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1.
Front Cell Infect Microbiol ; 14: 1398077, 2024.
Article in English | MEDLINE | ID: mdl-38836056

ABSTRACT

Mycobacterium tuberculosis (M.tb), the causative agent of Tuberculosis, is an intracellular bacterium well known for its ability to subvert host energy and metabolic pathways to maintain its intracellular survival. For this purpose, the bacteria utilize various mechanisms of which extracellular vehicles (EVs) related mechanisms attracted more attention. EVs are nanosized particles that are released by almost all cell types containing active biomolecules from the cell of origin and can target bioactive pathways in the recipient cells upon uptake. It is hypothesized that M.tb dictates the processes of host EV biogenesis pathways, selectively incorporating its molecules into the host EV to direct immune responses in its favor. During infection with Mtb, both mycobacteria and host cells release EVs. The composition of these EVs varies over time, influenced by the physiological and nutritional state of the host environment. Additionally, different EV populations contribute differently to the pathogenesis of disease at various stages of illness participating in a complex interplay between host cells and pathogens. These interactions ultimately influence immune responses and disease outcomes. However, the precise mechanisms and roles of EVs in pathogenicity and disease outcomes remain to be fully elucidated. In this review, we explored the properties and function of EVs in the context of M.tb infection within the host microenvironment and discussed their capacity as a novel therapeutic strategy to combat tuberculosis.


Subject(s)
Extracellular Vesicles , Host-Pathogen Interactions , Mycobacterium tuberculosis , Tuberculosis , Extracellular Vesicles/metabolism , Extracellular Vesicles/immunology , Mycobacterium tuberculosis/immunology , Humans , Tuberculosis/immunology , Tuberculosis/microbiology , Tuberculosis/metabolism , Host-Pathogen Interactions/immunology , Animals
2.
Front Immunol ; 15: 1401867, 2024.
Article in English | MEDLINE | ID: mdl-38846947

ABSTRACT

Tuberculosis (TB), caused by the bacterial pathogen Mycobacterium tuberculosis (MTB), remains one of the most prevalent and deadly infectious diseases worldwide. Currently, there are complex interactions between host cells and pathogens in TB. The onset, progression, and regression of TB are correlated not only with the virulence of MTB but also with the immunity of TB patients. Exosomes are cell-secreted membrane-bound nanovesicles with lipid bilayers that contain a variety of biomolecules, such as metabolites, lipids, proteins, and nucleic acids. Exosome-mediated cell-cell communication and interactions with the microenvironment represent crucial mechanisms through which exosomes exert their functional effects. Exosomes harbor a wide range of regulatory roles in physiological and pathological conditions, including MTB infection. Exosomes can regulate the immune response, metabolism, and cellular death to remodel the progression of MTB infection. During MTB infection, exosomes display distinctive profiles and quantities that may act as diagnostic biomarkers, suggesting that exosomes provide a revealing glimpse into the evolving landscape of MTB infections. Furthermore, exosomes derived from MTB and mesenchymal stem cells can be harnessed as vaccine platforms and drug delivery vehicles for the precise targeting and treatment of TB. In this review, we highlight the functions and mechanisms through which exosomes influence the progression of TB. Additionally, we unravel the critical significance of exosomal constituents in the diagnosis and therapeutic applications of TB, aiming to offer novel perspectives and strategies for combating TB.


Subject(s)
Biomarkers , Exosomes , Mycobacterium tuberculosis , Tuberculosis , Exosomes/immunology , Exosomes/metabolism , Humans , Tuberculosis/immunology , Tuberculosis/diagnosis , Tuberculosis/therapy , Tuberculosis/microbiology , Mycobacterium tuberculosis/immunology , Animals , Antitubercular Agents/therapeutic use
3.
Front Immunol ; 15: 1360412, 2024.
Article in English | MEDLINE | ID: mdl-38745652

