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The Journal of Experimental Medicine Dec 2023The functional role of CD8+ lymphocytes in tuberculosis remains poorly understood. We depleted innate and/or adaptive CD8+ lymphocytes in macaques and showed that loss...
The functional role of CD8+ lymphocytes in tuberculosis remains poorly understood. We depleted innate and/or adaptive CD8+ lymphocytes in macaques and showed that loss of all CD8α+ cells (using anti-CD8α antibody) significantly impaired early control of Mycobacterium tuberculosis (Mtb) infection, leading to increased granulomas, lung inflammation, and bacterial burden. Analysis of barcoded Mtb from infected macaques demonstrated that depletion of all CD8+ lymphocytes allowed increased establishment of Mtb in lungs and dissemination within lungs and to lymph nodes, while depletion of only adaptive CD8+ T cells (with anti-CD8β antibody) worsened bacterial control in lymph nodes. Flow cytometry and single-cell RNA sequencing revealed polyfunctional cytotoxic CD8+ lymphocytes in control granulomas, while CD8-depleted animals were unexpectedly enriched in CD4 and γδ T cells adopting incomplete cytotoxic signatures. Ligand-receptor analyses identified IL-15 signaling in granulomas as a driver of cytotoxic T cells. These data support that CD8+ lymphocytes are required for early protection against Mtb and suggest polyfunctional cytotoxic responses as a vaccine target.
Topics: Animals; Macaca; Tuberculosis; CD8-Positive T-Lymphocytes; Mycobacterium tuberculosis; Granuloma; CD4-Positive T-Lymphocytes
PubMed: 37843832
DOI: 10.1084/jem.20230707 -
The Journal of Experimental Medicine Jun 2023The hallmark of tuberculosis (TB) is the formation of immune cell-enriched aggregates called granulomas. While granulomas are pathologically diverse, their tissue-wide...
The hallmark of tuberculosis (TB) is the formation of immune cell-enriched aggregates called granulomas. While granulomas are pathologically diverse, their tissue-wide heterogeneity has not been spatially resolved at the single-cell level in human tissues. By spatially mapping individual immune cells in every lesion across entire tissue sections, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more diverse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages. The cellular composition of non-necrotizing structures also correlates with their proximity to necrotizing lesions, indicating these are foci of distinct immune reactions adjacent to necrotizing granulomas. Together, we show that during TB, diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.
Topics: Humans; Tuberculosis; Granuloma; Lung; Macrophages; Mycobacterium tuberculosis
PubMed: 36920308
DOI: 10.1084/jem.20221392 -
Ugeskrift For Laeger Apr 2024This review focuses on the treatment of nontuberculous pulmonary disease caused by Mycobacterium avium complex and M. abscessus. It covers treatment indications,... (Review)
Review
This review focuses on the treatment of nontuberculous pulmonary disease caused by Mycobacterium avium complex and M. abscessus. It covers treatment indications, antibiotic choice, resistance and side effects. Treatment of nontuberculous pulmonary disease is complex, lengthy, and fraught with side effects. Increased attention on this disease is needed in order to alleviate the severe consequences of this growing disease. Cooperation between pulmonologists and infectious disease specialists is needed to ensure uniform treatment, and to account for the heterogeneity seen in patients and mycobacteria alike.
Topics: Humans; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Lung Diseases; Pneumonia; Anti-Bacterial Agents
PubMed: 38606709
DOI: 10.61409/V06230603 -
Nature Communications Oct 2023We report on the existence of two phosphatidic acid biosynthetic pathways in mycobacteria, a classical one wherein the acylation of the sn-1 position of...
We report on the existence of two phosphatidic acid biosynthetic pathways in mycobacteria, a classical one wherein the acylation of the sn-1 position of glycerol-3-phosphate (G3P) precedes that of sn-2 and another wherein acylations proceed in the reverse order. Two unique acyltransferases, PlsM and PlsB2, participate in both pathways and hold the key to the unusual positional distribution of acyl chains typifying mycobacterial glycerolipids wherein unsaturated substituents principally esterify position sn-1 and palmitoyl principally occupies position sn-2. While PlsM selectively transfers a palmitoyl chain to the sn-2 position of G3P and sn-1-lysophosphatidic acid (LPA), PlsB2 preferentially transfers a stearoyl or oleoyl chain to the sn-1 position of G3P and an oleyl chain to sn-2-LPA. PlsM is the first example of an sn-2 G3P acyltransferase outside the plant kingdom and PlsB2 the first example of a 2-acyl-G3P acyltransferase. Both enzymes are unique in their ability to catalyze acyl transfer to both G3P and LPA.
Topics: Acyltransferases; Glycerol-3-Phosphate O-Acyltransferase; Acylation; Mycobacterium
PubMed: 37872138
DOI: 10.1038/s41467-023-42478-x -
CMAJ : Canadian Medical Association... Dec 2023
Topics: Humans; Mycobacterium abscessus; Scalp; Central America; Skin Transplantation; Hair
PubMed: 38110217
DOI: 10.1503/cmaj.230794-f -
Frontiers in Immunology 2023Tuberculosis is a major infectious disease caused by infection. The pathogenesis and immune mechanism of tuberculosis are not clear, and it is urgent to find new drugs,... (Review)
Review
Tuberculosis is a major infectious disease caused by infection. The pathogenesis and immune mechanism of tuberculosis are not clear, and it is urgent to find new drugs, diagnosis, and treatment targets. A useful tool in the quest to reveal the enigmas related to infection and disease is the single-cell sequencing technique. By clarifying cell heterogeneity, identifying pathogenic cell groups, and finding key gene targets, the map at the single cell level enables people to better understand the cell diversity of complex organisms and the immune state of hosts during infection. Here, we briefly reviewed the development of single-cell sequencing, and emphasized the different applications and limitations of various technologies. Single-cell sequencing has been widely used in the study of the pathogenesis and immune response of tuberculosis. We review these works summarizing the most influential findings. Combined with the multi-molecular level and multi-dimensional analysis, we aim to deeply understand the blank and potential future development of the research on infection using single-cell sequencing technology.
