNF-α and IFN-β in mice infected with Beijing-1585 and EAI-1627, which could be detected from the third day post infection onwards. Our findings suggest that increased virulence of two clinical isolates compared to H37Rv is associated with a fundamentally different systemic immune response, which already can be detected early during infection.
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Affiliation(s)
- Bas C Mourik
- Department Medical Microbiology & Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jurriaan E M de Steenwinkel
- Department Medical Microbiology & Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Gerjo J de Knegt
- Department Medical Microbiology & Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Ruth Huizinga
- Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Annelies Verbon
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Dick van Soolingen
- National Tuberculosis Reference Laboratory, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Pieter J M Leenen
- Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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Abstract
Tuberculosis (TB) is the leading killer among all infectious diseases worldwide despite extensive use of the Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine. A safer and more effective vaccine than BCG is urgently required. More than a dozen TB vaccine candidates are under active evaluation in clinical trials aimed to prevent infection, disease, and recurrence. After decades of extensive research, renewed promise of an effective vaccine against this ancient airborne disease has recently emerged. In two innovative phase 2b vaccine clinical trials, one for the prevention of Mycobacterium tuberculosis infection in healthy adolescents and another for the prevention of TB disease in M. tuberculosis-infected adults, efficacy signals were observed. These breakthroughs, based on the greatly expanded knowledge of the M. tuberculosis infection spectrum, immunology of TB, and vaccine platforms, have reinvigorated the TB vaccine field. Here, we review our current understanding of natural immunity to TB, limitations in BCG immunity that are guiding vaccinologists to design novel TB vaccine candidates and concepts, and the desired attributes of a modern TB vaccine. We provide an overview of the progress of TB vaccine candidates in clinical evaluation, perspectives on the challenges faced by current vaccine concepts, and potential avenues to build on recent successes and accelerate the TB vaccine research-and-development trajectory.
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Bénard A, Sakwa I, Schierloh P, Colom A, Mercier I, Tailleux L, Jouneau L, Boudinot P, Al-Saati T, Lang R, Rehwinkel J, Loxton AG, Kaufmann SHE, Anton-Leberre V, O'Garra A, Sasiain MDC, Gicquel B, Fillatreau S, Neyrolles O, Hudrisier D. B Cells Producing Type I IFN Modulate Macrophage Polarization in Tuberculosis. Am J Respir Crit Care Med 2019; 197:801-813. [PMID: 29161093 DOI: 10.1164/rccm.201707-1475oc] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
RATIONALE In addition to their well-known function as antibody-producing cells, B lymphocytes can markedly influence the course of infectious or noninfectious diseases via antibody-independent mechanisms. In tuberculosis (TB), B cells accumulate in lungs, yet their functional contribution to the host response remains poorly understood. OBJECTIVES To document the role of B cells in TB in an unbiased manner. METHODS We generated the transcriptome of B cells isolated from Mycobacterium tuberculosis (Mtb)-infected mice and validated the identified key pathways using in vitro and in vivo assays. The obtained data were substantiated using B cells from pleural effusion of patients with TB. MEASUREMENTS AND MAIN RESULTS B cells isolated from Mtb-infected mice displayed a STAT1 (signal transducer and activator of transcription 1)-centered signature, suggesting a role for IFNs in B-cell response to infection. B cells stimulated in vitro with Mtb produced type I IFN, via a mechanism involving the innate sensor STING (stimulator of interferon genes), and antagonized by MyD88 (myeloid differentiation primary response 88) signaling. In vivo, B cells expressed type I IFN in the lungs of Mtb-infected mice and, of clinical relevance, in pleural fluid from patients with TB. Type I IFN expression by B cells induced an altered polarization of macrophages toward a regulatory/antiinflammatory profile in vitro. In vivo, increased provision of type I IFN by B cells in a murine model of B cell-restricted Myd88 deficiency correlated with an enhanced accumulation of regulatory/antiinflammatory macrophages in Mtb-infected lungs. CONCLUSIONS Type I IFN produced by Mtb-stimulated B cells favors macrophage polarization toward a regulatory/antiinflammatory phenotype during Mtb infection.
