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Signal Transduction and Targeted Therapy Jun 2024
Topics: Tuberculosis; Macrophages; Humans; Nanoparticles; Cell Membrane; Animals; Mycobacterium tuberculosis; Macrophage Activation; Mice
PubMed: 38918362
DOI: 10.1038/s41392-024-01855-8 -
PloS One 2024Combining data from experiments on multispecies studies provides invaluable contributions to the understanding of basic disease mechanisms and pathophysiology of...
Combining data from experiments on multispecies studies provides invaluable contributions to the understanding of basic disease mechanisms and pathophysiology of pathogens crossing species boundaries. The task of multispecies gene expression analysis, however, is often challenging given annotation inconsistencies and in cases of small sample sizes due to bias caused by batch effects. In this work we aim to demonstrate that an alternative approach to standard differential expression analysis in single cell RNA-sequencing (scRNA-seq) based on effect size profiles is suitable for the fusion of data from small samples and multiple organisms. The analysis pipeline is based on effect size metric profiles of samples in specific cell clusters. The effect size substitutes standard differentiation analyses based on p-values and profiles identified based on these effect size metrics serve as a tool to link cell type clusters between the studied organisms. The algorithms were tested on published scRNA-seq data sets derived from several species and subsequently validated on own data from human and bovine peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis. Correlation of the effect size profiles between clusters allowed for the linkage of human and bovine cell types. Moreover, effect size ratios were used to identify differentially regulated genes in control and stimulated samples. The genes identified through effect size profiling were confirmed experimentally using qPCR. We demonstrate that in situations where batch effects dominate cell type variation in single cell small sample size multispecies studies, effect size profiling is a valid alternative to traditional statistical inference techniques.
Topics: Single-Cell Analysis; Animals; Humans; Cattle; Mycobacterium tuberculosis; Gene Expression Profiling; Algorithms; Leukocytes, Mononuclear; Sequence Analysis, RNA
PubMed: 38917129
DOI: 10.1371/journal.pone.0305874 -
PloS One 2024The presence of SNPs in genes related to DNA damage repair in M. tuberculosis can trigger hypermutagenic phenotypes with a higher probability of generating drug...
The presence of SNPs in genes related to DNA damage repair in M. tuberculosis can trigger hypermutagenic phenotypes with a higher probability of generating drug resistance. The aim of this research was to compare the presence of SNPs in genes related to DNA damage repair between sensitive and DR isolates, as well as to describe the dynamics in the presence of SNPs in M. tuberculosis isolated from recently diagnosed TB patients of the state of Veracruz, Mexico. The presence of SNPs in the coding regions of 65 genes related to DNA damage repair was analyzed. Eighty-six isolates from 67 patients from central Veracruz state, Mexico, were sequenced. The results showed several SNPs in 14 genes that were only present in drug-resistant genomes. In addition, by following of 15 patients, it was possible to describe three different dynamics of appearance and evolution of non-synonymous SNPs in genes related to DNA damage repair: 1) constant fixed SNPs, 2) population substitution, and 3) gain of fixed SNPs. Further research is required to discern the biological significance of each of these pathways and their utility as markers of DR or for treatment prognosis.
Topics: Polymorphism, Single Nucleotide; Humans; DNA Repair; Mycobacterium tuberculosis; DNA Damage; Mexico; Longitudinal Studies; Female; Male; Tuberculosis; Adult
PubMed: 38917091
DOI: 10.1371/journal.pone.0295464 -
International Journal of... Apr 2024Leprosy, caused by the bacterium Mycobacterium leprae, is known to primarily affect the skin and peripheral nerves. We present a rare case of leprosy initially...
Leprosy, caused by the bacterium Mycobacterium leprae, is known to primarily affect the skin and peripheral nerves. We present a rare case of leprosy initially manifesting as demyelinating polyneuropathy. A 46-year-old female presented with progressive weakness, tingling, and numbness in her extremities. Nerve conduction studies revealed evidence of demyelination, prompting further investigations. Skin slit-skin smears confirmed the diagnosis of leprosy, with the presence of acid-fast bacilli. The patient was subsequently started on multidrug therapy, leading to significant clinical improvement. This case highlights the importance of considering leprosy as a differential diagnosis in patients presenting with demyelinating polyneuropathy, especially in endemic regions.
Topics: Humans; Female; Middle Aged; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Leprosy; Diagnosis, Differential; Mycobacterium leprae; Skin; Leprostatic Agents
PubMed: 38916395
DOI: 10.4103/ijmy.ijmy_39_24 -
International Journal of... Apr 2024Bacille Calmette-Guérin (BCG) is a live-attenuated vaccine routinely administered to newborns to prevent severe forms of tuberculosis (TB) in TB-endemic countries.... (Review)
Review
Infantile Disseminated Bacille Calmette-Guérin Disease with Hemophagocytosis and Mimicking Juvenile Myelomonocytic Leukemia: A Case Report with Concise Literature Review.
