Tuberculosis最新文献

{"title":"The rv2820c K114N mutation is related with capreomycin tolerance","authors":"Jin-Tian Xu ,&nbsp;Yi Lin ,&nbsp;Tao Cheng ,&nbsp;Jiao-Yu Deng","doi":"10.1016/j.tube.2024.102551","DOIUrl":"10.1016/j.tube.2024.102551","url":null,"abstract":"<div><p>As one of the factors affecting the treatment outcomes, drug tolerance in mycobacteriosis has not been paid due attention. Genome-wide association studies on 607 <em>Mycobacterium tuberculosis</em> clinical isolates with phenotypic drug susceptibility test data revealed that a K114N mutation on the <em>rv2820c</em> gene was highly enriched in capreomycin-resistant isolates (32/213, 15.02%). However, the mutation was also observed in capreomycin-sensitive isolates (10/394, 2.53%). In most cases (31/42, 73.81%), the <em>rv2820c</em> K114N mutation occurred in isolates with the known capreomycin resistance conferring mutation <em>rrs</em> A1401G. In contrast, the general frequency of the <em>rv2820c</em> K114N mutation was low in 7061 genomes downloaded from the National Center for Biotechnology Information database. To determine the impact of this mutation on the antimycobacterial activity of capreomycin, the intact <em>rv2820c</em> gene and the <em>rv2820c</em> K114N mutant were over-expressed in <em>Mycobacterium smegmatis</em> (<em>Ms</em>), and the results of susceptibility tests showed that the <em>rv2820c</em> K114N mutation did not affect the minimum inhibition concentration (MIC) of capreomycin. Subsequently, the data of time-kill assays showed that, it took only 2 h of capreomycin treatment (40 μg/ml, 5 × MIC) to kill 99.9% bacterial cells of <em>Ms</em> MC²155 pMV261::<em>rv2820c</em>_H37Rv, while it took 6 h to achieve that for <em>Ms</em> MC²155 pMV261::<em>rv2820c</em>_K114N. Taken together, these data suggested that the <em>rv2820c</em> K114N mutation is related with capreomycin tolerance, which merits further investigation.</p></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102551"},"PeriodicalIF":2.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141845544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidemiology and molecular characterization of Mycobacterium tuberculosis including a drug-resistant strain associated with mortality of Asian elephants in Nepal 2019–2022","authors":"Arjun Pandit ,&nbsp;Jeewan Thapa ,&nbsp;Amir Sadaula ,&nbsp;Yasuhiko Suzuki ,&nbsp;Chie Nakajima ,&nbsp;Susan K. Mikota ,&nbsp;Naresh Subedi ,&nbsp;Bijaya Kumar Shrestha ,&nbsp;Michito Shimozuru ,&nbsp;Bhawana Shrestha ,&nbsp;Bijendra Raya ,&nbsp;Sanjay Chaudhary ,&nbsp;Sarad Paudel ,&nbsp;Toshio Tsubota","doi":"10.1016/j.tube.2024.102550","DOIUrl":"10.1016/j.tube.2024.102550","url":null,"abstract":"<div><p>Tuberculosis (TB) is an emerging threat to the survival of elephants in Nepal. We investigated the lung tissue samples from nine elephants that died from 2019 to 2022 in Nepal using culture, conventional PCR, and loop-mediated isothermal amplification (LAMP) and then performed genotyping of five PCR-positive isolates to understand the possible transmission dynamics of <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>). Results showed that two-thirds (6/9) of elephants were confirmed to be infected from <em>Mtb</em> by LAMP, 5/9 by PCR, and 4/9 by culture. Genotyping of <em>Mtb</em> isolates showed that elephants were infected with the Indo-Oceanic and Beijing lineages including an isoniazid-resistant Beijing lineage. MIRU-VNTR-based phylogeny, <em>gyrA,</em> and <em>katG</em> sequencing showed the possibility of ongoing transmission of Indo-Oceanic lineages and likely transmission of the drug-resistant Beijing lineage from human to elephant. Implementation of comprehensive surveillance and preventive measures are urgently needed to address this zoonotic disease and protect elephants from TB in Nepal.</p></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102550"},"PeriodicalIF":2.