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Affiliation(s)
- Alan Bénard
- 1 Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier, Toulouse, France.,2 International Associated Laboratory CNRS "IM-TB/HIV (Immunometabolism and Macrophages in Tuberculosis/Human Immunodeficiency Virus-1 Co-infection)," Toulouse, France, and Buenos Aires, Argentina.,3 Department of Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany
| | - Imme Sakwa
- 4 Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Berlin, Germany
| | - Pablo Schierloh
- 2 International Associated Laboratory CNRS "IM-TB/HIV (Immunometabolism and Macrophages in Tuberculosis/Human Immunodeficiency Virus-1 Co-infection)," Toulouse, France, and Buenos Aires, Argentina.,5 Instituto de Medicina Experimental-Consejo Nacional de Investigaciones Científicas y Técnicas, Academia Nacional de Medicina, Pacheco de Melo, Buenos Aires, Argentina
| | - André Colom
- 1 Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier, Toulouse, France.,2 International Associated Laboratory CNRS "IM-TB/HIV (Immunometabolism and Macrophages in Tuberculosis/Human Immunodeficiency Virus-1 Co-infection)," Toulouse, France, and Buenos Aires, Argentina
| | - Ingrid Mercier
- 1 Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier, Toulouse, France.,2 International Associated Laboratory CNRS "IM-TB/HIV (Immunometabolism and Macrophages in Tuberculosis/Human Immunodeficiency Virus-1 Co-infection)," Toulouse, France, and Buenos Aires, Argentina.,6 Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés, Université de Toulouse, CNRS, Institut National de la Recherche Agronomique (INRA), Institut National des Sciences Appliquées, Toulouse, France
| | - Ludovic Tailleux
- 7 Unit of Mycobacterial Genetics and.,8 Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, Paris, France
| | - Luc Jouneau
- 9 Virologie et Immunologie Moléculaires, INRA, Jouy-en-Josas, France
| | - Pierre Boudinot
- 9 Virologie et Immunologie Moléculaires, INRA, Jouy-en-Josas, France
| | - Talal Al-Saati
- 10 Institut National de la Santé et de la Recherche Médicale (INSERM)/Université Paul Sabatier/École Nationale Vétérinaire de Toulouse/Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales, Service d'Histopathologie, Centre Hospitalier Universitaire, Purpan, Toulouse, France
| | - Roland Lang
- 11 Institute of Clinical Microbiology, Immunology, and Hygiene, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Jan Rehwinkel
- 12 Radcliffe Department of Medicine, Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Andre G Loxton
- 13 South African Medical Research Council Centre for Tuberculosis Research, Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa
| | - Stefan H E Kaufmann
- 14 Department of Immunology, Max Planck Institute of Infection Biology, Berlin, Germany
| | - Véronique Anton-Leberre
- 6 Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés, Université de Toulouse, CNRS, Institut National de la Recherche Agronomique (INRA), Institut National des Sciences Appliquées, Toulouse, France
| | - Anne O'Garra
- 15 Division of Immunoregulation, Medical Research Council, National Institute for Medical Research, London, United Kingdom.,16 National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Maria Del Carmen Sasiain
- 2 International Associated Laboratory CNRS "IM-TB/HIV (Immunometabolism and Macrophages in Tuberculosis/Human Immunodeficiency Virus-1 Co-infection)," Toulouse, France, and Buenos Aires, Argentina.,5 Instituto de Medicina Experimental-Consejo Nacional de Investigaciones Científicas y Técnicas, Academia Nacional de Medicina, Pacheco de Melo, Buenos Aires, Argentina
| | - Brigitte Gicquel
- 9 Virologie et Immunologie Moléculaires, INRA, Jouy-en-Josas, France
| | - Simon Fillatreau
- 4 Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Berlin, Germany.,17 Institut Necker-Enfants Malades, INSERM U1151-CNRS Unité Mixte de Recherche 8253, Paris, France.,18 Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and.,19 Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Paris, France
| | - Olivier Neyrolles
- 1 Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier, Toulouse, France.,2 International Associated Laboratory CNRS "IM-TB/HIV (Immunometabolism and Macrophages in Tuberculosis/Human Immunodeficiency Virus-1 Co-infection)," Toulouse, France, and Buenos Aires, Argentina
| | - Denis Hudrisier
- 1 Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier, Toulouse, France.,2 International Associated Laboratory CNRS "IM-TB/HIV (Immunometabolism and Macrophages in Tuberculosis/Human Immunodeficiency Virus-1 Co-infection)," Toulouse, France, and Buenos Aires, Argentina
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Steigler P, Verrall AJ, Kirman JR. Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection. Immunol Cell Biol 2019; 97:647-655. [PMID: 31141205 DOI: 10.1111/imcb.12278] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 05/26/2019] [Accepted: 05/26/2019] [Indexed: 12/29/2022]
Abstract
Tuberculosis (TB) is a serious infectious disease caused by infection with Mycobacterium tuberculosis, and kills more people annually than any other single infectious agent. Although a vaccine is available, it is only moderately effective and an improved vaccine is urgently needed. The ability to develop a more effective vaccine has been thwarted by a lack of understanding of the mechanism of vaccine-induced immune protection. Over recent decades, many novel TB vaccines have been developed and almost all have aimed to generate memory CD4 T cells. In this review, we critically evaluate evidence in the literature that supports the contention that memory CD4 T cells are the prime mediators of vaccine-induced protection against TB. Because of the lack of robust evidence supporting memory CD4 T cells in this role, the potential for B-cell antibody and "trained" innate cells as alternative mediators of protective immunity is explored.
