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LncRNA C5orf64 polymorphisms (rs12518552 and rs2950218) decreases pulmonary tuberculosis susceptibility.

BACKGROUND: Pulmonary tuberculosis (PTB) remains a significant global health issue, with genetic factors playing a crucial role in susceptibility. Long noncoding RNA (lncRNA) C5orf64 has been implicated in immune responses and cancer, but its association with PTB risk has not been fully explored. METHODS: Genomic DNA was extracted from peripheral blood samples of 955 participants (474 PTB cases and 481 controls). Rs12518552 and rs2950218 in C5orf64 were genotyped using the Agena MassARRAY system. Logistic regression analysis was performed to assess the association between these polymorphisms and PTB risk. Stratified analysis was conducted to evaluate the influence of age, gender, and smoking status. RESULTS: Rs12518552-G (OR = 0.82, p = 0.034) and rs2950218-T (OR = 0.77, p = 0.012) were associated with a reduced PTB risk. Stratified analysis revealed that rs12518552 was associated with a protective effect against PTB in individuals over 40 years old (OR = 0.73, p = 0.024), females (OR = 0.77, p = 0.034), and non-smokers (OR = 0.78, p = 0.040), and rs2950218 was also associated with a reduced PTB risk in individuals over 40 years old (OR = 0.73, p = 0.040), females (OR = 0.72, p = 0.046), and non-smokers (OR = 0.72, p = 0.011). CONCLUSION: C5orf64 polymorphisms, particularly rs12518552 and rs2950218, are associated with a reduced risk of PTB. These findings suggest that C5orf64 polymorphisms contribute to genetic susceptibility to PTB, with implications for PTB targeted screening and personalized therapeutic strategies.

Humans

Evaluation of the SLC11A1 non-synonymous variant rs17235409 and tuberculosis susceptibility in a multi-ethnic population from southwestern China.

Tuberculosis (TB) remains a major infectious disease burden, and inter-individual heterogeneity in progression from exposure to active disease suggests contributions from host genetic factors. SLC11A1 (formerly NRAMP1) encodes a phagosomal divalent cation transporter implicated in macrophage-mediated antimicrobial defense; the non-synonymous rs17235409 polymorphism (D543N) has been evaluated in multiple populations with inconsistent results. We conducted a retrospective matched case-control study in Qiandongnan, Guizhou Province, China, including 50 patients diagnosed with TB (2022-2023) and 50 healthy controls frequency-matched by ethnicity and selected demographics. Participants were drawn from Miao, Dong, and other minority groups. Among TB cases, the frequencies of the GG, GA, and AA genotypes were 80.0%, 20.0%, and 0%, respectively, compared with 74.0%, 18.0%, and 8.0% among controls. The overall genotype distribution did not differ significantly between the 2 groups (P = .124). Under the dominant model, no significant association was observed between rs17235409 and TB susceptibility (OR = 0.71, 95% CI: 0.28-1.82; P = .635). Allelic analysis showed that the frequency of the A allele was lower in cases than in controls (10.0% vs 17.0%), but this difference was not statistically significant (OR = 0.54, 95% CI: 0.24-1.25; P = .214). Ethnicity-stratified analyses similarly showed no statistically detectable associations in Miao, Dong, or other groups. The minor allele frequency was 0.095, lower than the Han Chinese reference from 1000 Genomes. In this pilot study of multi-ethnic populations from southwestern China, no statistically significant association was identified between the SLC11A1 rs17235409 polymorphism and tuberculosis susceptibility. Although the A allele appeared less frequent among cases, the limited sample size and statistical power preclude definitive conclusions regarding modest or ethnic-specific effects. These findings provide preliminary genetic data from underrepresented ethnic minority populations and warrant validation in larger multicenter studies.

Adult

Lipid peroxidation and type I interferon coupling fuels pathogenic macrophage activation causing tuberculosis susceptibility.