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141842081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of Mycobacterium tuberculosis transrenal DNA in urine samples among adults in Peru","authors":"Annelies W. Mesman ,&nbsp;Roger I. Calderon ,&nbsp;Laura Hauns ,&nbsp;Nira R. Pollock ,&nbsp;Milagros Mendoza ,&nbsp;Rebecca C. Holmberg ,&nbsp;Molly F. Franke","doi":"10.1016/j.tube.2024.102549","DOIUrl":"10.1016/j.tube.2024.102549","url":null,"abstract":"<div><p>Diagnosis of pulmonary tuberculosis (TB) relies on a sputum sample, which cannot be obtained from all symptomatic individuals. <em>Mycobacterium tuberculosis (Mtb)</em> transrenal DNA (trDNA) has been detected in urine, an easily obtainable, noninvasive, alternative sample type. However, reported sensitivities have been variable and likely depend on collection and assay procedures and aspects of trDNA biology. We analyzed three serial urine samples from each of 75 adults with culture-confirmed pulmonary TB disease in Lima, Peru for detection of trDNA using short-fragment real-time PCR. Additionally, we examined host, urine, and sampling factors associated with detection. Overall per-sample sensitivity was 38 % (95 % Confidence Interval [CI] 30–45 %). On an individual level (i.e., any of the three samples positive), sensitivity was 73 % (95 % CI: 62–83 %). Sensitivity was highest among samples from patients with smear-positive TB, 92 % (95 % CI: 62–100 %). Specificity from a single sample from each of 10 healthy controls was 100 % (95 % CI: 69–100 %). Adjusting our assay positivity threshold increased individual-level sensitivity to 88 % (95 % CI: 78–94 %) overall without affecting the specificity. We did not find associations between <em>Mtb</em> trDNA detection and individual characteristics or urine sample characteristics. Overall, our results support the potential of trDNA detection for TB diagnosis.</p></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102549"},"PeriodicalIF":2.8,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1472979224000751/pdfft?md5=b29c2b797b3ffd1bc9783e0e65c2b591&pid=1-s2.0-S1472979224000751-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141890222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin modulates corticosteroids hormones in adrenals cells promoting Mycobacterium tuberculosis elimination in human macrophages","authors":"Oscar E. Gonzalez-Muñiz ,&nbsp;Adrián Rodriguez-Carlos ,&nbsp;Alan Santos-Mena ,&nbsp;Yolanda M. Jacobo-Delgado ,&nbsp;Irma Gonzalez-Curiel ,&nbsp;Cesar Rivas-Santiago ,&nbsp;Gabriela Navarro-Tovar ,&nbsp;Bruno Rivas-Santiago","doi":"10.1016/j.tube.2024.102548","DOIUrl":"10.1016/j.tube.2024.102548","url":null,"abstract":"<div><p>Research suggests that both tuberculosis (TB) and type 2 diabetes mellitus (T2DM) have an immuno-endocrine imbalance characterized by dysregulated proinflammatory molecules and hormone levels (high cortisol/DHEA ratio), impeding an effective immune response against <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) driven by cytokines, antimicrobial peptides (AMPs), and androgens like DHEA. Insulin, sulfonylurea derivatives, and metformin are commonly used glucose-lowering drugs in patients suffering from TB and T2DM. For this comorbidity, metformin is an attractive target to restore the immunoendocrine mechanisms dysregulated against <em>Mtb</em>. This study aimed to assess whether metformin influences cortisol and DHEA synthesis in adrenal cells and if these hormones influence the expression of proinflammatory cytokines and AMPs in <em>Mtb</em>-infected macrophages. Our results suggest that metformin may enhance DHEA synthesis while maintaining cortisol homeostasis. In addition, supernatants from metformin-treated adrenal cells decreased mycobacterial loads in macrophages, which related to rising proinflammatory cytokines and AMP expression (HBD-2 and 3). Intriguingly, we find that HBD-3 and LL-37 can modulate steroid synthesis in adrenal cells with diminished levels of cortisol and DHEA, highlighting the importance of crosstalk communication between adrenal hormones and these effectors of innate immunity. We suggest that metformin's effects can promote innate immunity against Mtb straight or through modulation of corticosteroid hormones.