ABSTRACT

A robust immune response is required for resistance to pulmonary tuberculosis (TB), the primary disease caused by Mycobacterium tuberculosis (Mtb). However, pharmaceutical inhibition of T cell immune checkpoint molecules can result in the rapid development of active disease in latently infected individuals, indicating the importance of T cell immune regulation. In this study, we investigated the potential role of CD200R during Mtb infection, a key immune checkpoint for myeloid cells. Expression of CD200R was consistently downregulated on CD14+ monocytes in the blood of subjects with active TB compared to healthy controls, suggesting potential modulation of this important anti-inflammatory pathway. In homogenized TB-diseased lung tissue, CD200R expression was highly variable on monocytes and CD11b+HLA-DR+ macrophages but tended to be lowest in the most diseased lung tissue sections. This observation was confirmed by fluorescent microscopy, which showed the expression of CD200R on CD68+ macrophages surrounding TB lung granuloma and found expression levels tended to be lower in macrophages closest to the granuloma core and inversely correlated with lesion size. Antibody blockade of CD200R in a biomimetic 3D granuloma-like tissue culture system led to significantly increased Mtb growth. In addition, Mtb infection in this system reduced gene expression of CD200R. These findings indicate that regulation of myeloid cells via CD200R is likely to play an important part in the immune response to TB and may represent a potential target for novel therapeutic intervention.


Subject(s)
Mycobacterium tuberculosis , Myeloid Cells , Tuberculosis, Pulmonary , Humans , Mycobacterium tuberculosis/immunology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiology , Myeloid Cells/immunology , Myeloid Cells/metabolism , Orexin Receptors/metabolism , Macrophages/immunology , Macrophages/metabolism , Adult , Female , Male , Antigens, CD/metabolism , Antigens, CD/genetics , Middle Aged , Lung/immunology , Lung/microbiology , Lung/pathology , Lung/metabolism , Biomimetics , Monocytes/immunology , Monocytes/metabolism
4.
Front Immunol ; 15: 1387808, 2024.
Article in English | MEDLINE | ID: mdl-38745656

ABSTRACT

Background: Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB) causing high mortality and disability. TBM arises due to immune dysregulation, but the underlying immune mechanisms are unclear. Methods: We performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells isolated from children (n=6) with TBM using 10 xGenomics platform. We used unsupervised clustering of cells and cluster visualization based on the gene expression profiles, and validated the protein and cytokines by ELISA analysis. Results: We revealed for the first time 33 monocyte populations across the CSF cells and PBMCs of children with TBM. Within these populations, we saw that CD4_C04 cells with Th17 and Th1 phenotypes and Macro_C01 cells with a microglia phenotype, were enriched in the CSF. Lineage tracking analysis of monocyte populations revealed myeloid cell populations, as well as subsets of CD4 and CD8 T-cell populations with distinct effector functions. Importantly, we discovered that complement-activated microglial Macro_C01 cells are associated with a neuroinflammatory response that leads to persistent meningitis. Consistently, we saw an increase in complement protein (C1Q), inflammatory markers (CRP) and inflammatory factor (TNF-α and IL-6) in CSF cells but not blood. Finally, we inferred that Macro_C01 cells recruit CD4_C04 cells through CXCL16/CXCR6. Discussion: We proposed that the microglial Macro_C01 subset activates complement and interacts with the CD4_C04 cell subset to amplify inflammatory signals, which could potentially contribute to augment inflammatory signals, resulting in hyperinflammation and an immune response elicited by Mtb-infected tissues.


Subject(s)
Microglia , Single-Cell Analysis , Transcriptome , Tuberculosis, Meningeal , Humans , Tuberculosis, Meningeal/immunology , Microglia/immunology , Microglia/metabolism , Child , Male , Female , Child, Preschool , Cytokines/metabolism , Complement Activation/immunology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Gene Expression Profiling , Mycobacterium tuberculosis/immunology
5.
Sci Rep ; 14(1): 10375, 2024 05 06.
Article in English | MEDLINE | ID: mdl-38710737

ABSTRACT

Tuberculosis (TB) a disease caused by Mycobacterium tuberculosis (Mtb) poses a significant threat to human life, and current BCG vaccinations only provide sporadic protection, therefore there is a need for developing efficient vaccines. Numerous immunoinformatic methods have been utilized previously, here for the first time a deep learning framework based on Deconvolutional Neural Networks (DCNN) and Bidirectional Long Short-Term Memory (DCNN-BiLSTM) was used to predict Mtb Multiepitope vaccine (MtbMEV) subunits against six Mtb H37Rv proteins. The trained model was used to design MEV within a few minutes against TB better than other machine learning models with 99.5% accuracy. The MEV has good antigenicity, and physiochemical properties, and is thermostable, soluble, and hydrophilic. The vaccine's BLAST search ruled out the possibility of autoimmune reactions. The secondary structure analysis revealed 87% coil, 10% beta, and 2% alpha helix, while the tertiary structure was highly upgraded after refinement. Molecular docking with TLR3 and TLR4 receptors showed good binding, indicating high immune reactions. Immune response simulation confirmed the generation of innate and adaptive responses. In-silico cloning revealed the vaccine is highly expressed in E. coli. The results can be further experimentally verified using various analyses to establish a candidate vaccine for future clinical trials.


