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In vitro and in vivo activities of a novel benzothiopyranone candidate NTB-3119M against Mycobacterium tuberculosis 新型苯并噻吩吡喃酮候选物NTB-3119M抗结核分枝杆菌的体内外活性研究
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-06-02 DOI: 10.1016/j.tube.2025.102654
Manyi Xu , Lei Zhang , Bin Wang , Lei Fu , Shaochen Guo , Xi Chen , Weiyan Zhang , Gang Li , Peng Li , Haihong Huang , Yu Lu

Objectives

NTB-3119M, a novel benzothiopyranone derivative identified through comprehensive drug development studies, was selected as a promising antituberculosis (anti-TB) candidate. This study systematically evaluated its anti-TB efficacy in vitro and in vivo.

Methods

In vitro analyses encompassed antimicrobial susceptibility testing to determine minimum inhibitory concentrations (MICs) against Mycobacterium tuberculosis H37Rv, 10 drug-susceptible clinical isolates, and 30 multidrug-resistant (MDR) strains, alongside evaluations of minimal bactericidal concentrations (MBCs) using H37Rv and seven clinical isolates. Additionally, intracellular anti-mycobacterial activity was assessed in H37Rv-infected macrophages, and cytotoxicity was profiled through MTT assays on Vero cells. In vivo studies utilized acute and chronic murine tuberculosis infection models to investigate the dose-dependent efficacy of NTB-3119M (50 and 100 mg/kg) against H37Rv, with concurrent comparative histopathological analysis of lung and spleen tissues.

Results

NTB-3119M demonstrated superior in vitro potency against both drug-sensitive and drug-resistant M. tuberculosis strains compared to first-line agents, Isoniazid (INH), Rifampicin (RIF), Moxifloxacin (MOFX), Levofloxacin (LVFX), and Streptomycin (SM), exhibiting comparable activity to PBTZ169. Time-kill curves for NTB-3119M indicate its potent bactericidal activity. Meanwhile, No cytotoxicity was observed on Vero cells. Spontaneous resistant mutants of NTB-3119M appears at a frequency of 6.44 × 10−7 to 3.65 × 10−6. Most importantly, NTB-3119M demonstrates comparable activity of PBTZ169 and better bactericidal activity against M. tuberculosis than INH and RIF in the 50- and 100- mg/kg groups in acute and chronic murine models.

Conclusion

Our research provided comprehensive evidence that NTB-3119M with increased water solubility and bioavailability based on previous research performed excellent anti-tuberculosis activity and less cytotoxicity, which effectively tackled the undesirable drug properties associated with previous benzothiopyrone derivatives. It is warranted that NTB-3119M, as a highly promising candidate anti tuberculosis drug, deserves further research and clinical trial.
目的通过综合药物开发研究,鉴定出一种新型苯并噻吩吡喃酮衍生物ntb - 3119m,作为抗结核药物的候选药物。本研究系统评价了其体外和体内抗结核效果。方法采用体外药敏试验确定对结核分枝杆菌H37Rv、10株药敏临床分离株和30株多药耐药(MDR)菌株的最低抑菌浓度(mic),同时对H37Rv和7株临床分离株的最低杀菌浓度(MBCs)进行评估。此外,在h37rv感染的巨噬细胞中评估细胞内抗分枝杆菌活性,并通过MTT测定Vero细胞的细胞毒性。体内研究采用急性和慢性小鼠结核感染模型,研究NTB-3119M(50和100 mg/kg)对H37Rv的剂量依赖性作用,同时对肺和脾组织进行比较组织病理学分析。结果与一线药物异烟肼(INH)、利福平(RIF)、莫西沙星(MOFX)、左氧氟沙星(LVFX)和链霉素(SM)相比,sntb - 3119m对药敏和耐药结核分枝杆菌均表现出更强的体外药效,其活性与PBTZ169相当。NTB-3119M的时间杀伤曲线表明其具有较强的杀菌活性。同时,对Vero细胞无细胞毒性作用。NTB-3119M的自发耐药突变体出现频率为6.44 × 10−7 ~ 3.65 × 10−6。最重要的是,在急性和慢性小鼠模型中,NTB-3119M在50和100 mg/kg组中表现出与PBTZ169相当的活性,并且对结核分枝杆菌的杀菌活性优于INH和RIF。结论NTB-3119M具有较高的水溶性和生物利用度,具有较好的抗结核活性和较低的细胞毒性,有效地解决了以往苯并噻唑吡酮类药物的不良药性问题。NTB-3119M作为一种极具发展前景的抗结核候选药物,值得进一步研究和临床试验。
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引用次数: 0
Gut bacterial diversity in bovines infected with Mycobacterium tuberculosis var. bovis: insights on tuberculosis pathogenesis 牛结核分枝杆菌感染的肠道细菌多样性:对结核病发病机制的见解
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-05-27 DOI: 10.1016/j.tube.2025.102652
Cristine Cerva , Fabio Marcelo de Lima , Ana Paula Muterle Varela , Gabriela Merker Breyer , Jerônimo Miguel Vicenzi , Angélica Cavalheiro Bertagnolli , Vinícius Freitas Klain , Franciele Maboni Siqueira , Fabiana Quoos Mayer
Bovine tuberculosis susceptibility and pathogenesis are influenced by host immunity, which may be modulated by the host microbiota. While intestinal microbiota composition affects pulmonary diseases in humans, its role in bovine tuberculosis remains unclear. This study explores the intestinal microbiota of cattle and its association with tuberculosis to better understand disease pathophysiology. A case-control study was conducted using small intestine content samples from cattle with and without tuberculosis, slaughtered in Rio Grande do Sul, Brazil. DNA extraction, 16S rRNA (V4) sequencing, and bioinformatics analyses assessed alpha and beta diversity, taxa characterization, differential abundance, and metabolic pathways. No significant differences in alpha and beta diversities between the groups were detected. However, the Bacillota/Bacteroidota ratio suggested dysbiosis associated with bovine tuberculosis. Differential abundance analysis showed that microorganisms belonging to the Bacillota phylum, the Eubacterium cellulosolvens group, Colidextribacter and Coprococcus genera were enriched in healthy cattle. Conversely, animals with tuberculosis showed higher abundances of Verrucomicrobiota phylum, Sphingomonadaceae and Eubacteriaceae families, and Solobacterium and Clostridia-UCG-014 genera. Moreover, metabolic pathways related to carbohydrate degradation were enriched in healthy animals, and biosynthetic pathways related to disease were enriched in tuberculosis animals. This study highlights associations between intestinal microbiota and bovine tuberculosis, providing insights into disease mechanisms.
牛结核病的易感性和发病机制受宿主免疫的影响,宿主免疫可能受宿主微生物群的调节。虽然肠道菌群组成影响人类肺部疾病,但其在牛结核病中的作用尚不清楚。本研究探讨了牛的肠道微生物群及其与结核病的关系,以更好地了解疾病的病理生理。对巴西南大德州里约热内卢屠宰的患有和未患结核病牛的小肠内容物样本进行了病例对照研究。DNA提取、16S rRNA (V4)测序和生物信息学分析评估了α和β多样性、分类群特征、差异丰度和代谢途径。组间α和β多样性无显著差异。然而,芽孢杆菌/拟杆菌的比例表明与牛结核病相关的生态失调。差异丰度分析表明,健康牛体内富集了杆菌门、纤维素溶剂真杆菌群、Colidextribacter和Coprococcus属的微生物。相反,结核动物的Verrucomicrobiota门、Sphingomonadaceae和Eubacteriaceae以及Solobacterium和clostridium - ucg -014属的丰度较高。此外,与碳水化合物降解相关的代谢途径在健康动物中丰富,与疾病相关的生物合成途径在结核病动物中丰富。这项研究强调了肠道微生物群与牛结核病之间的联系,为疾病机制提供了见解。
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引用次数: 0
Hippocampal syndrome secondary to tuberculosis: From neuroinflammation to neurodegeneration 继发于结核的海马综合征:从神经炎症到神经退行性变
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-05-26 DOI: 10.1016/j.tube.2025.102653
José Cruz Mendoza-Torres , Nayar Durán-Hernández , José Alberto Choreño-Parra , Carlos Sánchez-Garibay , Citlaltepetl Salinas-Lara