</p></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102548"},"PeriodicalIF":2.8,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141789149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host urinary biomarkers in HIV positive and HIV negative patients with tubercular uveitis and other uveitic diseases","authors":"Dian P. van der Westhuizen ,&nbsp;Candice I. Snyders ,&nbsp;Martin Kidd ,&nbsp;Gerhard Walzl ,&nbsp;Novel N. Chegou ,&nbsp;Derrick P. Smit","doi":"10.1016/j.tube.2024.102547","DOIUrl":"10.1016/j.tube.2024.102547","url":null,"abstract":"<div><h3>Purpose</h3><p>To determine if host urinary biomarker profiles could distinguish between tubercular uveitis (TBU) and other uveitic diseases (OUD) in patients with and without HIV infection.</p></div><div><h3>Methods</h3><p>Concentrations of 29 different host biomarkers were measured in urine samples using the Luminex platform. Data were analyzed to describe differences between patients diagnosed with and without TBU and with and without HIV co-infection.</p></div><div><h3>Results</h3><p>One-hundred-and-eighteen urine samples were collected and 39% participants were diagnosed as TBU+. Mean age TBU+ was 39.3±13.6 years with 45.7% males. Anterior and panuveitis and unilateral involvement were most common. 32.6% were TBU+HIV+ (median CD4+=215) while 40.2% were OUD+HIV+ (median CD4+=234). Only sVEGF3 was decreased in TBU+ versus OUD+ (p=0.03), regardless of HIV status. Some biomarkers were significantly raised in HIV+ TBU+ compared to HIV- TBU+: sIL-6Rα, CD30, sRAGE , sTNFR I&amp;-II, IP-10, MIP-1β, sEGFR and Ferritin. HIV+ OUD+ had increased sVEGFR3, CD30, sIL-6Rα, IP-10, sTNFR I&amp;-II, Ferritin and Haptoglobin compared to HIV- OUD+. VEGF-A (p = 0.04) was decreased in HIV+ OUD+ versus HIV- OUD+.</p></div><div><h3>Conclusion</h3><p>Decreased urinary concentrations of VEGFR3 were observed in TBU+ compared to TBU-. HIV+ individuals demonstrated increased concentrations of multiple urinary analytes when compared to HIV- patients with uveitis.</p></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102547"},"PeriodicalIF":2.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1472979224000738/pdfft?md5=13c131cee83acb721d2afded6319ff35&pid=1-s2.0-S1472979224000738-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141841030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study on the role and molecular mechanism of METTL3-mediated miR-29a-3p in the inflammatory response of spinal tuberculosis","authors":"Xiaojun Ma ,&nbsp;Yuxin Gao ,&nbsp;Zhibo Ren ,&nbsp;Hui Dong ,&nbsp;Xu Zhang ,&nbsp;Ningkui Niu","doi":"10.1016/j.tube.2024.102546","DOIUrl":"10.1016/j.tube.2024.102546","url":null,"abstract":"<div><h3>Background</h3><p>Spinal Tuberculosis (STB) is a common cause of spinal malformation caused by extrapulmonary tuberculosis in developing countries, which seriously affects the quality of life of patients. It was found that the expression of miRNAs in macrophages was stable, specific and readily available after Mycobacterium tuberculosis (MTB) infection. Our research group determined the differential expression of miR-29a-3p in the vertebra of spinal tuberculosis and intervertebral disc lesions through RNAs chip screening and bioinformatics analysis. However, the specific molecular mechanism of miR-29a-3p in the inflammatory response of spinal tuberculosis remains unclear.</p></div><div><h3>Objective</h3><p>In this study, we mainly discussed the expression of miR-29a-3p in the focal tissue of spinal tuberculosis and the role and molecular mechanism of miR-29a-3p mediated by METTL3 in the inflammatory response of spinal tuberculosis.</p></div><div><h3>Methods</h3><p>The tissues of 15 cases of lumbar degenerative diseases and vertebral lesions of spinal tuberculosis were collected, and the THP-1 macrophage model infected by Mycobacterium tuberculosis was constructed, and verified by qRT-PCR, Western blot, fluorescence in situ hybridization, immunohistochemistry, Cell fluorescence and ELISA.</p></div><div><h3>Results and conclusion</h3><p>We found that the expression of miR-29a-3p was significantly down-regulated in the vertebral body and disc lesion tissues of patients with spinal tuberculosis. Overexpression of miR-29a-3p inhibited the levels of inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and inhibition of miR-29a-3p expression promoted the release of the levels of TNF-α, IL-1β and IL-6 inflammatory factors. Our study also shows that knockout of methyltransferase 3 (METTL3) can significantly reduce the expression of miR-29a-3p and promote the release of pro-inflammatory cytokines in macrophages.