A quarter of the human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop pulmonary TB. We developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: the development of necrotic lung granulomas and determined that the sst1-susceptible phenotype was driven by the aberrant macrophage activation. This study demonstrates that the aberrant response of the sst1-susceptible macrophages to prolonged stimulation with TNF is primarily driven by conflicting Myc and antioxidant response pathways leading to a coordinated failure (1) to properly sequester intracellular iron and (2) to activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled superinduction of Ifnβ and sustained the type I interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within the granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. The upregulation of the Myc pathway in peripheral blood cells of human TB patients was significantly associated with poor outcomes of TB treatment. Thus, Myc dysregulation in activated macrophages results in an aberrant macrophage activation and represents a novel target for host-directed TB therapies.

Animals

Discrepancies in isoniazid susceptibility profiles: Bactec MGIT 960-resistant but GenoType MTBDRplus-susceptible Mycobacterium tuberculosis strains in Hunan, China.

UNLABELLED: Discordant drug susceptibility testing (DST) results between the Bactec MGIT 960 system (MGIT) and the GenoType MTBDRplus assay (MTBDRplus) for isoniazid (INH) complicate clinical decision-making. In this study, we performed minimum inhibitory concentration (MIC) assays and whole-genome sequencing (WGS) on 53 Mycobacterium tuberculosis strains identified as INH-resistant by MGIT but INH-susceptible by MTBDRplus. The variants conferring INH resistance were evaluated by the WHO mutation catalogue. Our results showed that only five strains carried variants classified as "associated with resistance" (Group 1/2), including katG Trp39STOP, katG Ser315Asn, inhA -154G>A, and inhA Ser94Ala. In addition, 44 strains carried 70 variants classified as "Group 3: Uncertain significance" across nine genes, including katG, ahpC, inhA, Rv0010c, Rv1129c, Rv2752c, mshA, dnaA, and Rv1258c. The remaining four strains carried no variants (Groups 1-3) linked to INH resistance. No significant difference in the prevalence of high-level INH resistance was observed between lineage 2 and lineage 4 strains (χ² = 0.232, P = 0.630). Our findings indicate that the variants classified as "uncertain significance" may be the main genetic determinants causing discordant results, highlighting their associations with INH resistance that need to be further investigated. IMPORTANCE: This study addresses a critical challenge in drug susceptibility testing (DST): the discrepancies in DST results for isoniazid (INH) between the Bactec MGIT 960 system and the GenoType MTBDRplus assay. These discordant results significantly complicate treatment decisions, potentially leading to suboptimal patient outcomes. Using MIC assays and WGS on 53 clinical Mycobacterium tuberculosis strains, we provide valuable insights into the genetic basis of INH resistance. Our findings showed that only a small fraction of strains carried variants definitively linked to INH resistance, while a larger number harbored variants of uncertain significance across multiple genes, underscoring the complexity of INH resistance mechanisms. This study highlights the urgent need to refine our understanding of these "Group 3: uncertain significance" variants, as they appear to be a primary driver of the discrepancies. Additionally, this study emphasizes the importance of integrating advanced sequencing tools into DST to improve the accuracy of INH resistance detection.

Isoniazid

Virulence of Mycobacterium tuberculosis and susceptibility to peroxidative killing systems.

At sub-bactericidal concentrations of hydrogen peroxide, Mycobacterium tuberculosis was killed by hydrogen peroxide/peroxidase/halide microbicidal systems. The halide cofactor could be either iodide or, with much lower efficiency, chloride. Omission of any one of the reactants eliminated the tuberculocidal effect. Differences in susceptibility between different strains of M. tuberculosis did not correlate with virulence differences. The observations are discussed in the context of host defence mechanisms against tuberculosis.

Chlorides

MIC-based tuberculosis drug susceptibility testing using Sensititre MYCOTB: a diagnostic accuracy meta-analysis.