Bacille Calmette-Guérin (BCG) is a live-attenuated vaccine routinely administered to newborns to prevent severe forms of tuberculosis (TB) in TB-endemic countries. Disseminated BCG vaccine disease is a classic feature of children with human immunodeficiency virus (HIV) or primary immunodeficiency disorders (PIDs) and is associated with high mortality. We report a case of a 6-month-old infant with disseminated BCG disease and hemophagocytic lymphohistiocytosis mimicking juvenile myelomonocytic leukemia with no demonstrable features of HIV or PID even after extensive laboratory work-up and succumbed to progressive disease. Disseminated BCG disease is a rare and potentially fatal complication of BCG vaccine, and prompt immunological evaluation complemented by initiation of 4-drug antitubercular therapy and definitive treatment with antiretroviral therapy or hematopoietic stem cell transplant is warranted.
Topics: Humans; Leukemia, Myelomonocytic, Juvenile; Infant; Lymphohistiocytosis, Hemophagocytic; BCG Vaccine; Tuberculosis; Diagnosis, Differential; Fatal Outcome; Male; Mycobacterium bovis; Antitubercular Agents
PubMed: 38916394
DOI: 10.4103/ijmy.ijmy_48_24 -
International Journal of... Apr 2024Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing...
BACKGROUND
Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing challenge is the variable occurrence of adverse drug reactions in some TB patients. Previous studies have indicated that genetic variations in the N-acetyltransferase 2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) genes can impact the blood concentrations of the first-line anti-TB drugs isoniazid (INH) and rifampicin (RIF), respectively. This study aimed to investigate the influence of pharmacogenetic markers in the NAT2 and SLCO1B1 genes on TB treatment outcomes using whole-exome sequencing (WES) analysis.
METHODS
DNA samples were collected from 30 healthy Iranian adults aged 18-40 years. The allelic frequencies of single-nucleotide polymorphisms (SNPs) in the NAT2 and SLCO1B1 genes were determined through WES.
RESULTS
Seven frequent SNPs were identified in the NAT2 gene (rs1041983, rs1801280, rs1799929, rs1799930, rs1208, rs1799931, rs2552), along with 16 frequent SNPs in the SLCO1B1 gene (rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs2291075, rs201722521, rs11045852, rs11045854, rs756393362, rs11045859, rs74064211, rs201556175, rs34671512, rs71581985, rs4149085).
CONCLUSION
Genetic variations in NAT2 and SLCO1B1 can affect the metabolism of INH and RIF, respectively. A better understanding of the pharmacogenetic profile in the study population may facilitate the design of more personalized and effective TB treatment strategies. Further research is needed to directly correlate these genetic markers with clinical outcomes in TB patients.
Topics: Humans; Arylamine N-Acetyltransferase; Liver-Specific Organic Anion Transporter 1; Adult; Antitubercular Agents; Male; Young Adult; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Rifampin; Adolescent; Female; Isoniazid; Iran; Tuberculosis; Gene Frequency; Exome Sequencing; Pharmacogenomic Testing; Pharmacogenetics
PubMed: 38916393
DOI: 10.4103/ijmy.ijmy_106_24 -
International Journal of... Apr 2024Tuberculosis (TB), a global infectious threat, has seen a concerning rise in aminoglycoside-resistant Mycobacterium tuberculosis (M.tb) strains. The potential role of... (Comparative Study)
Comparative Study
Comparative Proteomic Analysis of Capsule Proteins in Aminoglycoside-Resistant and Sensitive Mycobacterium tuberculosis Clinical Isolates: Unraveling Potential Drug Targets.
BACKGROUND
Tuberculosis (TB), a global infectious threat, has seen a concerning rise in aminoglycoside-resistant Mycobacterium tuberculosis (M.tb) strains. The potential role of capsule proteins remains largely unexplored. This layer acts as the primary barrier for tubercle bacilli, attempting to infiltrate host cells and subsequent disease development.
METHODS
The study aims to bridge this gap by investigating the differentially expressed capsule proteins in aminoglycoside-resistant M.tb clinical isolates compared with drug-sensitive isolates employing two-dimensional gel electrophoresis, mass spectrometry, and bioinformatic approaches.