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Affiliation(s)
- Pia Steigler
- South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research (CIDRI), Cape Town, South Africa
| | - Ayesha J Verrall
- Department of Pathology and Molecular Medicine, University of Otago Wellington, Wellington, New Zealand
| | - Joanna R Kirman
- Department of Microbiology & Immunology, University of Otago, Dunedin, New Zealand
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45
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Tanner R, Villarreal-Ramos B, Vordermeier HM, McShane H. The Humoral Immune Response to BCG Vaccination. Front Immunol 2019; 10:1317. [PMID: 31244856 PMCID: PMC6579862 DOI: 10.3389/fimmu.2019.01317] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 05/23/2019] [Indexed: 01/19/2023] Open
Abstract
Bacillus Calmette Guérin (BCG) is the only currently available vaccine against tuberculosis (TB), but it confers incomplete and variable protection against pulmonary TB in humans and bovine TB (bTB) in cattle. Insights into the immune response induced by BCG offer an underexploited opportunity to gain knowledge that may inform the design of a more efficacious vaccine, which is urgently needed to control these major global epidemics. Humoral immunity in TB and bTB has been neglected, but recent studies supporting a role for antibodies in protection against TB has driven a growing interest in determining their relevance to vaccine development. In this manuscript we review what is known about the humoral immune response to BCG vaccination and re-vaccination across species, including evidence for the induction of specific B cells and antibodies; and how these may relate to protection from TB or bTB. We discuss potential explanations for often conflicting findings and consider how factors such as BCG strain, manufacturing methodology and route of administration influence the humoral response. As novel vaccination strategies include BCG prime-boost regimens, the literature regarding off-target immunomodulatory effects of BCG vaccination on non-specific humoral immunity is also reviewed. Overall, reported outcomes to date are inconsistent, but indicate that humoral responses are heterogeneous and may play different roles in different species, populations, or individual hosts. Further study is warranted to determine whether a new TB vaccine could benefit from the targeting of humoral as well as cell-mediated immunity.
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Affiliation(s)
- Rachel Tanner
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Bernardo Villarreal-Ramos
- Department of Bacteriology, Animal and Plant Health Agency, Addlestone, United Kingdom
- Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Aberystwyth, United Kingdom
| | - H. Martin Vordermeier
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Department of Bacteriology, Animal and Plant Health Agency, Addlestone, United Kingdom
- Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Aberystwyth, United Kingdom
| | - Helen McShane
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Yuan C, Qu ZL, Tang XL, Liu Q, Luo W, Huang C, Pan Q, Zhang XL. Mycobacterium tuberculosis Mannose-Capped Lipoarabinomannan Induces IL-10-Producing B Cells and Hinders CD4 +Th1 Immunity. iScience 2018; 11:13-30. [PMID: 30572206 PMCID: PMC6299163 DOI: 10.1016/j.isci.2018.11.039] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 11/08/2018] [Accepted: 11/28/2018] [Indexed: 12/26/2022] Open
Abstract
The importance of Th1/interferon (IFN)-γ-mediated responses in mycobacterial infection has been well established. However, little is known about B cell-mediated immunity during Mycobacterium tuberculosis (Mtb) infection. Interleukin (IL)-10-producing B cells (B10 cells), a subset of B regulatory cells (Bregs), are implicated in modulating the immune response. Herein, we found that B10 cells were significantly increased in patients with tuberculosis. Furthermore, mannose-capped lipoarabinomannan (ManLAM), a major surface lipoglycan component from Mtb, induced a significant increase in B10 cells, which enriched in CD5+ B1a B cells. ManLAM induced IL-10 production mainly by activating MyD88/PI3K/AKT/Ap-1 and K63-linked ubiquitination of NF-κB essential modulator/nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathways in B cells via Toll-like receptor 2. IL-10 production by ManLAM-treated B cells further inhibited CD4+ Th1 polarization, leading to increased susceptibility to mycobacterial infection compared with ManLAM-treated IL-10−/− B group. Thus, we report a new immunoregulation mechanism in which Mtb ManLAM-induced B10 cells negatively regulate host anti-TB cellular immunity.