Subject(s)
Mycobacterium tuberculosis , Neural Networks, Computer , Tuberculosis Vaccines , Tuberculosis Vaccines/immunology , Mycobacterium tuberculosis/immunology , Humans , Molecular Docking Simulation , Vaccine Development/methods , Epitopes/immunology , Tuberculosis/prevention & control , Tuberculosis/immunology , Antigens, Bacterial/immunology , Antigens, Bacterial/chemistry
6.
Cell Mol Biol Lett ; 29(1): 70, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38741147

ABSTRACT

BACKGROUND: Mycobacterium tuberculosis heat-resistant antigen (Mtb-HAg) is a peptide antigen released from the mycobacterial cytoplasm into the supernatant of Mycobacterium tuberculosis (Mtb) attenuated H37Ra strain after autoclaving at 121 °C for 20 min. Mtb-HAg can specifically induce γδ T-cell proliferation in vitro. However, the exact composition of Mtb-HAg and the protein antigens that are responsible for its function are currently unknown. METHODS: Mtb-HAg extracted from the Mtb H37Ra strain was subjected to LC‒MS mass spectrometry. Twelve of the identified protein fractions were recombinantly expressed in Escherichia coli by genetic engineering technology using pET-28a as a plasmid and purified by Ni-NTA agarose resin to stimulate peripheral blood mononuclear cells (PBMCs) from different healthy individuals. The proliferation of γδ T cells and major γδ T-cell subset types as well as the production of TNF-α and IFN-γ were determined by flow cytometry. Their proliferating γδ T cells were isolated and purified using MACS separation columns, and Mtb H37Ra-infected THP-1 was co-cultured with isolated and purified γδ T cells to quantify Mycobacterium viability by counting CFUs. RESULTS: In this study, Mtb-HAg from the attenuated Mtb H37Ra strain was analysed by LC‒MS mass spectrometry, and a total of 564 proteins were identified. Analysis of the identified protein fractions revealed that the major protein components included heat shock proteins and Mtb-specific antigenic proteins. Recombinant expression of 10 of these proteins in by Escherichia coli genetic engineering technology was used to successfully stimulate PBMCs from different healthy individuals, but 2 of the proteins, EsxJ and EsxA, were not expressed. Flow cytometry results showed that, compared with the IL-2 control, HspX, GroEL1, and GroES specifically induced γδ T-cell expansion, with Vγ2δ2 T cells as the main subset, and the secretion of the antimicrobial cytokines TNF-α and IFN-γ. In contrast, HtpG, DnaK, GroEL2, HbhA, Mpt63, EsxB, and EsxN were unable to promote γδ T-cell proliferation and the secretion of TNF-α and IFN-γ. None of the above recombinant proteins were able to induce the secretion of TNF-α and IFN-γ by αß T cells. In addition, TNF-α, IFN-γ-producing γδ T cells inhibit the growth of intracellular Mtb. CONCLUSION: Activated γδ T cells induced by Mtb-HAg components HspX, GroES, GroEL1 to produce TNF-α, IFN-γ modulate macrophages to inhibit intracellular Mtb growth. These data lay the foundation for subsequent studies on the mechanism by which Mtb-HAg induces γδ T-cell proliferation in vitro, as well as the development of preventive and therapeutic vaccines and rapid diagnostic reagents.


Subject(s)
Antigens, Bacterial , Cell Proliferation , Mycobacterium tuberculosis , T-Lymphocytes , Humans , Antigens, Bacterial/immunology , Antigens, Bacterial/metabolism , Antigens, Bacterial/genetics , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/genetics , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Interferon-gamma/metabolism , Interferon-gamma/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, Antigen, T-Cell, gamma-delta/immunology , Receptors, Antigen, T-Cell, gamma-delta/genetics , Tumor Necrosis Factor-alpha/metabolism , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/immunology , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/immunology
7.
Cell Mol Life Sci ; 81(1): 203, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38698289

