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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 -
Molecular Microbiology Aug 2023Advances in sequencing technologies have enabled unprecedented insights into bacterial genome composition and dynamics. However, the disconnect between the rapid... (Review)
Review
Advances in sequencing technologies have enabled unprecedented insights into bacterial genome composition and dynamics. However, the disconnect between the rapid acquisition of genomic data and the (much slower) confirmation of inferred genetic function threatens to widen unless techniques for fast, high-throughput functional validation can be applied at scale. This applies equally to Mycobacterium tuberculosis, the leading infectious cause of death globally and a pathogen whose genome, despite being among the first to be sequenced two decades ago, still contains many genes of unknown function. Here, we summarize the evolution of bacterial high-throughput functional genomics, focusing primarily on transposon (Tn)-based mutagenesis and the construction of arrayed mutant libraries in diverse bacterial systems. We also consider the contributions of CRISPR interference as a transformative technique for probing bacterial gene function at scale. Throughout, we situate our analysis within the context of functional genomics of mycobacteria, focusing specifically on the potential to yield insights into M. tuberculosis pathogenicity and vulnerabilities for new drug and regimen development. Finally, we offer suggestions for future approaches that might be usefully applied in elucidating the complex cellular biology of this major human pathogen.
Topics: Humans; DNA Transposable Elements; Genomics; Mutagenesis; Mycobacterium tuberculosis; Phenotype; Genome, Bacterial; High-Throughput Nucleotide Sequencing
PubMed: 37278255
DOI: 10.1111/mmi.15103 -
Cell Nov 2023Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with...
Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.
Topics: Humans; Male; Cell Cycle Proteins; Interferon-gamma; Interleukin-12; Interleukin-23; Janus Kinase 2; Mycobacterium; Mycobacterium Infections; Oncogene Proteins
PubMed: 37875108
DOI: 10.1016/j.cell.2023.09.024 -
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 -
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 -
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 -
Chest Nov 2023Nontuberculous mycobacterial pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Nontuberculous mycobacterial pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at increased risk of developing the disease. Understanding patients at risk is essential to allow for prompt testing and diagnosis and appropriate management to prevent disease progression.
RESEARCH QUESTION
What are the risk factors for NTM-PD that should prompt a physician to consider NTM testing and diagnosis?
STUDY DESIGN AND METHODS
Electronic searches of PubMed and EMBASE were conducted in July 2021 for the period 2011-2021. Inclusion criteria were studies of patients with NTM-PD with associated risk factors. Data were extracted and assessed using the Newcastle-Ottawa Scale. Data analysis was conducted using the R-based "meta" package. Only studies that reported association outcomes for cases with NTM-PD compared with control participants (healthy populations or participants without NTM-PD) were considered for the meta-analysis.
RESULTS
Of the 9,530 searched publications, 99 met the criteria for the study. Of these, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population and were included in the meta-analysis. Comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD (bronchiectasis [OR, 21.43; 95% CI, 5.90-77.82], history of TB [OR, 12.69; 95% CI, 2.39-67.26], interstitial lung disease [OR, 6.39; 95% CI, 2.65-15.37], COPD [OR, 6.63; 95% CI, 4.57-9.63], and asthma [OR, 4.15; 95% CI, 2.81-6.14]). Other factors noted to be associated with an increased risk of NTM-PD were the use of inhaled corticosteroids (OR 4.46; 95% CI, 2.13-9.35), solid tumors (OR, 4.66; 95% CI, 1.04-20.94) and the presence of pneumonia (OR, 5.54; 95% CI, 2.72-11.26).
INTERPRETATION
The greatest risk for NTM-PD is conferred by comorbid respiratory diseases such as bronchiectasis. These findings could help with identification of patient populations at risk for NTM-PD to drive prompt testing and appropriate initiation of therapy.
Topics: Humans; Mycobacterium Infections, Nontuberculous; Risk Factors; Bronchiectasis; Asthma; Respiratory Tract Diseases; Nontuberculous Mycobacteria; Lung Diseases; Retrospective Studies
PubMed: 37429481
DOI: 10.1016/j.chest.2023.06.014 -
CMAJ : Canadian Medical Association... Dec 2023
Topics: Humans; Mycobacterium abscessus; Scalp; Central America; Skin Transplantation; Hair
PubMed: 38110217
DOI: 10.1503/cmaj.230794-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 -
Clinical Microbiology and Infection :... Jun 2024Mycobacterium abscessus (Mab) is considered as the most pathogenic rapid-growing mycobacteria in humans, causing pulmonary and extra-pulmonary diseases, especially in... (Review)
Review
BACKGROUND
Mycobacterium abscessus (Mab) is considered as the most pathogenic rapid-growing mycobacteria in humans, causing pulmonary and extra-pulmonary diseases, especially in patients with cystic fibrosis. Mab shows intrinsic and acquired resistance to many drugs, leaving limited treatment options that lead to a generally poor prognosis. The standard therapeutic regimen last for more than 6 months and consists of a drug cocktail that ideally includes a macrolide and amikacin. Yet, toxicity and efficacy are suboptimal due also to the high toxicity. There is a need to introduce innovative and out-of-the-box approaches to improve treatments.
OBJECTIVES
In this narrative review, we summarize the recent research on the alternative strategies proposed and discuss the importance of using appropriate experimental assays to assess their activity.
SOURCES
Included articles were identified by searching PubMed and MEDLINE until June 2023. The search terms were 'Mycobacterium abscessus', 'antimicrobial', and 'alternative therapies'. Additional relevant references were obtained from articles retrieved from the primary search.
CONTENT
Therapies against Mab including host directed therapies, repurposed drugs, phage therapy, anti-virulence strategies, essential oils, and inhalation therapies.
IMPLICATIONS
Alternative treatments may represent a valid tool to cope the burden of antimicrobial resistance in Mab-caused diseases.
Topics: Mycobacterium abscessus; Humans; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Complementary Therapies; Drug Repositioning; Phage Therapy
PubMed: 37820951
DOI: 10.1016/j.cmi.2023.10.001