Mtb mannose-capped lipoarabinomannan (ManLAM) induces IL-10 production in B cells ManLAM-induced B10 cells enrich in CD5+ B1a B cells ManLAM binding with TLR2 triggers MyD88 signaling pathways of B cells ManLAM-induced B10 cells hinder CD4+Th1 immunity during Mtb infection in mice
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Affiliation(s)
- Chunhui Yuan
- State Key Laboratory of Virology and Medical Research Institute, Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuchang, Wuhan 430071, China; Department of Laboratory Medicine, Wuhan Children's Hospital, Huazhong University of Science and Technology, Jiangan, Wuhan 430015, China
| | - Zi-Lu Qu
- State Key Laboratory of Virology and Medical Research Institute, Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuchang, Wuhan 430071, China
| | - Xiao-Lei Tang
- State Key Laboratory of Virology and Medical Research Institute, Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuchang, Wuhan 430071, China
| | - Qi Liu
- State Key Laboratory of Virology and Medical Research Institute, Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuchang, Wuhan 430071, China
| | - Wei Luo
- State Key Laboratory of Virology and Medical Research Institute, Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuchang, Wuhan 430071, China
| | - Chun Huang
- State Key Laboratory of Virology and Medical Research Institute, Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuchang, Wuhan 430071, China
| | - Qin Pan
- State Key Laboratory of Virology and Medical Research Institute, Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuchang, Wuhan 430071, China.
| | - Xiao-Lian Zhang
- State Key Laboratory of Virology and Medical Research Institute, Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuchang, Wuhan 430071, China.
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Dyatlov AV, Apt AS, Linge IA. B lymphocytes in anti-mycobacterial immune responses: Pathogenesis or protection? Tuberculosis (Edinb) 2018; 114:1-8. [PMID: 30711147 DOI: 10.1016/j.tube.2018.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/12/2018] [Accepted: 10/23/2018] [Indexed: 12/12/2022]
Abstract
The role of B cells and antibodies in tuberculosis (TB) immunity, protection and pathogenesis remain contradictory. The presence of organized B cell follicles close to active TB lesions in the lung tissue raises the question about the role of these cells in local host-pathogen interactions. In this short review, we summarize the state of our knowledge concerning phenotypes of B cells populating tuberculous lungs, their secretory activity, interactions with other immune cells and possible involvement in protective vs. pathogenic TB immunity.
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Affiliation(s)
- Alexander V Dyatlov
- Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia
| | - Alexander S Apt
- Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia; Department of Immunology, School of Biology, M. V. Lomonosov Moscow State University, Russia.
| | - Irina A Linge
- Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia
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Cavalcanti-Neto MP, Prado RQ, Piñeros AR, Sérgio CA, Bertolini TB, Gembre AF, Ramos SG, Bonato VL. Improvement of the resistance against early Mycobacterium tuberculosis-infection in the absence of PI3Kγ enzyme is associated with increase of CD4+IL-17+ cells and neutrophils. Tuberculosis (Edinb) 2018; 113:1-9. [PMID: 30514491 DOI: 10.1016/j.tube.2018.08.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 08/19/2018] [Accepted: 08/21/2018] [Indexed: 02/06/2023]
Abstract
Given the impossibility to study the lung immune response during Mycobacterium tuberculosis-latent infection, and consequently, the mechanisms that control the bacterial load, it is reasonable to determine the activation of local immunity in the early phase of the infection. The phosphatidylinositol-3-kinase gamma enzyme (PI3Kγ) is involved in the leukocyte recruitment, phagocytosis and cellular differentiation, and therefore, it is considered a promising target for the development of immunotherapies for chronic inflammatory diseases. Mice genetically deficient in PI3Kγ (PI3Kγ-/-) or WT (Wild Type) were evaluated 15 days post-infection. The enzyme deficiency improved the resistance against infection, increased the frequency of CD4+IL-17+ cells, the production of IL-17 as well as the gene and protein expression of molecules associated with Th17 cell differentiation and neutrophil recruitment. Our findings show, for the first time, the participation of the PI3Kγ in vivo in the M. tuberculosis-infection, and suggest an association of Th17 cells with protection in the early phase of tuberculosis.
