ABSTRACT
Evidence has increasingly shown that the lungs are a major site of immune regulation. A robust and highly regulated immune response in the lung protects the host from pathogen infection, whereas an inefficient or deleterious response can lead to various pulmonary diseases. Many cell types, such as epithelial cells, dendritic cells, macrophages, neutrophils, eosinophils, and B and T lymphocytes, contribute to lung immunity. This review focuses on the recent advances in understanding how T lymphocytes mediate pulmonary host defenses against bacterial, viral, and fungal pathogens.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Lung/immunology , Lung/pathology , Tuberculosis, Pulmonary/immunology , Animals , CD4-Positive T-Lymphocytes/metabolism , Host-Pathogen Interactions/immunology , Humans , Lung/microbiology , Lymph Nodes/immunology , Lymph Nodes/microbiology , Lymph Nodes/pathology , Mycobacterium tuberculosis/immunology , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathologyABSTRACT
Mycobacterium tuberculosis infects two billion people across the globe, and results in 8-9 million new tuberculosis (TB) cases and 1-1.5 million deaths each year. Most patients have no known genetic basis that predisposes them to disease. Here, we investigate the complex genetic basis of pulmonary TB by modelling human genetic diversity with the Diversity Outbred mouse population. When infected with M. tuberculosis, one-third develop early onset, rapidly progressive, necrotizing granulomas and succumb within 60 days. The remaining develop non-necrotizing granulomas and survive longer than 60 days. Genetic mapping using immune and inflammatory mediators; and clinical, microbiological, and granuloma correlates of disease identified five new loci on mouse chromosomes 1, 2, 4, 16; and three known loci on chromosomes 3 and 17. Further, multiple positively correlated traits shared loci on chromosomes 1, 16, and 17 and had similar patterns of allele effects, suggesting these loci contain critical genetic regulators of inflammatory responses to M. tuberculosis. To narrow the list of candidate genes, we used a machine learning strategy that integrated gene expression signatures from lungs of M. tuberculosis-infected Diversity Outbred mice with gene interaction networks to generate scores representing functional relationships. The scores were used to rank candidates for each mapped trait, resulting in 11 candidate genes: Ncf2, Fam20b, S100a8, S100a9, Itgb5, Fstl1, Zbtb20, Ddr1, Ier3, Vegfa, and Zfp318. Although all candidates have roles in infection, inflammation, cell migration, extracellular matrix remodeling, or intracellular signaling, and all contain single nucleotide polymorphisms (SNPs), SNPs in only four genes (S100a8, Itgb5, Fstl1, Zfp318) are predicted to have deleterious effects on protein functions. We performed methodological and candidate validations to (i) assess biological relevance of predicted allele effects by showing that Diversity Outbred mice carrying PWK/PhJ alleles at the H-2 locus on chromosome 17 QTL have shorter survival; (ii) confirm accuracy of predicted allele effects by quantifying S100A8 protein in inbred founder strains; and (iii) infection of C57BL/6 mice deficient for the S100a8 gene. Overall, this body of work demonstrates that systems genetics using Diversity Outbred mice can identify new (and known) QTLs and functionally relevant gene candidates that may be major regulators of complex host-pathogens interactions contributing to granuloma necrosis and acute inflammation in pulmonary TB.
Subject(s)
Mycobacterium tuberculosis , Animals , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/pathogenicity , Mice , Quantitative Trait Loci , Tuberculosis, Pulmonary/genetics , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology , Disease Models, Animal , Animals, Outbred Strains , Humans , Chromosome Mapping , Systems BiologyABSTRACT
Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after the development of T cell responses, CD11clo monocyte-derived cells harbor more live Mtb than alveolar macrophages (AM), neutrophils, and CD11chi monocyte-derived cells. Transcriptomic and functional studies revealed that the lysosome pathway is underexpressed in this highly permissive subset, characterized by less lysosome content, acidification, and proteolytic activity than AM, along with less nuclear TFEB, a regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in CD11clo monocyte-derived cells but promotes recruitment of monocytes that develop into permissive lung cells, mediated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome functions of macrophages in vitro and in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor lung cells for persistence and targeting lysosome biogenesis is a potential host-directed therapy for tuberculosis.