Accurate drug susceptibility testing (DST) is crucial for designing effective regimens for multidrug-resistant (MDR) and pre-extensively drug-resistant tuberculosis (pre-XDR TB). Sensititre MYCOTB enables simultaneous determination of minimum inhibitory concentrations (MICs) for multiple drugs, but its diagnostic performance varies across studies. This meta-analysis evaluated the diagnostic performance of Sensititre MYCOTB for key MDR and pre-XDR TB drugs. The protocol was registered in PROSPERO (CRD420251230599). PubMed, Cochrane, Google Scholar, Scopus, ONOS, Web of Science, ScienceDirect, and registries were systematically searched for studies published between 2010 and 2025. Studies comparing the Sensititre MYCOTB with reference DST for Mycobacterium tuberculosis complex (MTBC) were included. Bias assessment and pooled diagnostic accuracy estimates were generated. Fourteen studies, including 1,728 isolates, were analyzed. Rifampicin and isoniazid demonstrated high sensitivity (0.976 [95% CI: 0.94-0.99] and 0.977 [95% CI: 0.95-0.99]) and specificity (0.958 [95% CI: 0.84-0.98] and 0.957 [95% CI: 0.83-0.99], respectively) with low heterogeneity. Amikacin, kanamycin, and ofloxacin demonstrate good diagnostic accuracy, with high specificity (>0.98 [95% CI]). Moderate diagnostic accuracy was observed for ethambutol, streptomycin, ethionamide, and rifabutin. Cycloserine, moxifloxacin, and para-aminosalicylic acid showed inconsistent performance despite excellent specificity (>0.97 [95% CI]). Sensitivity analysis partially improved pooled sensitivity for moxifloxacin 0.801 (95% CI: 0.585-0.924) and para-aminosalicylic acid 0.76 (95% CI: 0.518-0.894), whereas cycloserine remained at 0.436 (95% CI: 0.190-0.725), although heterogeneity persisted. Sensititre MYCOTB DST demonstrates high diagnostic accuracy for MDR-TB and pre-XDR-TB drugs, while caution is required with cycloserine, moxifloxacin, and para-aminosalicylic acid. These findings support the integration of MIC-based testing into clinical decision-making.

Microbial Sensitivity Tests

[Sensitivity of m. kansasii strains to various antibiotics and chemotherapeutics in vitro and in vivo (author's transl)].

Sensitivity of 40 strains of M. kansasii (var. luciflava) to various antibiotics and chemotherapeutics in vitro and in vivo was examined. The strains showed considerable individual variability in their susceptibility in vitro, most were more resistant to isoniazid and PAS and about one half of the investigated strains to streptomycin, too, if correlated to "wild" strains of M. tuberculosis. Susceptibility to ethionamide, thiosemicarbazone (Conteben), viomycin, kanamycin and cycloserine appears to be the same as in the case of M. tuberculosis strains, but the resistance to pyrazinamide is higher. Good effect has been observed in vitro with rifampicin, ethambutol, capreomycin and phenazine derivative B 663. Oleandomycin and gentamycin are ineffectual in the dosages of drugs we used. The activity of most of these drugs was observed in experimental infections of white mice--in mono-therapy and in various combinations-provoked by different strains of M. kansasii. The main criterion of the effectivity of the treatment was the enumeration of viable mycobacterial units in the lungs of the mice in ten-days intervals; in one part of the experiments the histological examination of the various organs of the mice was performed. The drugs of the I. and II. line of antituberculotics were ineffective or showed only a slight effect. A very good effect of rifampicin, ethambutol and phenazine derivative B 663 in monotherapy and in multiply drug therapy was observed.

Animals

Association of Vitamin D Receptor Gene Polymorphism (FokI) with Susceptibility to Musculoskeletal Tuberculosis: A Case-Control Study from Central India.

AIM AND BACKGROUND: Musculoskeletal tuberculosis (MSKTB) constitutes a significant proportion of extra-pulmonary tuberculosis (TB), particularly in developing countries like India. While host genetic factors are known to influence susceptibility to TB, the Vitamin D receptor (VDR) gene, particularly the FokI polymorphism, has been implicated in immune regulation and susceptibility to pulmonary and extra-pulmonary TB, data on genetic predisposition to MSKTB remain limited. The present study aimed to investigate the role of the VDR FokI gene polymorphism in determining susceptibility to MSKTB. MATERIALS AND METHODS: This study included 110 patients with confirmed MSKTB and 112 controls without TB, recruited from a tertiary care institution over a 3-year period. Clinical and demographic data were obtained. Genomic DNA was extracted from peripheral venous blood samples, and VDR FokI polymorphism was detected using polymerase chain reaction-based restriction fragment length polymorphism analysis. Genotype and allele frequencies were compared using a Chi-square test, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: The ff genotype was significantly more frequent in cases (17.3%) compared to controls (9.8%) and was associated with increased risk of MSKTB (OR = 2.30, 95% CI: 1.03-5.15, P = 0.04). The polymorphic f allele frequency was also significantly higher in cases than controls (38.2% vs. 28.1%; OR = 1.58, 95% CI: 1.05-2.37, P = 0.023). However, the dominant and recessive genetic models showed a non-significant association. Demographically, MSKTB was more common among females, individuals from rural backgrounds, those of lower socioeconomic status, and those with low body mass index. CONCLUSION: The VDR FokI polymorphism, particularly the ff genotype and f allele, is associated with increased susceptibility to MSKTB. These findings highlight the potential role of genetic factors in MSKTB and may aid in identifying at-risk populations.