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Affiliation(s)
- M P Cavalcanti-Neto
- Basic and Applied Immunology Programe, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Laboratory of Cell Signaling and Metabolic Modulation, Institute of Health and Biotechnology, Federal University of Amazonas, Coari, Brazil
| | - R Q Prado
- Basic and Applied Immunology Programe, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - A R Piñeros
- Basic and Applied Immunology Programe, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - C A Sérgio
- Basic and Applied Immunology Programe, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - T B Bertolini
- Basic and Applied Immunology Programe, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - A F Gembre
- Basic and Applied Immunology Programe, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - S G Ramos
- Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - V L Bonato
- Basic and Applied Immunology Programe, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
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Krishnamoorthy M, Buhari FHM, Zhao T, Brauer PM, Burrows K, Cao EY, Moxley-Paquette V, Mortha A, Zúñiga-Pflücker JC, Treanor B. The ion channel TRPM7 is required for B cell lymphopoiesis. Sci Signal 2018; 11:11/533/eaan2693. [PMID: 29871911 DOI: 10.1126/scisignal.aan2693] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The transient receptor potential (TRP) family is a large family of widely expressed ion channels that regulate the intracellular concentration of ions and metals and respond to various chemical and physical stimuli. TRP subfamily M member 7 (TRPM7) is unusual in that it contains both an ion channel and a kinase domain. TRPM7 is a divalent cation channel with preference for Ca2+ and Mg2+ It is required for the survival of DT40 cells, a B cell line; however, deletion of TRPM7 in T cells does not impair their development. We found that expression of TRPM7 was required for B cell development in mice. Mice that lacked TRPM7 in B cells failed to generate peripheral B cells because of a developmental block at the pro-B cell stage. The loss of TRPM7 kinase activity alone did not affect the proportion of peripheral mature B cells or the development of B cells in the bone marrow. However, supplementation with a high concentration of extracellular Mg2+ partially rescued the development of TRPM7-deficient B cells in vitro. Thus, our findings identify a critical role for TRPM7 ion channel activity in B cell development.
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Affiliation(s)
- Mithunah Krishnamoorthy
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | | | - Tiantian Zhao
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | | | - Kyle Burrows
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Eric Yixiao Cao
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Vincent Moxley-Paquette
- Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario M1C 1A4, Canada
| | - Arthur Mortha
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Juan Carlos Zúñiga-Pflücker
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.,Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada
| | - Bebhinn Treanor
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada. .,Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario M1C 1A4, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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Bai X, Aerts SL, Verma D, Ordway DJ, Chan ED. Epidemiologic Evidence of and Potential Mechanisms by Which Second-Hand Smoke Causes Predisposition to Latent and Active Tuberculosis. Immune Netw 2018; 18:e22. [PMID: 29984040 PMCID: PMC6026693 DOI: 10.4110/in.2018.18.e22] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/15/2018] [Accepted: 06/16/2018] [Indexed: 12/13/2022] Open
Abstract
Many studies have linked cigarette smoke (CS) exposure and tuberculosis (TB) infection and disease although much fewer have studied second-hand smoke (SHS) exposure. Our goal is to review the epidemiologic link between SHS and TB as well as to summarize the effects SHS and direct CS on various immune cells relevant for TB. PubMed searches were performed using the key words "tuberculosis" with "cigarette," "tobacco," or "second-hand smoke." The bibliography of relevant papers were examined for additional relevant publications. Relatively few studies associate SHS exposure with TB infection and active disease. Both SHS and direct CS can alter various components of host immunity resulting in increased vulnerability to TB. While the epidemiologic link of these 2 health maladies is robust, more definitive, mechanistic studies are required to prove that SHS and direct CS actually cause increased susceptibility to TB.
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Affiliation(s)
- Xiyuan Bai
- Department of Medicine, Denver Veterans Affairs Medical Center, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA
- Department of Medicine and Office of Academic Affairs, National Jewish Health, Denver, CO 80206, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Denver, CO 80045, USA
| | - Shanae L. Aerts
- Department of Medicine and Office of Academic Affairs, National Jewish Health, Denver, CO 80206, USA
| | - Deepshikha Verma
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO 80523, USA
| | - Diane J. Ordway
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO 80523, USA
| | - Edward D. Chan
- Department of Medicine, Denver Veterans Affairs Medical Center, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA
- Department of Medicine and Office of Academic Affairs, National Jewish Health, Denver, CO 80206, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Denver, CO 80045, USA
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