Subject(s)
Lysosomes , Macrophages, Alveolar , Monocytes , Mycobacterium tuberculosis , Lysosomes/metabolism , Lysosomes/microbiology , Animals , Monocytes/metabolism , Monocytes/microbiology , Mice , Macrophages, Alveolar/microbiology , Macrophages, Alveolar/metabolism , Lung/microbiology , Lung/metabolism , Mice, Inbred C57BL , Chronic Disease , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/metabolism , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/pathology , Humans , Tuberculosis/microbiology , Tuberculosis/immunology , Tuberculosis/metabolism , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolismABSTRACT
Granulomas are an important hallmark of Mycobacterium tuberculosis infection. They are organized and dynamic structures created when immune cells assemble around the sites of infection in the lungs that locally restrict M. tuberculosis growth and the host's inflammatory responses. The cellular architecture of granulomas is traditionally studied by immunofluorescence labeling of surface markers on the host cells. However, very few Abs are available for model animals used in tuberculosis research, such as nonhuman primates and rabbits, and secreted immunological markers such as cytokines cannot be imaged in situ using Abs. Furthermore, traditional phenotypic surface markers do not provide sufficient resolution for the detection of the many subtypes and differentiation states of immune cells. Using single-molecule fluorescence in situ hybridization (smFISH) and its derivatives, amplified smFISH and iterative smFISH, we developed a platform for imaging mRNAs encoding immune markers in rabbit and macaque tuberculosis granulomas. Multiplexed imaging for several mRNA and protein markers was followed by quantitative measurement of the expression of these markers in single cells. An analysis of the combinatorial expressions of these markers allowed us to classify the cells into several subtypes, and to chart their densities within granulomas. For one mRNA target, hypoxia-inducible factor-1α, we imaged its mRNA and protein in the same cells, demonstrating the specificity of the probes. This method paves the way for defining granular differentiation states and cell subtypes from transcriptomic data, identifying key mRNA markers for these cell subtypes, and then locating the cells in the spatial context of granulomas.
Subject(s)
Granuloma , In Situ Hybridization, Fluorescence , Mycobacterium tuberculosis , Animals , Rabbits , In Situ Hybridization, Fluorescence/methods , Mycobacterium tuberculosis/immunology , Granuloma/immunology , Granuloma/microbiology , Granuloma/pathology , Tuberculosis/immunology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/pathology , Biomarkers , Lung/immunology , Lung/pathology , Lung/microbiology , Disease Models, AnimalABSTRACT
Because most humans resist Mycobacterium tuberculosis infection, there is a paucity of lung samples to study. To address this gap, we infected Diversity Outbred mice with M. tuberculosis and studied the lungs of mice in different disease states. After a low-dose aerosol infection, progressors succumbed to acute, inflammatory lung disease within 60 days, while controllers maintained asymptomatic infection for at least 60 days, and then developed chronic pulmonary tuberculosis (TB) lasting months to more than 1 year. Here, we identified features of asymptomatic M. tuberculosis infection by applying computational and statistical approaches to multimodal data sets. Cytokines and anti-M. tuberculosis cell wall antibodies discriminated progressors vs controllers with chronic pulmonary TB but could not classify mice with asymptomatic infection. However, a novel deep-learning neural network trained on lung granuloma images was able to accurately classify asymptomatically infected lungs vs acute pulmonary TB in progressors vs chronic pulmonary TB in controllers, and discrimination was based on perivascular and peribronchiolar lymphocytes. Because the discriminatory lesion was rich in lymphocytes and CD4 T cell-mediated immunity is required for resistance, we expected CD4 T-cell genes would be elevated in asymptomatic infection. However, the significantly different, highly expressed genes were from B-cell pathways (e.g., Bank1, Cd19, Cd79, Fcmr, Ms4a1, Pax5, and H2-Ob), and CD20+ B cells were enriched in the perivascular and peribronchiolar regions of mice with asymptomatic M. tuberculosis infection. Together, these results indicate that genetically controlled B-cell responses are important for establishing asymptomatic M. tuberculosis lung infection.