</p></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102546"},"PeriodicalIF":2.8,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1472979224000726/pdfft?md5=cc5548338614bb1ad9040d2badd745e8&pid=1-s2.0-S1472979224000726-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141841998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical tests for salicylhydrazones derivatives to explore their potential for new antituberculosis agents","authors":"Andressa Lorena Ieque ,&nbsp;Carolina Trevisolli Palomo ,&nbsp;Vitória Gabriela de Freitas Spanhol ,&nbsp;Maria Luiza Fróes da Motta Dacome ,&nbsp;José Júnior do Carmo Pereira ,&nbsp;Francielli Cavalcante Candido ,&nbsp;Katiany Rizzieri Caleffi-Ferracioli ,&nbsp;Vera Lucia Dias Siqueira ,&nbsp;Rosilene Fressatti Cardoso ,&nbsp;Fábio Vandresen ,&nbsp;Vanessa Guimarães Alves-Olher ,&nbsp;Regiane Bertin de Lima Scodro","doi":"10.1016/j.tube.2024.102545","DOIUrl":"10.1016/j.tube.2024.102545","url":null,"abstract":"<div><h3>Purpose</h3><p>This study target the synthesis of 22 salicylhydrazones derivatives to apply <em>in vitro</em> screening to explore their potential in the search for new anti-TB prototypes drugs.</p></div><div><h3>Methods</h3><p>The minimum inhibitory concentration (MIC) were evaluated against <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) H₃₇Rv and clinical isolates. Drug combination assay, cytotoxicity assay, ethidium bromide accumulation assay (EtBr) and <em>in silico</em> analysis regarding the absorption, distribution, metabolism, excretion and toxicity (ADMET) and pharmacological properties were also performed.</p></div><div><h3>Results</h3><p>Three most promising compounds were selected (10, 11 and 18) to proceed with screening tests. Compound 18 presented the lowest MIC value (0.49 μg/mL) against <em>Mtb</em> H₃₇Rv strain, followed by compounds 11 (3.9 μg/mL) and 10 (7.8 μg/mL). All compounds showed activity against drug susceptible and resistant clinical isolates. Cytotoxicity results were promising for all salicylhydrazones, with SI values up to 4,205 for compound 18. The derivative 10 was the only one that demonstrated a non-promising cytotoxicity scenario for a single cell line. All derivatives showed an additive effect (FICI &gt;0.5 to 4.0) in combination with isoniazid, ethambutol and rifampicin.</p></div><div><h3>Conclusion</h3><p>All salicylhydrazones showed potential in the screening tests performed in this study and compound 18 stood out due to its activity against susceptible and resistant bacilli at low concentrations and low cytotoxicity.</p></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102545"},"PeriodicalIF":2.8,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141845962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional analysis of the Mycobacterium bovis AF2122/97 PhoPR system","authors":"Jose Maria Urtasun-Elizari ,&nbsp;Ruoyao Ma ,&nbsp;Hayleah Pickford ,&nbsp;Damien Farrell ,&nbsp;Gabriel Gonzalez ,&nbsp;Viktor Perets ,&nbsp;Chie Nakajima ,&nbsp;Yasuhiko Suzuki ,&nbsp;David E. MacHugh ,&nbsp;Apoorva Bhatt ,&nbsp;Stephen V. Gordon","doi":"10.1016/j.tube.2024.102544","DOIUrl":"10.1016/j.tube.2024.102544","url":null,"abstract":"<div><p>The PhoPR system is a master regulator in <em>Mycobacterium tuberculosis</em>. A key difference between <em>M</em>. <em>tuberculosis</em> and <em>Mycobacterium bovis</em> is a G71I substitution in the <em>M. bovis</em> PhoR orthologue. Functional studies of the <em>M. bovis</em> PhoPR system have generated conflicting findings, with some research suggesting that the <em>M. bovis</em> PhoPR is defective while others indicate it is functional.</p><p>We sought to revisit the functionality of the <em>M. bovis</em> PhoPR system. To address this, we constructed a <em>phoPR</em> mutant in the reference strain <em>M. bovis</em> AF2122/97. We employed a combination of growth assays and transcriptomics analyses to assess the phenotype of the mutant vs wild type and complemented strains. We found that the <em>M. bovis</em> AF2122/97 Δ<em>phoPR</em> mutant showed a growth defect on solid and liquid media compared to the wild type and complemented strains. The transcriptome of the <em>M. bovis</em> AF2122/97 Δ<em>phoPR</em> mutant was also altered as compared to wild type, including differential expression of genes involved in lipid metabolism and secretion. Our work provides further insight into the activity of PhoPR in <em>M. bovis</em> and underlines the importance of the PhoPR system as a master regulator of gene expression in the <em>Mycobacterium tuberculosis</em> complex.