FokI polymorphism

Cathepsin Z is a conserved susceptibility factor underlying tuberculosis severity.

Tuberculosis (TB) outcomes vary widely, from asymptomatic infection to mortality, yet most animal models do not recapitulate human phenotypic and genotypic variation. The genetically diverse Collaborative Cross mouse panel models distinct facets of TB disease that occur in humans and allows identification of genomic loci underlying clinical outcomes. We previously mapped a TB susceptibility locus on mouse chromosome 2. Here, we identify cathepsin Z (Ctsz) as a lead candidate underlying this TB susceptibility and show that Ctsz ablation leads to increased bacterial burden, pulmonary inflammation and decreased survival in mice. Ctsz disturbance within murine macrophages enhances production of chemokine (C-X-C motif) ligand 1 (CXCL1), a known biomarker of TB severity. From a Ugandan household contact study, we identify significant associations between CTSZ variants and TB disease severity. Finally, we examine patient-derived TB granulomas and report CTSZ localization within granuloma-associated macrophages, placing human CTSZ at the host-pathogen interface. These findings implicate a conserved CTSZ-CXCL1 axis in humans and genetically diverse mice that mediates TB disease severity.

Animals

Rapid radiometric susceptibility testing of Mycobacterium tuberculosis.

A 48-hour radiometric test for determining the drug susceptibility of Mycobacterium tuberculosis has been developed. The test is based on the measurement of 14CO2 produced by the oxidation of formate labeled with carbon-14. The test system uses 5 X 10(7) organisms in 1 ml of Middlebrook 7H9 medium plus albumin-dextrose-catalase enrichment and 1 muCi of [14C]formate. The 14CO2 produced is measured in an ionization chamber at 24-, 48-, and 72-hour intervals, with and without the addition of antituberculous drugs. Isoniazid, streptomycin, rifampin, and ethambutol were each tested at 3 concentrations by the radiometric method and the reference (agar dilution) method. Six standard strains and 21 patient isolates were compared by both methods. Production of 14CO2 was quantitatively decreased in the presence of drugs that inhibit the organism. The radiometric method requires 2 days; the agar dilution, 14 to 21 days.

Antitubercular Agents

Human genetic variation associates with infection by derived Ugandan M. tuberculosis lineage.

BACKGROUND: Several studies have examined host and pathogen genetic influences on tuberculosis (TB) susceptibility separately, but relatively few studied their combined effects. However, host-pathogen interactions or co-evolution may explain the inability to replicate many reported human genetic effects across global populations and provide additional insight into TB risk. In this study, we address such possible interactions by focusing on the outcome of infection with the L4-Uganda M. tuberculosis sub-lineage and human genetic variants as independent variables. This is possible because the L4-Uganda sub-lineage is both restricted to Uganda and nearby locations and is recent there, compared to other more ancestral L4 lineages. METHODS: Our study consisted of 276 culture-confirmed adult TB cases from a long-standing household contact study. We conducted a genome-wide association study, with infection with L4-Uganda versus L4-NonUganda as the outcome. RESULTS: Multiple loci with results suggestive of association (p<10-5) also demonstrated convergent relevant evidence for strain specific infection via: evidence of gene expression in relevant cells and lung tissue, signatures of natural selection, eQTL expression, and CRISPR screens for immunity-related genes. We also replicated previously published host-pathogen interaction effects, demonstrating that effects seen for other sub-lineages were also present for L4-Uganda. CONCLUSIONS: These results provide evidence for host-pathogen co-evolution in TB, consistent with our previous work, and indicate these interactions involve genes highly relevant to the host immune response to Mycobacterium infection.