Subject(s)
B-Lymphocytes , Lung , Mycobacterium tuberculosis , Tuberculosis, Pulmonary , Animals , Mice , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology , Mycobacterium tuberculosis/immunology , B-Lymphocytes/immunology , Lung/microbiology , Lung/pathology , Lung/immunology , Granuloma/microbiology , Granuloma/immunology , Granuloma/pathology , Lymphoid Tissue/immunology , Lymphoid Tissue/microbiology , Lymphoid Tissue/pathology , Disease Models, Animal , Female , Asymptomatic Infections , Cytokines/metabolism , Cytokines/geneticsABSTRACT
Host immune response is key for protection in tuberculosis, but the causative agent, Mycobacterium (M.) tuberculosis, manages to survive despite immune surveillance. Key mechanisms of immune protection have been identified, but the role of immunopathology in the peripheral blood of tuberculosis patients remains unclear. Tuberculosis immunopathology in the blood is characterised by patterns of immunosuppression and hyperinflammation. These seemingly contradictory findings and the pronounced heterogeneity made it difficult to interpret the results from previous studies and to derive implications of immunopathology. However, novel approaches based on comprehensive data analyses and revitalisation of an ancient plasma milieu in vitro assay connected inflammation with immunosuppressive factors in tuberculosis. Moreover, interrelations between the aberrant plasma milieu and immune cell pathology were observed. This review provides an overview of studies on changes in plasma milieu and discusses recent findings linking plasma factors to T-cell and monocyte/macrophage pathology in pulmonary tuberculosis patients.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Pulmonary , Humans , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/blood , Tuberculosis, Pulmonary/pathology , Mycobacterium tuberculosis/immunology , Inflammation/immunology , Macrophages/immunology , T-Lymphocytes/immunology , Monocytes/immunology , Host-Pathogen Interactions/immunology , AnimalsABSTRACT
BACKGROUND: Microbiological diagnosis of pulmonary tuberculosis (PTB) is hampered by a low pathogen burden, low compliance and unreliable sputum sampling. Although endobronchial ultrasound-guided transbronchoscopic lung biopsy (EBUS-TBLB) has been found to be useful for the assessment of intrapulmonary nodules in adults, few data are available for the clinical diagnosis of pulmonary tuberculosis. Here, we evaluated EBUS-TBLB as a diagnostic procedure in adult patients with radiologically suspected intrapulmonary tuberculous nodules. METHODS: This was a retrospective analysis of patients admitted with pulmonary nodules between January 2022 and January 2023 at Hangzhou Red Cross Hospital. All patients underwent EBUS-TBLB, and lung biopsy samples were obtained during hospitalization. All samples were tested for Mycobacterium tuberculosis using acidâfast smears, Bactec MGIT 960, Xpert MTB/RIF, next-generation sequencing (NGS), and DNA (TBâDNA) and RNA (TBâRNA). The concordance between different diagnostic methods and clinical diagnosis was analysed via kappa concordance analysis. The diagnostic efficacy of different diagnostic methods for PTB was analysed via ROC curve. RESULTS: A total of 107 patients were included in this study. Among them, 86 patients were diagnosed by EBUS-TBLB, and the overall diagnostic rate was 80.37%. In addition, 102 enrolled patients had benign lesions, and only 5 were diagnosed with lung tumours. Univariate analysis revealed that the diagnostic rate of EBUS-TBLB in pulmonary nodules was related to the location of the probe. The consistency analysis and ROC curve analysis revealed that NGS had the highest concordance with the clinical diagnosis results (agreement = 78.50%, κ = 0.558) and had the highest diagnostic efficacy for PTB (AUC = 0.778). In addition, Xpert MTB/RIF + NGS had the highest concordance with the clinical diagnosis results (agreement = 84.11%, κ = 0.667) and had the highest efficacy in the diagnosis of PTB (AUC = 0.826). CONCLUSION: EBUS-TBLB is a sensitive and safe method for the diagnosis of pathological pulmonary nodules. Xpert MTB/RIF combined with NGS had the highest diagnostic efficacy and can be used in the initial diagnosis of PTB.