RESULTS
We identified eight proteins that exhibited significant upregulation in aminoglycoside-resistant isolates. Protein Rv3029c and Rv2110c were associated with intermediary metabolism and respiration; Rv2462c with cell wall and cell processes; Rv3804c with lipid metabolism; Rv2416c and Rv2623 with virulence and detoxification/adaptation; Rv0020c with regulatory functions; and Rv0639 with information pathways. Notably, the Group-based Prediction System for Prokaryotic Ubiquitin-like Protein (GPS-PUP) algorithm identified potential pupylation sites within all proteins except Rv3804c. Interactome analysis using the STRING 12.0 database revealed potential interactive partners for these proteins, suggesting their involvement in aminoglycoside resistance. Molecular docking studies revealed suitable binding between amikacin and kanamycin drugs with Rv2462c, Rv3804c, and Rv2623 proteins.
CONCLUSION
As a result, our findings illustrate the multifaceted nature of aminoglycoside resistance in M.tb and the importance of understanding how capsule proteins play a role in counteracting drug efficacy. Identifying the role of these proteins in drug resistance is crucial for developing more effective treatments and diagnostics for TB.
Topics: Mycobacterium tuberculosis; Humans; Proteomics; Bacterial Proteins; Aminoglycosides; Drug Resistance, Bacterial; Bacterial Capsules; Antitubercular Agents; Microbial Sensitivity Tests; Computational Biology; Electrophoresis, Gel, Two-Dimensional; Tuberculosis
PubMed: 38916392
DOI: 10.4103/ijmy.ijmy_47_24 -
International Journal of... Apr 2024On a global scale, India holds the distinction of having the greatest number of tuberculosis (TB) cases caused by Mycobacterium tuberculosis (MTB) complex. The study... (Comparative Study)
Comparative Study
BACKGROUND
On a global scale, India holds the distinction of having the greatest number of tuberculosis (TB) cases caused by Mycobacterium tuberculosis (MTB) complex. The study aimed at evaluating the sensitivity, specificity, accuracy, cost, rapidity, and feasibility of the performance of the colorimetric nitrate reductase-based antibiotic susceptibility (CONRAS) test against the indirect proportion method (IPM) on Lowenstein-Jensen media as the gold standard.
METHODS
A comparative cross-sectional study was performed on 51 MTB isolates. Fresh subcultures were used for drug susceptibility testing by IPM on the Lowenstein-Jensen medium and the CONRAS method in liquid medium. Quality control for drug susceptibility testing was done using a known sensitive strain of MTB (H37Rv) and strains resistant to both isoniazid (INH) and rifampicin (RIF) - multidrug-resistant (MDR), mono-resistant to RIF, streptomycin (STM), and ethambutol (EMB). Statistical analysis was performed using MedCalc software (Version 20.027).
RESULTS
CONRAS, carried out in microfuge tubes, was cost-efficient and easy to perform/interpret with most results being available in 10 days compared to 42 days in the case of IPM. The sensitivity, specificity, and accuracy of RIF and INH were 100%, 97.37%, and 98.04 and 93.33%, 97.59%, and 96.08%, respectively, which translates into an almost perfect agreement between the two methods as indicated by κ value of 0.905 and 0.949, respectively, for the two drugs. The performance of CONRAS was less satisfactory for STM and EMB when compared to IPM.
CONCLUSIONS
CONRAS may serve as a useful test for the detection of MDR-TB because of its accuracy, low cost, ease of performance/interpretation, and rapidity when compared to IPM on LJ medium. It does not involve the use of expensive reagents and equipment, as is the case with molecular methods like GeneXpert and line probe assay, making it a suitable option for the detection of MDR-TB in resource-poor settings.
Topics: Nitrate Reductase; Mycobacterium tuberculosis; Colorimetry; Microbial Sensitivity Tests; Antitubercular Agents; Humans; Cross-Sectional Studies; Sensitivity and Specificity; Culture Media; India; Tuberculosis, Multidrug-Resistant
PubMed: 38916391
DOI: 10.4103/ijmy.ijmy_69_24 -
International Journal of... Apr 2024Extrapulmonary tuberculosis (EPTB) makes for 25% of all instances of tuberculosis (TB) patients. The enigmatic clinical presentation of EPTB makes identification...
BACKGROUND
Extrapulmonary tuberculosis (EPTB) makes for 25% of all instances of tuberculosis (TB) patients. The enigmatic clinical presentation of EPTB makes identification difficult since it simulates other chronic conditions such as neoplastic and inflammatory disorders and could culminate in treatment that is either insufficient or not required. For an affirmative and confirmed diagnosis, a substantial level of suspicion is imperative. The paucibacillary feature of EPTB makes diagnosis extremely difficult and necessitates the use of many diagnostic methods to arrive at a precise diagnosis. In December 2010, the World Health Organization recommended using GeneXpert/cartridge-based nucleic acid amplification test (CBNAAT) for the initial assessment of suspected cases of EPTB. Furthermore, fine-needle aspiration cytology (FNAC), Ziehl-Neelsen (ZN) stain, and the CBNAAT have to be utilized to exclude other possible origins of granulomatous inflammation. The goal of the current investigation is to comprehend how FNAC and ZN stains relate to CBNAAT and their diagnostic value.