ABSTRACT

Nitrogen metabolism of M. tuberculosis is critical for its survival in infected host cells. M. tuberculosis has evolved sophisticated strategies to switch between de novo synthesis and uptake of various amino acids from host cells for metabolic demands. Pyridoxal phosphate-dependent histidinol phosphate aminotransferase-HspAT enzyme is critically required for histidine biosynthesis. HspAT is involved in metabolic synthesis of histidine, phenylalanine, tyrosine, tryptophan, and novobiocin. We showed that M. tuberculosis Rv2231c is a conserved enzyme with HspAT activity. Rv2231c is a monomeric globular protein that contains α-helices and ß-sheets. It is a secretory and cell wall-localized protein that regulates critical pathogenic attributes. Rv2231c enhances the survival and virulence of recombinant M. smegmatis in infected RAW264.7 macrophage cells. Rv2231c is recognized by the TLR4 innate immune receptor and modulates the host immune response by suppressing the secretion of the antibacterial pro-inflammatory cytokines TNF, IL-12, and IL-6. It also inhibits the expression of co-stimulatory molecules CD80 and CD86 along with antigen presenting molecule MHC-I on macrophage and suppresses reactive nitrogen species formation, thereby promoting M2 macrophage polarization. Recombinant M. smegmatis expressing Rv2231c inhibited apoptosis in macrophages, promoting efficient bacterial survival and proliferation, thereby increasing virulence. Our results indicate that Rv2231c is a moonlighting protein that regulates multiple functions of M. tuberculosis pathophysiology to increase its virulence. These mechanistic insights can be used to better understand the pathogenesis of M. tuberculosis and to design strategies for tuberculosis mitigation.


Subject(s)
Macrophages , Mycobacterium tuberculosis , Transaminases , Mice , Mycobacterium tuberculosis/pathogenicity , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/metabolism , Animals , RAW 264.7 Cells , Virulence , Macrophages/microbiology , Macrophages/immunology , Macrophages/metabolism , Transaminases/metabolism , Transaminases/genetics , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Mycobacterium smegmatis/pathogenicity , Mycobacterium smegmatis/metabolism , Mycobacterium smegmatis/genetics , Mycobacterium smegmatis/enzymology , Cytokines/metabolism , Toll-Like Receptor 4/metabolism , Humans , Immunity, Innate , Host-Pathogen Interactions/immunology , Tuberculosis/immunology , Tuberculosis/microbiology
8.
BMC Infect Dis ; 24(1): 481, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38730343

ABSTRACT

BACKGROUND: Tuberculosis (TB) poses a major public health challenge, particularly in children. A substantial proportion of children with TB disease remain undetected and unconfirmed. Therefore, there is an urgent need for a highly sensitive point-of-care test. This study aims to assess the performance of serological assays based on various antigen targets and antibody properties in distinguishing children (0-18 years) with TB disease (1) from healthy TB-exposed children, (2) children with non-TB lower respiratory tract infections, and (3) from children with TB infection. METHODS: The study will use biobanked plasma samples collected from three prospective multicentric diagnostic observational studies: the Childhood TB in Switzerland (CITRUS) study, the Pediatric TB Research Network in Spain (pTBred), and the Procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infections in children and adolescents (ProPAED) study. Included are children diagnosed with TB disease or infection, healthy TB-exposed children, and sick children with non-TB lower respiratory tract infection. Serological multiplex assays will be performed to identify M. tuberculosis antigen-specific antibody features, including isotypes, subclasses, Fc receptor (FcR) binding, and IgG glycosylation. DISCUSSION: The findings from this study will help to design serological assays for diagnosing TB disease in children. Importantly, those assays could easily be developed as low-cost point-of-care tests, thereby offering a potential solution for resource-constrained settings. GOV IDENTIFIER: NCT03044509.


Subject(s)
Serologic Tests , Tuberculosis , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Antibodies, Bacterial/blood , Antigens, Bacterial/immunology , Mycobacterium tuberculosis/immunology , Point-of-Care Testing , Prospective Studies , Serologic Tests/methods , Spain , Switzerland , Tuberculosis/diagnosis , Tuberculosis/blood
10.
Commun Biol ; 7(1): 584, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38755239

ABSTRACT

B cells are important in tuberculosis (TB) immunity, but their role in the human lung is understudied. Here, we characterize B cells from lung tissue and matched blood of patients with TB and found they are decreased in the blood and increased in the lungs, consistent with recruitment to infected tissue, where they are located in granuloma associated lymphoid tissue. Flow cytometry and transcriptomics identify multiple B cell populations in the lung, including those associated with tissue resident memory, germinal centers, antibody secretion, proinflammatory atypical B cells, and regulatory B cells, some of which are expanded in TB disease. Additionally, TB lungs contain high levels of Mtb-reactive antibodies, specifically IgM, which promotes Mtb phagocytosis. Overall, these data reveal the presence of functionally diverse B cell subsets in the lungs of patients with TB and suggest several potential localized roles that may represent a target for interventions to promote immunity or mitigate immunopathology.