GWAS

[Changes in the cellular elements of the thymus gland in experimental destructive pulmonary tuberculosis].

Lymphoid elements of the thymus were studied by scanning electron microscopy in rabbits susceptible to tuberculosis. The complete Freund adjuvant causes in the thymus a 3-fold decrease in the number of cells with the properties of T-lymphocytes, and an appearance of a new type of cell elements (polygonal shape, with cytoplasmic outgrowths). Formation of a focus of tuberculosis and the development of destructive changes in the lungs occur under conditions of a progressive decrease in the number of T- and B-lymphocytes in the thymus. Delimitation of the pathological process in the lung is characterized by an increase in the number of T- and B-lymphocytes and considerable predominance of polygonally shaped cells with cytoplasmic outgrowths of different lengths and their subsequent replacement by a cell form transitory between T- and B-lymphocytes. A relatively favourable course of the process in the lungs is observed when the cell elements in the thymus differentiate towards B-lymphocytes.

Animals

Genetic Variants at the NAT2 and HLA-DOA are Associated With Anti-Tuberculosis Drug-Induced Liver Injury Susceptibility and Clinical Manifestations in Western Chinese Populations.

BACKGROUND: Anti-tuberculosis drug-induced liver injury (ATDILI) is one of the most prevalent and serious adverse reactions during anti-tuberculosis treatment and can potentially lead to liver failure or mortality. This study aims to investigate whether genetic variants in the N-acetyltransferase 2 gene (NAT2) and the HLA-DOA gene (HLA-DOA) are associated with ATDILI susceptibility and clinical manifestations in a Western Chinese population. METHODS: A total of 1358 participants with active tuberculosis were enrolled and genotyped for four NAT2 polymorphisms and five HLA-DOA loci. Associations between candidate genetic variants and ATDILI were evaluated using logistic regression analyses, with multiple comparisons adjusted by Bonferroni correction. RESULTS: The overall incidence of ATDILI was 28.4% (385/1358) in this cohort. Under a recessive model, NAT2 rs1799930 was found to increase the risk of ATDILI (odds ratio [OR]&#x2009;=&#x2009;1.88, 95% confidence interval [CI]: 1.20-2.95, p&#x2009;=&#x2009;0.006), which remained significant after Bonferroni correction (adjusted p&#x2009;=&#x2009;0.048). Meanwhile, while HLA-DOA rs1367731 (OR&#x2009;=&#x2009;0.41, 95% CI: 0.18-0.93, p&#x2009;=&#x2009;0.033), rs6913008 (OR&#x2009;=&#x2009;0.39, 95% CI: 0.17-0.89, p&#x2009;=&#x2009;0.024), and rs9276975 (OR&#x2009;=&#x2009;0.47, 95% CI: 0.23-0.98, p&#x2009;=&#x2009;0.045) demonstrated a promising protective genomic characteristic that may mitigate the development of ATDILI. However, none of the reported HLA-DOA associations remained statistically significant after applying Bonferroni corrections. Regarding clinical manifestations, NAT2 rs1799930 and rs1799931 have been linked to poor ATDILI clinical presentations, whereas certain HLA-DOA variants (rs1367731, rs6913008, and rs9276975) were possibly linked to milder ATDILI severity. CONCLUSION: Our findings preliminarily suggest that the NAT2 and HLA-DOA genetic variants may play a role in ATDILI susceptibility and clinical outcomes. NAT2 rs1799930 represents a potential genetic risk marker, while HLA-DOA variants may serve as protective factors warranting further validation. These findings may contribute to the precision management of ATDILI and the prevention of anti-TB drug-associated liver injury.

Adult

HLA-Bw15 and tuberculosis in a North American black population.