Subject(s)
Bronchoscopy , Mycobacterium tuberculosis , Tuberculosis, Pulmonary , Humans , Male , Female , Middle Aged , Retrospective Studies , Tuberculosis, Pulmonary/diagnosis , Tuberculosis, Pulmonary/pathology , Tuberculosis, Pulmonary/microbiology , Bronchoscopy/methods , Mycobacterium tuberculosis/isolation & purification , Adult , Aged , Lung/pathology , Lung/microbiology , Lung/diagnostic imaging , Image-Guided Biopsy/methods , Sensitivity and SpecificityABSTRACT
Despite the availability of antibiotic therapy, tuberculosis (TB) is prevailing as a leading killer among human infectious diseases, which highlights the need for better intervention strategies to control TB. Several animal model systems, including mice, guinea pigs, rabbits, and non-human primates have been developed and explored to understand TB pathogenesis. Although each of these models contributes to our current understanding of host-Mycobacterium tuberculosis (Mtb) interactions, none of these models fully recapitulate the pathological spectrum of clinical TB seen in human patients. Recently, humanized mouse models are being developed to improvise the limitations associated with the standard mouse model of TB, including lack of necrotic caseation of granulomas, a pathological hallmark of TB in humans. However, the spatial immunopathology of pulmonary TB in humanized mice is not fully understood. In this study, using a novel humanized mouse model, we evaluated the spatial immunopathology of pulmonary Mtb infection with a low-dose inoculum. Humanized NOD/LtSscidIL2Rγ null mice containing human fetal liver, thymus, and hematopoietic CD34+ cells and treated with human cytokines were aerosol challenged to implant <50 pathogenic Mtb (low dose) in the lungs. At 2 and 4 weeks post infection, the tissue bacterial load, disease pathology, and spatial immunohistology were determined in the lungs, liver, spleen, and adipose tissue using bacteriological, histopathological, and immunohistochemical techniques. The results indicate that implantation of <50 bacteria can establish a progressive disease in the lungs that transmits to other tissues over time. The disease pathology in organs correspondingly increased with the bacterial load. A distinct spatial distribution of T cells, macrophages, and natural killer cells were noted in the lung granulomas. The kinetics of spatial immune cell distribution were consistent with the disease pathology in the lungs. Thus, the novel humanized model recapitulates several key features of human pulmonary TB granulomatous response and can be a useful preclinical tool to evaluate potential anti-TB drugs and vaccines.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Pulmonary , Tuberculosis , Humans , Rabbits , Animals , Mice , Guinea Pigs , Mice, Inbred NOD , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/pathology , Tuberculosis/microbiology , Lung/pathology , Granuloma/pathologyABSTRACT
The World Health Organization (WHO) highlights a greater susceptibility of males to tuberculosis (TB), a vulnerability attributed to sex-specific variations in body fat and dietary factors. Our study delves into the unexplored terrain of how alterations in body fat influence Mycobacterium tuberculosis (Mtb) burden, lung pathology, immune responses, and gene expression, with a focus on sex-specific dynamics. Utilizing a low-dose Mtb-HN878 clinical strain infection model, we employ transgenic FAT-ATTAC mice with modulable body fat to explore the impact of fat loss (via fat ablation) and fat gain (via a medium-fat diet, MFD). Firstly, our investigation unveils that Mtb infection triggers severe pulmonary pathology in males, marked by shifts in metabolic signaling involving heightened lipid hydrolysis and proinflammatory signaling driven by IL-6 and localized pro-inflammatory CD8+ cells. This stands in stark contrast to females on a control regular diet (RD). Secondly, our findings indicate that both fat loss and fat gain in males lead to significantly elevated (1.6-fold (p ≤ 0.01) and 1.7-fold (p ≤ 0.001), respectively) Mtb burden in the lungs compared to females during Mtb infection (where fat loss and gain did not alter Mtb load in the lungs). This upsurge is associated with impaired lung lipid metabolism and intensified mitochondrial oxidative phosphorylation-regulated activity in lung CD8+ cells during Mtb infection. Additionally, our research brings to light that females exhibit a more robust systemic IFNγ (p ≤ 0.001) response than males during Mtb infection. This heightened response may either prevent active disease or contribute to latency in females during Mtb infection. In summary, our comprehensive analysis of the interplay between body fat changes and sex bias in Mtb infection reveals that alterations in body fat critically impact pulmonary pathology in males. Specifically, these changes significantly reduce the levels of pulmonary CD8+ T-cells and increase the Mtb burden in the lungs compared to females. The reduction in CD8+ cells in males is linked to an increase in mitochondrial oxidative phosphorylation and a decrease in TNFα, which are essential for CD8+ cell activation.