Subject(s)
B-Lymphocytes , Humans , B-Lymphocytes/immunology , Lung/immunology , Lung/microbiology , Lung/pathology , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/physiology , Phenotype , Tuberculosis/immunology , Tuberculosis/microbiology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/pathology , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/genetics , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Male , Female , Adult
11.
PLoS One ; 19(5): e0291215, 2024.
Article in English | MEDLINE | ID: mdl-38787869

ABSTRACT

Tuberculosis (TB) transmission and prevalence are dynamic over time, and heterogeneous within populations. Public health programmes therefore require up-to-date, accurate epidemiological data to appropriately allocate resources, target interventions, and track progress towards End TB goals. Current methods of TB surveillance often rely on case notifications, which are biased by access to healthcare, and TB disease prevalence surveys, which are highly resource-intensive, requiring many tens of thousands of people to be tested to identify high-risk groups or capture trends. Surveys of "latent TB infection", or immunoreactivity to Mycobacterium tuberculosis (Mtb), using tests such as interferon-gamma release assays (IGRAs) could provide a way to identify TB transmission hotspots, supplementing information from disease notifications, and with greater spatial and temporal resolution than is possible to achieve in disease prevalence surveys. This cross-sectional survey will investigate the prevalence of Mtb immunoreactivity amongst young children, adolescents and adults in Blantyre, Malawi, a high HIV-prevalence city in southern Africa. Through this study we will estimate the annual risk of TB infection (ARTI) in Blantyre and explore individual- and area-level risk factors for infection, as well as investigating geospatial heterogeneity of Mtb infection (and its determinants), and comparing these to the distribution of TB disease case-notifications. We will also evaluate novel diagnostics for Mtb infection (QIAreach QFT) and sampling methodologies (convenience sampling in healthcare settings and community sampling based on satellite imagery), which may increase the feasibility of measuring Mtb infection at large scale. The overall aim is to provide high-resolution epidemiological data and provide new insights into methodologies which may be used by TB programmes globally.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Malawi/epidemiology , Humans , Cross-Sectional Studies , Mycobacterium tuberculosis/immunology , Adult , Adolescent , Tuberculosis/epidemiology , Tuberculosis/diagnosis , Prevalence , Child , Female , Male , Interferon-gamma Release Tests/methods , Young Adult , Risk Factors
12.
Biochem Biophys Res Commun ; 717: 150040, 2024 Jul 12.
Article in English | MEDLINE | ID: mdl-38718566

ABSTRACT

Mtb12, a small protein secreted by Mycobacterium tuberculosis, is known to elicit immune responses in individuals infected with the pathogen. It serves as an antigen recognized by the host's immune system. Due to its immunogenic properties and pivotal role in tuberculosis (TB) pathogenesis, Mtb12 is considered a promising candidate for TB diagnosis and vaccine development. However, the structural and functional properties of Mtb12 are largely unexplored, representing a significant gap in our understanding of M. tuberculosis biology. In this study, we present the first structure of Mtb12, which features a unique tertiary configuration consisting of four beta strands and four alpha helices. Structural analysis reveals that Mtb12 has a surface adorned with a negatively charged pocket adjacent to a central cavity. The features of these structural elements and their potential effects on the function of Mtb12 warrant further exploration. These findings offer valuable insights for vaccine design and the development of diagnostic tools.


Subject(s)
Antigens, Bacterial , Bacterial Proteins , Mycobacterium tuberculosis , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/metabolism , Antigens, Bacterial/chemistry , Antigens, Bacterial/immunology , Bacterial Proteins/chemistry , Bacterial Proteins/immunology , Bacterial Proteins/metabolism , Models, Molecular , Molecular Weight , Amino Acid Sequence , Protein Conformation , Humans
13.
Zhonghua Jie He He Hu Xi Za Zhi ; 47(5): 485-489, 2024 May 12.
Article in Chinese | MEDLINE | ID: mdl-38706074

ABSTRACT

Programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2, expressed on a variety of immune cells, play multiple regulatory roles in the host immune response to Mycobacterium tuberculosis infection. In this study, we reviewed that the regulatory roles of PD-1/PD-L1, PD-L2 signaling in the host adaptive immune response, such as the innate response of macrophages, and the interaction between T cells and macrophages in response to MTB. In addition, during MTB infection, PD-1/PD-L1, PD-L2 signaling is also involved in the host inflammatory response, as well as the potential roles of PD-1/PD-L1, PD-L2 in the diagnosis and treatment of tuberculosis.