Topics: Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 37901241
DOI: 10.3389/fimmu.2023.1276194 -
Frontiers in Immunology 2023Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. Global research efforts to improve TB control are hindered by insufficient understanding of... (Review)
Review
Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. Global research efforts to improve TB control are hindered by insufficient understanding of the role that antibodies play in protective immunity and pathogenesis. This impacts knowledge of rational and optimal vaccine design, appropriate diagnostic biomarkers, and development of therapeutics. Traditional approaches for the prevention and diagnosis of TB may be less efficacious in high prevalence, remote, and resource-poor settings. An improved understanding of the immune response to the causative agent of TB, (), will be crucial for developing better vaccines, therapeutics, and diagnostics. While memory CD4+ T cells and cells and cytokine interferon gamma (IFN-g) have been the main identified correlates of protection in TB, mounting evidence suggests that other types of immunity may also have important roles. TB serology has identified antibodies and functional characteristics that may help diagnose infection and distinguish between different TB disease states. To date, no serological tests meet the World Health Organization (WHO) requirements for TB diagnosis, but multiplex assays show promise for improving the sensitivity and specificity of TB serodiagnosis. Monoclonal antibody (mAb) therapies and serum passive infusion studies in murine models of TB have also demonstrated some protective outcomes. However, animal models that better reflect the human immune response to are necessary to fully assess the clinical utility of antibody-based TB prophylactics and therapeutics. Candidate TB vaccines are not designed to elicit an -specific antibody response, but evidence suggests BCG and novel TB vaccines may induce protective antibodies. The potential of the humoral immune response in TB monitoring and control is being investigated and these studies provide important insight into the functional role of antibody-mediated immunity against TB. In this review, we describe the current state of development of antibody-based clinical tools for TB, with a focus on diagnostic, therapeutic, and vaccine-based applications.
Topics: Humans; Animals; Mice; Tuberculosis; Mycobacterium tuberculosis; Tuberculosis Vaccines; Cytokines; Interferon-gamma; Antibodies
PubMed: 38162666
DOI: 10.3389/fimmu.2023.1278947 -
Microbiology (Reading, England) May 2024(Mtb) senses and adapts to host environmental cues as part of its pathogenesis. One important cue sensed by Mtb is the acidic pH of its host niche - the macrophage.... (Review)
Review
(Mtb) senses and adapts to host environmental cues as part of its pathogenesis. One important cue sensed by Mtb is the acidic pH of its host niche - the macrophage. Acidic pH induces widespread transcriptional and metabolic remodelling in Mtb. These adaptations to acidic pH can lead Mtb to slow its growth and promote pathogenesis and antibiotic tolerance. Mutants defective in pH-dependent adaptations exhibit reduced virulence in macrophages and animal infection models, suggesting that chemically targeting these pH-dependent pathways may have therapeutic potential. In this review, we discuss mechanisms by which Mtb regulates its growth and metabolism at acidic pH. Additionally, we consider the therapeutic potential of disrupting pH-driven adaptations in Mtb and review the growing class of compounds that exhibit pH-dependent activity or target pathways important for adaptation to acidic pH.
Topics: Mycobacterium tuberculosis; Hydrogen-Ion Concentration; Adaptation, Physiological; Animals; Humans; Tuberculosis; Macrophages; Virulence; Gene Expression Regulation, Bacterial; Bacterial Proteins; Antitubercular Agents
PubMed: 38717801
DOI: 10.1099/mic.0.001458 -
CMAJ : Canadian Medical Association... Oct 2023
Topics: Female; Humans; Adolescent; Mycobacterium bovis; Mycobacterium Infections, Nontuberculous; Lymphadenitis
PubMed: 37903520
DOI: 10.1503/cmaj.230700-f -
FEMS Microbiology Reviews Mar 2024Tuberculosis (TB) remains one of the deadliest infectious diseases in human history, prevailing even in the 21st century. The causative agents of TB are represented by a... (Review)
Review
Tuberculosis (TB) remains one of the deadliest infectious diseases in human history, prevailing even in the 21st century. The causative agents of TB are represented by a group of closely related bacteria belonging to the Mycobacterium tuberculosis complex (MTBC), which can be subdivided into several lineages of human- and animal-adapted strains, thought to have shared a last common ancestor emerged by clonal expansion from a pool of recombinogenic Mycobacterium canettii-like tubercle bacilli. A better understanding of how MTBC populations evolved from less virulent mycobacteria may allow for discovering improved TB control strategies and future epidemiologic trends. In this review, we highlight new insights into the evolution of mycobacteria at the genus level, describing different milestones in the evolution of mycobacteria, with a focus on the genomic events that have likely enabled the emergence and the dominance of the MTBC. We also review the recent literature describing the various MTBC lineages and highlight their particularities and differences with a focus on host preferences and geographic distribution. Finally, we discuss on putative mechanisms driving the evolution of tubercle bacilli and mycobacteria in general, by taking the mycobacteria-specific distributive conjugal transfer as an example.
Topics: Animals; Humans; Mycobacterium tuberculosis; Bacillus; Genomics
PubMed: 38365982
DOI: 10.1093/femsre/fuae006