Subject(s)
Adipose Tissue , Lung , Mycobacterium tuberculosis , Animals , Female , Male , Mice , Lung/immunology , Lung/microbiology , Lung/pathology , Lung/metabolism , Adipose Tissue/metabolism , Adipose Tissue/immunology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/pathology , Tuberculosis, Pulmonary/microbiology , Mice, Transgenic , Sex Factors , Disease Models, Animal , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Sex Characteristics , Mice, Inbred C57BLABSTRACT
More than a quarter of the world's population is infected with Mycobacterium tuberculosis. However, only about 10% of those infected develop active TB. This indicates a key role for innate immunity in limiting M. tuberculosis replication. Most often, bacteria can regulate the expression of host-specific molecules and weaken host immunity. OBJECTIVE: To use a biological model, in order to determine significant molecular immunohistochemical markers characterizing the virulence of the "Buryat" and "Omsk" subtypes of the M. tuberculosis Beijing genotype in lung tissue. MATERIAL AND METHODS: Lung samples of the C57BL/6 male mice were obtained during experimental infection with M. tuberculosis strains: the reference laboratory strain H37Rv, multidrug-resistant clinical strains 396 (highly lethal and hypervirulent «Buryat¼ genotype Beijing 14717-15) and 6691 (low-lethal and low-virulent "Omsk" genotype Beijing 1071-32) on days 14, 21, 60 and 120. They were studied by histological and immunohistochemical methods. The relative areas of expression of IL-6, IL-12A, iNOS, and TNF-α in the lung tissue of model animals were established. RESULTS: A study of strain 396 showed that both disease progression and damage to lung tissue are associated with a highly reactive immune response and increased synthesis of iNOS and strain characteristics that block the production of TNF-α. On the contrary, for strain 6691 a low reactivity of the immune response was revealed, with statistically significantly lower values of the relative area of expression of NOS and TNF-α during all observation periods (days 14-120). All animals that survived to day 120 showed a similar morphological picture with differences in cytokine levels, indicating a nonlinear relationship between proinflammatory factors and the damage substratum. CONCLUSION: The progression of the disease and damage of lung tissue were associated with a highly reactive immune response and increased synthesis of iNOS, strain properties that block the TNF-α production. Thus, iNOS and TNF-α can act as molecular markers characterizing the virulence of the "Buryat" and "Omsk" subtypes of M. tuberculosis in lung tissue.
Subject(s)
Lung , Mycobacterium tuberculosis , Nitric Oxide Synthase Type II , Animals , Mycobacterium tuberculosis/pathogenicity , Mice , Lung/pathology , Lung/microbiology , Lung/immunology , Lung/metabolism , Male , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Virulence , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/genetics , Tuberculosis, Pulmonary/metabolism , Mice, Inbred C57BL , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/genetics , Interleukin-6/genetics , Interleukin-6/metabolism , Disease Models, Animal , BiomarkersABSTRACT
BACKGROUND: Organizing pneumonia (OP) is a pathologic concept characterized by the formation of granulation tissue from fibroblasts, myofibroblasts, collagen, and fibrotic exudate in the respiratory fine bronchi, alveolar ducts, and alveoli. The clinical imaging of mechanized pneumonia is variable, and histopathological examination is required to clarify the nature of the lesion when imaging is atypical. We report a case of OP with imaging resem-blance to pulmonary tuberculosis and false-positive next-generation sequencing (NGS), which was first misdiag-nosed as pulmonary tuberculosis. METHODS: Appropriate laboratory tests, alveolar lavage fluid NGS, chest CT, bronchoscopy, percutaneous lung puncture, pathology. RESULTS: Chest CT showed a nodular high-density shadow in the lower lobe of the right lung. According to the chest CT, bronchoalveolar lavage was performed in the dorsal segment of the right lower lobe of the lung. NGS of lavage fluid: the sequence number of Moraxella osseae was 1,423; the sequence number of Prevotella melanogaster was 1,129. Based on lung histopathology, fibrous emboli and necrotic material were seen in the alveolar lumen, and the final diagnosis of the OP was confirmed. CONCLUSIONS: It should be noted that physicians should not blindly believe the NGS result report. When the diagnosis is not clear and anti-infection treatment is ineffective, lung tissue should be obtained promptly for pathological examination to obtain pathological evidence to differentiate from misdiagnosed diseases.
Subject(s)
Organizing Pneumonia , Pneumonia , Tuberculosis, Pulmonary , Tuberculosis , Humans , Lung/diagnostic imaging , Lung/pathology , Pneumonia/diagnostic imaging , Tuberculosis/diagnosis , Fibrosis , Tuberculosis, Pulmonary/diagnostic imaging , Tuberculosis, Pulmonary/pathology , High-Throughput Nucleotide SequencingABSTRACT
The ubiquitous gasotransmitter hydrogen sulfide (H2S) has been recognized to play a crucial role in human health. Using cystathionine γ-lyase (CSE)-deficient mice, we demonstrate an unexpected role of H2S in Mycobacterium tuberculosis (Mtb) pathogenesis. We showed that Mtb-infected CSE-/- mice survive longer than WT mice, and support reduced pathology and lower bacterial burdens in the lung, spleen, and liver. Similarly, in vitro Mtb infection of macrophages resulted in reduced colony forming units in CSE-/- cells. Chemical complementation of infected WT and CSE-/- macrophages using the slow H2S releaser GYY3147 and the CSE inhibitor DL-propargylglycine demonstrated that H2S is the effector molecule regulating Mtb survival in macrophages. Furthermore, we demonstrate that CSE promotes an excessive innate immune response, suppresses the adaptive immune response, and reduces circulating IL-1ß, IL-6, TNF-α, and IFN-γ levels in response to Mtb infection. Notably, Mtb infected CSE-/- macrophages show increased flux through glycolysis and the pentose phosphate pathway, thereby establishing a critical link between H2S and central metabolism. Our data suggest that excessive H2S produced by the infected WT mice reduce HIF-1α levels, thereby suppressing glycolysis and production of IL-1ß, IL-6, and IL-12, and increasing bacterial burden. Clinical relevance was demonstrated by the spatial distribution of H2S-producing enzymes in human necrotic, nonnecrotic, and cavitary pulmonary tuberculosis (TB) lesions. In summary, CSE exacerbates TB pathogenesis by altering immunometabolism in mice and inhibiting CSE or modulating glycolysis are potential targets for host-directed TB control.