</p></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102544"},"PeriodicalIF":2.8,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1472979224000702/pdfft?md5=02d2a9138ca63808bebfd78f2a56fe26&pid=1-s2.0-S1472979224000702-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141630071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Genomic investigation of bone tuberculosis highlighted the role of subclinical pulmonary tuberculosis in transmission” [Tuberculosis (2024) 102534]","authors":"Jinfeng Yin ,&nbsp;Guangxuan Yan ,&nbsp;Liyi Qin ,&nbsp;Chendi Zhu ,&nbsp;Jun Fan ,&nbsp;Yuwei Li ,&nbsp;Junnan Jia ,&nbsp;Zhaojun Wu ,&nbsp;Hui Jiang ,&nbsp;Muhammad Tahir Khan ,&nbsp;Jiangdong Wu ,&nbsp;Naihui Chu ,&nbsp;Howard E. Takiff ,&nbsp;Qian Gao ,&nbsp;Shibing Qin ,&nbsp;Qingyun Liu ,&nbsp;Weimin Li","doi":"10.1016/j.tube.2024.102539","DOIUrl":"10.1016/j.tube.2024.102539","url":null,"abstract":"","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102539"},"PeriodicalIF":2.8,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1472979224000659/pdfft?md5=75905efa7a2e6d8648e3f1438c86f6e9&pid=1-s2.0-S1472979224000659-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141604213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repression of BRD4 mitigates NLRP3 inflammasome-mediated pyroptosis in Mycobacterium-infected macrophages by repressing endoplasmic reticulum stress","authors":"Qi-yuan Wang,&nbsp;Xiu-feng Yu,&nbsp;Wen-lan Ji","doi":"10.1016/j.tube.2024.102542","DOIUrl":"10.1016/j.tube.2024.102542","url":null,"abstract":"<div><p>Tuberculosis (TB) is the leading cause of human death worldwide due to <em>Mycobacterium tuberculosis</em> (Mtb) infection. Multiple lines of evidences have illuminated the emerging role of NLRP3 inflammasome-mediated pyroptosis in the clearance of pathogenic infection. In the current study, we sought to investigate the functional role and feasible potential mechanism of BRD4 in Mtb-infected macrophages. We observed that BRD4 was distinctly ascended in THP-1 macrophages upon Mtb infection. Functionally, intervention of BRD4 or pretreated with JQ1 obviously restricted Mtb-triggered cell pyroptosis, as evidenced by declination of protein level of the specific pyroptosis markers including Cleaved Caspase 1, gasdermin D (GSDMD-N) and Cleaved-IL-1β. In the meanwhile, disruption of BRD4 or JQ1 application remarkably prohibited excessive inflammatory responses as characterized by reduce the production of the inflammatory factors such as IL-1β and IL-18. Concomitantly, disruption of BRD4 or administrated with JQ1 manifestly repressed Mtb-aroused Nod-like receptor family pyrindomain-containing 3 (NLRP3) inflammasome activation, as witnessed by attenuation of protein levels of NLRP3, Pro-Caspase1 and apoptosis-associated speck-like protein (ASC). The above findings clearly demonstrated that suppression of BRD4 exerted great influence on regulating Mtb-elicited inflammatory response by coordinating NLRP3 inflammasome-mediated pyroptosis. More importantly, perturbation of BRD4 or JQ1 employment notably restrained endoplasmic reticulum (ER) stress triggered by Mtb-infection, as reflected by noticeably lessened the levels of GRP78, CHOP and ATF6. In terms of mechanism, ER stress agonist tunicamycin profoundly abrogated the favorable effects of BRD4 inhibition on Mtb-triggered pyroptosis, inflammation reaction and inflammasome activation. Collectively, these preceding outcomes strongly illuminated that inhibition of BRD4 targeted ER stress to retard NLRP3 inflammasome activation and subsequent cell pyroptosis and prevention of inflammatory response in Mtb-infected macrophages, highlighting that blocking BRD4 might serve as a promising candidate for protection against Mtb-triggered inflammatory injury.</p></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"148 ","pages":"Article 102542"},"PeriodicalIF":2.8,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141637276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}