Subject(s)
B7-H1 Antigen , Macrophages , Mycobacterium tuberculosis , Programmed Cell Death 1 Ligand 2 Protein , Programmed Cell Death 1 Receptor , Signal Transduction , Tuberculosis , Humans , Tuberculosis/immunology , Tuberculosis/microbiology , B7-H1 Antigen/metabolism , B7-H1 Antigen/immunology , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Ligand 2 Protein/metabolism , Mycobacterium tuberculosis/immunology , Macrophages/immunology , Macrophages/metabolism , Immunity, Innate , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Animals , Adaptive Immunity
14.
Zhonghua Jie He He Hu Xi Za Zhi ; 47(5): 475-480, 2024 May 12.
Article in Chinese | MEDLINE | ID: mdl-38706072

ABSTRACT

Tuberculosis (TB) is the leading cause of death among people living with HIV/AIDS (PLWHA), posing a significant disease burden. Early TB screening in PLWHA is a key intervention to reduce transmission and control disease progression. ​Lipoarabinomannan (LAM) is a glycolipid of Mycobacterium tuberculosis (MTB) that can be detected in the urine of tuberculosis patients. LAM is useful for the rapid and accurate diagnosis of tuberculosis. This article reviews LAM and its application and limitations in the diagnosis of PLWHA, hoping to provide a reference for the diagnosis of tuberculosis in PLWHA.


Subject(s)
Lipopolysaccharides , Tuberculosis , Humans , Lipopolysaccharides/urine , Tuberculosis/diagnosis , Mycobacterium tuberculosis/isolation & purification , Mycobacterium tuberculosis/immunology , HIV Infections/complications , HIV Infections/diagnosis , Acquired Immunodeficiency Syndrome/complications , Antigens, Bacterial/urine
15.
Curr Microbiol ; 81(7): 197, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38816607

ABSTRACT

Identifying and evaluating potential vaccine candidates has become one of the main objectives to combat tuberculosis. Among them, mannosylated Apa antigen from Mycobacterium tuberculosis and the non-mannosylated protein expressed in Escherichia coli, have been studied. Although both proteins can induce a protective response in mice, it has been considered that native protein can be dispensed. In this work, we study the protective response induced by Apa expressed in E. coli and in Streptomyces lividans. The latter, like native is secreted as a double band of 45/47 kDa, however, only its 47 kDa band is mannosylated. Both antigens and BCG were intranasal administrated in mice, and animals were then challenged by aerosol with M. tuberculosis H37Rv. The results showed that both, Apa from S. lividans and E. coli conferred statistically significantly protection to animals compared to controls. The cytokine immune response was studied by an immunoassay after animals' immunization, revealing that Apa from S. lividans induced a statistically significant proliferation of T cell, as well as the expression of IFN-γ, IL-1ß, IL-17 and IL-10. In contrast, non-proliferation was obtained with non-mannosylated protein, but induction of IL-12 and IL-17 was observed. Together, these results demonstrate that both proteins were able to modulate a specific immune response against M. tuberculosis, that could be driven by different mechanisms possibly associated with the presence or not of mannosylation. Furthermore, stimulation of cells from BCG-vaccinated animals with the proteins could be an important tool, to help define the use of a given subunit-vaccine after BCG vaccination.