Subject(s)
Carbon/metabolism , Cystathionine gamma-Lyase/physiology , Hydrogen Sulfide/toxicity , Mycobacterium tuberculosis/immunology , Tuberculosis, Pulmonary/etiology , Alkynes/pharmacology , Animals , Cystathionine gamma-Lyase/antagonists & inhibitors , Cytokines/metabolism , Enzyme Inhibitors/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Glycolysis , Hydrogen Sulfide/metabolism , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/metabolism , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis/drug effects , Myeloid Cells/drug effects , Myeloid Cells/immunology , Myeloid Cells/metabolism , Signal Transduction , Tuberculosis, Pulmonary/metabolism , Tuberculosis, Pulmonary/pathologyABSTRACT
Microparticles (MPs) which circulate within the plasma are elevated in patients with active pulmonary tuberculosis infection. Circulating MPs isolated from the plasma of patients with active pulmonary tuberculosis infection modulate the cytokine production of immune cells in vitro.
Subject(s)
Cell-Derived Microparticles/metabolism , Immunomodulation , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/metabolism , Acute Disease , Cell-Derived Microparticles/immunology , Humans , Immunity , Tuberculosis, Pulmonary/pathologyABSTRACT
Mucosal-associated invariant T (MAIT) cells can recognize and respond to some bacterially infected cells. Several in vitro and in vivo models of Mycobacterium tuberculosis (Mtb) infection suggest that MAIT cells can contribute to control of Mtb, but these studies are often cross-sectional and use peripheral blood cells. Whether MAIT cells are recruited to Mtb-affected granulomas and lymph nodes (LNs) during early Mtb infection and what purpose they might serve there is less well understood. Furthermore, whether HIV/SIV infection impairs MAIT cell frequency or function at the sites of Mtb replication has not been determined. Using Mauritian cynomolgus macaques (MCM), we phenotyped MAIT cells in the peripheral blood and bronchoalveolar lavage (BAL) before and during infection with SIVmac239. To test the hypothesis that SIV co-infection impairs MAIT cell frequency and function within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb Erdman, and necropsied at 6 weeks post Mtb-challenge. MAIT cell frequency and function were examined within the peripheral blood, BAL, and Mtb-affected lymph nodes (LN) and granulomas. MAIT cells did not express markers indicative of T cell activation in response to Mtb in vivo within granulomas in animals infected with Mtb alone. SIV and Mtb co-infection led to increased expression of the activation/exhaustion markers PD-1 and TIGIT, and decreased ability to secrete TNFα when compared to SIV-naïve MCM. Our study provides evidence that SIV infection does not prohibit the recruitment of MAIT cells to sites of Mtb infection, but does functionally impair those MAIT cells. Their impaired function could have impacts, either direct or indirect, on the long-term containment of TB disease.