METHODS
The evaluation included all suspected instances of tubercular lymphadenopathy, and adequate aspirates were obtained from the site of the enlarged cervical lymph nodes. Smears were made following FNAC and stained with ZN stain as well as hematoxylin and eosin stain. Simultaneously, CBNAAT and culture evaluations were conducted on the same aspirates. This cross-sectional study took place at a tertiary care center and encompassed 200 individuals with clinical manifestations of EPTB.
RESULTS
There were 200 cases of suspected tubercular lymphadenitis (TBLN). According to the FNAC results, TBLN was detected in 71 (47.6%) of these 200 cases, followed by necrotizing lymphadenitis in 56 (37.5%), chronic caseating granulomatous lymphadenitis in 47 (31.5%), and reactive lymphadenitis in 26 (17.4%). They were correlated with CBNAAT results, which showed that all instances of tuberculous lymphadenitis, 85.71% of cases of necrotizing lymphadenitis, 55.32% of cases of chronic caseating granulomatous lymphadenitis, and 2 (7.69%) cases of reactive lymphadenitis were CBNAAT positive.
CONCLUSION
CBNAAT should be utilized with FNAC and ZN staining to diagnose EPTB. The CBNAAT assay demonstrated a significant advantage in the identification of previously unidentified FNAC patients. Despite being a simple diagnostic tool, FNAC has a lower specificity and significantly lower precision than CBNAAT in correctly identifying cases of EPTB because it exhibits similar cytomorphological characteristics with lesions that are not associated with TB.
Topics: Humans; Female; Male; Biopsy, Fine-Needle; Adult; Middle Aged; Tuberculosis, Lymph Node; Adolescent; Young Adult; Mycobacterium tuberculosis; Lymph Nodes; Aged; Nucleic Acid Amplification Techniques; Staining and Labeling; Lymphadenopathy; Child; Sensitivity and Specificity
PubMed: 38916388
DOI: 10.4103/ijmy.ijmy_45_24 -
International Journal of... Apr 2024Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), with a high global prevalence and mortality rate. To control the gruesome pathogen, a deep... (Comparative Study)
Comparative Study
BACKGROUND
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), with a high global prevalence and mortality rate. To control the gruesome pathogen, a deep understanding of pathophysiology and host-pathogen interaction is essential for early diagnosis and novel drug development. Cytokines play a crucial role in infection and susceptibility, and their expressions could serve as potential biomarkers to enhance our understanding of Mtb pathophysiology for improved therapeutic approaches. This cross-sectional study investigates the levels of four important T-cell immune-mediated cytokines: interleukins (IL-6 and IL-10), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha in 80 cohort samples, with 20 people in each group.
METHODS
Following proper ethics and patient consent, we collected blood samples and isolated serum from all four groups: TB, type 2 diabetes mellitus (T2DM), type 2 diabetes-TB comorbidity (T2DM + TB), and a healthy individual as a control group (C). Furthermore, cytokine expression was measured in individual serum samples through the enzyme-linked immunosorbent assay method using commercial kits (Diaclone, French). Statistical significance was observed by analyzing triplicate data using t-tests and the one-way ANOVA method with GraphPad Prism 10.
RESULTS
The results showed that all four cytokine levels were higher (P ≤ 0.0001) than the control, especially IL-6, IL-10, and IFN-γ, which were found to be upregulated in T2DM + TB samples (P ≤ 0.0001) than individual TB or T2DM samples.
CONCLUSION
The high levels of cytokines in comorbidity cases raise the risk of insulin resistance and the severity of TB infection. These levels of expression could be used to keep track of the Mtb infection status or severity, aid in early diagnosis as a possible biomarker, and suggest possible treatment plans.
Topics: Humans; Diabetes Mellitus, Type 2; Tuberculosis, Pulmonary; Cross-Sectional Studies; Male; Middle Aged; Female; Adult; Cytokines; Comorbidity; Mycobacterium tuberculosis; Interferon-gamma; Biomarkers; Interleukin-10; Tumor Necrosis Factor-alpha; Interleukin-6; Aged
PubMed: 38916387
DOI: 10.4103/ijmy.ijmy_40_24