Subject(s)
Administration, Intranasal , Cytokines , Mycobacterium tuberculosis , Streptomyces lividans , Tuberculosis , Animals , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/genetics , Mice , Cytokines/metabolism , Tuberculosis/prevention & control , Tuberculosis/immunology , Streptomyces lividans/genetics , Streptomyces lividans/immunology , Aerosols , Recombinant Proteins/immunology , Recombinant Proteins/genetics , Recombinant Proteins/administration & dosage , Bacterial Proteins/genetics , Bacterial Proteins/immunology , Bacterial Proteins/administration & dosage , Tuberculosis Vaccines/immunology , Tuberculosis Vaccines/administration & dosage , Tuberculosis Vaccines/genetics , Escherichia coli/genetics , Escherichia coli/metabolism , Female , Mice, Inbred BALB C , Antigens, Bacterial/immunology , Antigens, Bacterial/genetics , Antigens, Bacterial/administration & dosage
16.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 40(4): 367-372, 2024 Apr.
Article in Chinese | MEDLINE | ID: mdl-38710520

ABSTRACT

Toll-like receptor 2 (TLR2) is a pattern recognition receptor expressed on the surface of leukocytes. Various ligands can activate or inhibit TLR2, therefore regulating the inflammation and apoptosis of immune cells. Mycobacterium tuberculosis (MTB) typically parasitizes macrophages. Further, after infecting the body, MTB can interact with TLR2 on the surface of various immune cells, including macrophages, leading to the release of cytokines that can affect the state and proliferation of MTB in the body. Additional research is needed to understand the polymorphism of TLR2 at the molecular level. Current studies indicate that the majority of TLR2 polymorphisms are not associated with susceptibility to MTB infection. This review provides an overview of the researches related to TLR2 and its ligands, the immune regulation activities of TLR2 following MTB infection, and the association of TLR2 polymorphism with susceptibility to MTB.


Subject(s)
Mycobacterium tuberculosis , Toll-Like Receptor 2 , Tuberculosis , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 2/immunology , Humans , Tuberculosis/immunology , Tuberculosis/microbiology , Tuberculosis/genetics , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/physiology , Polymorphism, Genetic , Animals , Genetic Predisposition to Disease
17.
JCI Insight ; 9(9)2024 May 08.
Article in English | MEDLINE | ID: mdl-38716731

ABSTRACT

T cells are required for protective immunity against Mycobacterium tuberculosis. We recently described a cohort of Ugandan household contacts of tuberculosis cases who appear to "resist" M. tuberculosis infection (resisters; RSTRs) and showed that these individuals harbor IFN-γ-independent T cell responses to M. tuberculosis-specific peptide antigens. However, T cells also recognize nonprotein antigens via antigen-presenting systems that are independent of genetic background, known as donor-unrestricted T cells (DURTs). We used tetramer staining and flow cytometry to characterize the association between DURTs and "resistance" to M. tuberculosis infection. Peripheral blood frequencies of most DURT subsets were comparable between RSTRs and latently infected controls (LTBIs). However, we observed a 1.65-fold increase in frequency of MR1-restricted T (MR1T) cells among RSTRs in comparison with LTBIs. Single-cell RNA sequencing of 18,251 MR1T cells sorted from 8 donors revealed 5,150 clonotypes that expressed a common transcriptional program, the majority of which were private. Sequencing of the T cell receptor α/T cell receptor δ (TCRα/δ) repertoire revealed several DURT clonotypes were expanded among RSTRs, including 2 MR1T clonotypes that recognized mycobacteria-infected cells in a TCR-dependent manner. Overall, our data reveal unexpected donor-specific diversity in the TCR repertoire of human MR1T cells as well as associations between mycobacteria-reactive MR1T clonotypes and resistance to M. tuberculosis infection.


Subject(s)
Mycobacterium tuberculosis , Humans , Mycobacterium tuberculosis/immunology , Uganda , Adult , Male , Minor Histocompatibility Antigens/immunology , Minor Histocompatibility Antigens/genetics , Female , Tuberculosis/immunology , Tuberculosis/microbiology , T-Lymphocytes/immunology , Latent Tuberculosis/immunology , Latent Tuberculosis/microbiology , Clone Cells/immunology , Disease Resistance/immunology , Disease Resistance/genetics , Young Adult , Histocompatibility Antigens Class I
18.
Proc Natl Acad Sci U S A ; 121(19): e2318003121, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38691588

ABSTRACT

Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the inhA gene of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial inhA as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.