Subject(s)
Coinfection/immunology , Mucosal-Associated Invariant T Cells/immunology , Mycobacterium tuberculosis/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Immunodeficiency Virus/immunology , Tuberculosis, Pulmonary/immunology , Animals , Coinfection/pathology , Granuloma/immunology , Granuloma/pathology , Lymph Nodes/immunology , Lymph Nodes/pathology , Macaca fascicularis , Mucosal-Associated Invariant T Cells/pathology , Programmed Cell Death 1 Receptor/immunology , Receptors, Immunologic/immunology , Simian Acquired Immunodeficiency Syndrome/pathology , Tuberculosis, Pulmonary/pathologyABSTRACT
We highlight the ability of the tuberculosis (TB) causing bacterial pathogen, Mycobacterium tuberculosis (Mtb), to induce key characteristics that are associated with established IARC classified Group 1 and Group 2A carcinogenic agents. There is sufficient evidence from epidemiological case-control, cohort and meta-analysis studies of increased lung cancer (LC) risk in pre-existing/active/old TB cases. Similar to carcinogens and other pathogenic infectious agents, exposure to aerosol-containing Mtb sprays in mice produce malignant transformation of cells that result in squamous cell carcinoma. Convincing, mechanistic data show several characteristics shared between TB and LC which include chronic inflammation, genomic instability and replicative immortality, just to name a few cancer hallmarks. These hallmarks of cancer may serve as precursors to malignant transformation. Together, these findings form the basis of our postulate that Mtb is a complete human pulmonary carcinogen. We also discuss how Mtb may act as both an initiating agent and promoter of tumor growth. Forthcoming experimental studies will not only serve as proof-of-concept but will also pivot our understanding of how to manage/treat TB cases as well as offer solutions to clinical conundrums of TB lesions masquerading as tumors. Clinical validation of our concept may also help pave the way for next generation personalized medicine for the management of pulmonary TB/cancer particularly for cases that are not responding well to conventional chemotherapy or TB drugs.
Subject(s)
Cell Transformation, Neoplastic , Lung Neoplasms/etiology , Lung Neoplasms/microbiology , Lung/microbiology , Lung/pathology , Mycobacterium tuberculosis/pathogenicity , Tuberculosis, Pulmonary/complications , Tuberculosis, Pulmonary/microbiology , Adolescent , Adult , Aged , Alveolar Epithelial Cells/cytology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Animals , Carcinogens , Cell Transformation, Neoplastic/genetics , Child , Cohort Studies , Disease Models, Animal , Disease Progression , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Mice , Middle Aged , Models, Biological , Mycobacterium tuberculosis/genetics , Neoplasm Metastasis/genetics , Neoplastic Stem Cells/pathology , Risk Factors , Tuberculosis, Pulmonary/pathology , Young AdultABSTRACT
Mycobacterium bovis is the causative agent of bovine tuberculosis and also responsible for serious threat to public health. Koumiss is a fermented mare's milk product, used as traditional drink. Here, we explored the effect of koumiss on gut microbiota and the host immune response against M bovis infection. Therefore, mice were treated with koumiss and fresh mare milk for 14 days before M bovis infection and continue for 5 weeks after infection. The results showed a clear change in the intestinal flora of mice treated with koumiss, and the lungs of mice treated with koumiss showed severe edema, inflammatory infiltration, and pulmonary nodules in M bovis-infected mice. Notably, we found that the content of short-chain fatty acids was significantly lower in the koumiss-treated group compared with the control group. However, the expression of endoplasmic reticulum stress and apoptosis-related proteins in the lungs of koumiss-treated mice were significantly decreased. Collectively, these findings suggest that koumiss treatment disturb the intestinal flora of, which is associated with disease severity and the possible mechanism that induces lungs pathology. Our current findings can be exploited further to establish the "gut-lung" axis which might be a novel strategy for the control of tuberculosis.
Subject(s)
Endoplasmic Reticulum Stress/drug effects , Gastrointestinal Microbiome/drug effects , Koumiss/adverse effects , Mycobacterium bovis/drug effects , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology , Animals , Apoptosis/drug effects , Disease Models, Animal , Fatty Acids/analysis , Feces/chemistry , Feces/microbiology , Female , Gastrointestinal Microbiome/immunology , Horses , Lung/drug effects , Lung/microbiology , Lung/pathology , Mice , Mice, Inbred BALB C , Mycobacterium bovis/immunology , Tuberculosis, Pulmonary/diet therapy , Tuberculosis, Pulmonary/metabolismABSTRACT
TOLLIP (Toll-interacting protein) is an intracellular adaptor protein with diverse actions throughout the body. In a context- and cell type-specific manner, TOLLIP can function as an inhibitor of inflammation and endoplasmic-reticulum stress, an activator of autophagy, or a critical regulator of intracellular vacuole trafficking. The distinct functions of this protein have been linked to innate immune responses and lung epithelial-cell apoptosis. TOLLIP genetic variants have been associated with a variety of chronic lung diseases, including idiopathic pulmonary fibrosis, asthma, and primary graft dysfunction after lung transplantation, and with infections, such as tuberculosis, Legionella pneumonia, and respiratory viruses. TOLLIP exists in a delicate homeostatic balance, with both positive and negative effects on the trajectory of pulmonary diseases. This translational review summarizes the genetic and molecular associations that link TOLLIP to the development and progression of noninfectious and infectious pulmonary diseases. We highlight current limitations of in vitro and in vivo models in assessing the role of TOLLIP in these conditions, and we describe future approaches that will enable a more nuanced exploration of the role of TOLLIP in pulmonary conditions. There has been a surge in recent research evaluating the role of this protein in human diseases, but critical mechanistic pathways require further exploration. By understanding its biologic functions in disease-specific contexts, we will be able to determine whether TOLLIP can be therapeutically modulated to treat pulmonary diseases.