Peripheral blood lymphocytes from 60 black patients with Mycobacterium tuberculosis disease proved by culture and 100 healthy black persons were HLA phenotyped using a standard lymphocytotoxicity test. Statistical analysis of the results showed that only Bw15 antigen had a significantly increased frequency among patients with tuberculosis when they were compared to healthy persons. Furthermore, examination of disease manifestations among patients with tuberculosis demonstrated that patients with Bw15 had significantly more far-advanced pulmonary disease with cavitation than did patients without Bw15. These observations suggest that Bw15 may influence both susceptibility to tuberculosis and the course of the disease.

Adult

The effect of cortisone on the accumulation, activation, and necrosis of macrophages in tuberculous lesions.

Rabbits were injected intramuscularly with cortisone acetate (2 mg/kg) on alternate days. Six days after the first injection these rabbits and controls were injected intradermally in multiple sites with BCG (the vaccine strain of tubercle bacillus). Periodically, over the next 2 months, the resulting lesions were measured and surgically biopsied, and the animals were tuberculin-tested. Macrophage activation in the BCG lesions was evaluated histochemically by staining for beta-galactosidase activity. Both BCG lesions (and tuberculin reactions) in the cortisone-treated group were considerably smaller than those in the control group. Cortisone was highly effective in reducing the number of infiltrating mononuclear cells (MN), the amount of caseous necrosis and ulceration, and the percent of NM that were beta-galactosidase-positive. The decreased activation and reduced number of macrophages readily explains the increased susceptibility to tuberculosis found amoung patients receiving glucocorticosteroids. In the BCG lesions, the local decrease in the number and function of leukocytes probably explains the decreased tissue necrosis. Such antiinflammatory effects of corticosteroids may offset, in selected antimicrobial-treated cases, the hormone's detrimental effect on host resistance to infectious agents.

Animals

Addressing racism as a clinical competence: Robert Wilson, Jr. (1867-1946).

Addressing health inequity is now recognized as a clinical competency in medical education. We examined the career and writings of Robert Wilson Jr. (1867-1946), longtime dean of the Medical College of the State of South Carolina during the Jim Crow Era, using primary and secondary sources within the context of systemic and structural racism, particularly in South Carolina. Wilson used public health data to refute the "Black Extinction Hypothesis" rooted in social Darwinism. He challenged assumptions of inherent Black susceptibility to tuberculosis, linking disease instead to social determinants of health. He also identified disproportionate mortality from kidney and cardiovascular disease among Black populations, anticipating modern health disparities research. Wilson further acknowledged systemic injustice and implicated structural conditions, including housing, in shaping outcomes. In an era of continuing health inequity and racial health disparities, Wilson applied empirical evidence to reject biological determinism, identify outcomes disparities, and advocate for racial justice.

History, 20th Century

Primary drug resistance in children. Drug susceptibility of strains of Mycobacterium tuberculosis isolated from children during the years 1973 through 1977 at the Kings County Hospital Center of Brooklyn.

A continuing study of the frequency of primary drug resistance among children treated at the Kings County Hospital Center of Brooklyn during the years 1973 through 1977 showed a high incidence of primary drug resistance to isoniazid (8.8 per cent) and to streptomycin (12.3 per cent). In contrast, there were no strains resistant to cycloserine, viomycin, ethambutol, or rifampin, and only one of 57 strains (1.8 per cent) was resistant to ethionamide, and one (1.8 per cent) was resistant to para-aminosalicylic acid. Comparison with previous studies begun in 1961 showed no significant increase in resistance to isoniazid during 3 prior periods of study and no increase in resistance to streptomycin during the last 2 periods of study. It must be emphasized that these findings relate only to the children of a local community, and do not reflect the prevalence of primary drug resistance elsewhere in this country or among different age groups.

Adolescent

A clinical study of Pityriasis versicolor in Madras.

One hundred subjects with extensive pityriasis versicolor determined clinically and confirmed by wet preparations (potassium hydroxide positive) were studied. Its incidence in relation to sex, seasons and age groups was analyzed. More than fifty patients sought medical advice on grounds of cosmetic handicap. The most pronounced clinical feature was to be found on the trunk. One case was Confluent and Reticulated Papillomatosis of Gugerot-Carteaud (CRP) (16). Among the factors of susceptibility, pulmonary tuberculosis (P.T.) emerged statistically significant.

Age Factors