Subject(s)
Histocompatibility Antigens Class I , Mycobacterium tuberculosis , Receptors, Antigen, T-Cell , T-Lymphocytes , Mycobacterium tuberculosis/immunology , Humans , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , T-Lymphocytes/immunology , HLA-E Antigens , Bacterial Proteins/immunology , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Tuberculosis/immunology
19.
Front Immunol ; 15: 1347045, 2024.
Article in English | MEDLINE | ID: mdl-38756781

ABSTRACT

It is essential to understand the interactions and relationships between Mycobacterium tuberculosis (Mtb) and macrophages during the infection in order to design host-directed, immunomodulation-dependent therapeutics to control Mtb. We had reported previously that ornithine acetyltransferase (MtArgJ), a crucial enzyme of the arginine biosynthesis pathway of Mtb, is allosterically inhibited by pranlukast (PRK), which significantly reduces bacterial growth. The present investigation is centered on the immunomodulation in the host by PRK particularly the activation of the host's immune response to counteract bacterial survival and pathogenicity. Here, we show that PRK decreased the bacterial burden in the lungs by upregulating the population of pro-inflammatory interstitial macrophages (IMs) and reducing the population of Mtb susceptible alveolar macrophages (AMs), dendritic cells (DCs), and monocytes (MO). Additionally, we deduce that PRK causes the host macrophages to change their metabolic pathway from fatty acid metabolism to glycolytic metabolism around the log phage of bacterial multiplication. Further, we report that PRK reduced tissue injury by downregulating the Ly6C-positive population of monocytes. Interestingly, PRK treatment improved tissue repair and inflammation resolution by increasing the populations of arginase 1 (Arg-1) and Ym1+Ym2 (chitinase 3-like 3) positive macrophages. In summary, our study found that PRK is useful not only for reducing the tubercular burden but also for promoting the healing of the diseased tissue.


Subject(s)
Chromones , Disease Models, Animal , Mycobacterium tuberculosis , Animals , Mycobacterium tuberculosis/immunology , Mice , Chromones/pharmacology , Chromones/therapeutic use , Antitubercular Agents/therapeutic use , Antitubercular Agents/pharmacology , Tuberculosis/immunology , Tuberculosis/microbiology , Tuberculosis/drug therapy , Macrophages/immunology , Macrophages/microbiology , Macrophages/metabolism , Mice, Inbred C57BL , Female , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/drug therapy , Lung/microbiology , Lung/immunology , Lung/pathology
20.
Discov Med ; 36(184): 1002-1011, 2024 May.
Article in English | MEDLINE | ID: mdl-38798259

ABSTRACT

BACKGROUND: Tuberculosis (TB) is still the main cause of mortality due to a single transfectant, Mycobacterium tuberculosis (MTB). Latent tuberculosis infection (LTBI) is a condition characterized by the presence of tuberculosis (TB) that is not clinically apparent but nonetheless shows a sustained response to MTB. Presently, tuberculin skin test (TST) and interferon gamma (IFN-γ) release assays (IGRAs) are mainly used to detect LTBI via cell-mediated immunity of T-cells. For people with end-stage renal disease (ESRD), the diagnosis of patients infected with MTB is difficult because of T-cell dysfunction. To get more accurate diagnosis results of LTBI, it must compensate for the deficiency of IGRA tests. METHODS: Sixty-seven hemodialysis (HD) patients and 96 non-HD patients were enrolled in this study and the study population is continuously included. IFN-γ levels were measured by the QuantiFERON-TB Gold In-Tube (QFT-GIT) test. Kidney function indicators, blood urea nitrogen (BUN), serum creatinine (Cr), and estimated glomerular filtration rate (eGFR) were used to compensate for the declined IFN-γ levels in the IGRA test. RESULTS: In individuals who were previously undetected, the results of compensation with serum Cr increased by 10.81%, allowing for about 28% more detection, and compensation with eGFR increased by 5.41%, allowing for approximately 14% more detectable potential among them and employing both of them could enhance the prior shortcomings of IGRA tests. when both are used, the maximum compensation results show a sensitivity increase rate of 8.81%, and approximately 23% of patients who were previously undetectable may be found. CONCLUSION: Therefore, the renal function markers which are routine tests for HD patients to compensate for the deficiency of IGRA tests could increase the accuracy of LTBI diagnosis.


Subject(s)
Interferon-gamma Release Tests , Kidney Failure, Chronic , Latent Tuberculosis , Renal Dialysis , Humans , Latent Tuberculosis/diagnosis , Latent Tuberculosis/immunology , Latent Tuberculosis/blood , Male , Female , Middle Aged , Renal Dialysis/adverse effects , Interferon-gamma Release Tests/methods , Kidney Failure, Chronic/therapy , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/immunology , Aged , Interferon-gamma/blood , Adult , False Negative Reactions , Glomerular Filtration Rate , Creatinine/blood , Mycobacterium tuberculosis/immunology , Tuberculin Test/methods , Blood Urea Nitrogen
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