Subject(s)
Asthma/genetics , Graft Rejection/genetics , Idiopathic Pulmonary Fibrosis/genetics , Intracellular Signaling Peptides and Proteins/genetics , Animals , Asthma/immunology , Asthma/pathology , Cytokines/genetics , Cytokines/immunology , Disease Models, Animal , Gene Expression Regulation , Graft Rejection/immunology , Graft Rejection/pathology , Humans , Idiopathic Pulmonary Fibrosis/immunology , Idiopathic Pulmonary Fibrosis/pathology , Immunity, Innate , Intracellular Signaling Peptides and Proteins/immunology , Legionnaires' Disease/genetics , Legionnaires' Disease/immunology , Legionnaires' Disease/microbiology , Legionnaires' Disease/pathology , Lung Transplantation , Mice , MicroRNAs/genetics , MicroRNAs/immunology , Respirovirus Infections/genetics , Respirovirus Infections/immunology , Respirovirus Infections/pathology , Respirovirus Infections/virology , Signal Transduction , Tuberculosis, Pulmonary/genetics , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathologyABSTRACT
Pulmonary tuberculosis (PTB) is a major global public health problem. The purpose of this study was to find biomarkers that can be used to diagnose tuberculosis. We used four NCBI GEO data sets to conduct analysis. Among the four data sets, GSE139825 is lung tissue microarray, and GSE83456, GSE19491 and GSE50834 are blood microarray. The differential genes of GSE139825 and GSE83456 were 68 and 226, and intersection genes were 11. Gene ontology (GO) analyses of 11 intersection genes revealed that the changes were mostly enriched in regulation of leucocyte cell-cell adhesion and regulation of T-cell activation. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEGs revealed that the host response in TB strongly involves cytokine-cytokine receptor interactions and folate biosynthesis. In order to further narrow the range of biomarkers, we used protein-protein interaction to establish a hub gene network of two data sets and a network of 11 candidate genes. Eventually, IRF1 was selected as a biomarker. As validation, IRF1 levels were shown to be up-regulated in patients with TB relative to healthy controls in data sets GSE19491 and GSE50834. Additionally, IRF1 levels were measured in the new patient samples using ELISA. IRF1 was seen to be significantly up-regulated in patients with TB compared with healthy controls with an AUC of 0.801. These results collectively indicate that IRF1 could serve as a new biomarker for the diagnosis of pulmonary tuberculosis.
Subject(s)
Interferon Regulatory Factor-1/genetics , Tuberculosis, Pulmonary/metabolism , Up-Regulation , Biomarkers/metabolism , Cytokines/metabolism , Gene Regulatory Networks , Humans , Interferon Regulatory Factor-1/metabolism , Protein Interaction Maps , Transcriptome , Tuberculosis, Pulmonary/genetics , Tuberculosis, Pulmonary/pathologyABSTRACT
Online supplemental material is available for this article.
Subject(s)
Aneurysm, False/diagnostic imaging , Aneurysm, False/therapy , Bronchial Arteries/diagnostic imaging , Computed Tomography Angiography/methods , Embolization, Therapeutic/methods , Tuberculosis, Pulmonary/complications , Adult , Aneurysm, False/etiology , Humans , Lymph Nodes/pathology , Male , Tuberculosis, Pulmonary/pathologyABSTRACT
AIMS: To describe an anti-Strongyloides IgA, IgG and IgG immune complex antibody response profile in patients with pulmonary tuberculosis. METHODS AND RESULTS: Saliva and serum samples were collected from 100 individuals: group I, 50 apparently healthy individuals; and group II, 50 pulmonary tuberculosis patients. The IgA, IgG and IgG immune complex detection were carried out via an ELISA immunoenzymatic test. Optical density medians in saliva samples of IgA antibody (median of 7.21) and IgG-IC (median of 4.95) were significantly higher in tuberculosis group compared to control individuals (median IgA of 3.93 and IgG-IC of 2.38). CONCLUSION: This study presents antibody data to the field of pulmonary tuberculosis and strongyloidiasis coinfection, including saliva samples, and especially IgG immune complex detection.