Background

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a primary global health concern, with significant long-term sequelae. Central nervous system TB (CNS-TB) is a clinical spectrum with entities such as tuberculous meningitis and tuberculomas. Emerging evidence suggests that Mtb may directly or indirectly affect the hippocampus, a critical memory, learning, and cognition structure.

Objectives

This review aims to summarize the current biological understanding of Mtb's impact on the hippocampus, elucidate its potential role in neurodegeneration, and introduce the concept of “Hippocampal syndrome secondary to tuberculosis (HSST)" as a novel chronic entity within the CNS-TB spectrum.

Methods

A comprehensive literature review was conducted to analyze how Mtb gains access to the brain, its neurotropism, and the resulting neuroinflammatory and neurodegenerative effects on the hippocampus. Data from clinical, histopathological, and experimental studies were evaluated to assess potential links between TB and cognitive impairment.

Results

Mtb can access the CNS through hematogenous dissemination, the “Trojan Horse” mechanism, or via the olfactory pathway, bypassing the blood-brain barrier (BBB). Once in the brain, Mtb induces chronic neuroinflammation and disrupts hippocampal structure. Studies suggest that TB increases the risk of Alzheimer's and Parkinson's diseases, with evidence of Mtb-driven amyloid-beta accumulation and neuronal loss.
Furthermore, specific Mtb strains exhibit neurotropism and produce virulence factors that facilitate CNS invasion.

Conclusions

Understanding the interaction between TB and neurocognitive disorders is critical for improving post-TB care. Recognizing HSST as a chronic condition within the CNS-TB spectrum may support early diagnosis and targeted interventions to mitigate long-term neurological consequences.
由结核分枝杆菌(Mtb)引起的结核病(TB)仍然是全球主要的卫生问题,具有严重的长期后遗症。中枢神经系统结核(CNS-TB)是一种具有结核性脑膜炎和结核瘤等实体的临床谱。新出现的证据表明,结核分枝杆菌可能直接或间接影响海马体,一个重要的记忆、学习和认知结构。目的本综述旨在总结目前对结核分枝杆菌对海马体影响的生物学认识,阐明其在神经退行性变中的潜在作用,并介绍“结核分枝杆菌继发性海马体综合征(HSST)”作为CNS-TB谱中一种新的慢性实体的概念。方法通过文献综述,分析结核分枝杆菌如何进入大脑、嗜神经性以及对海马的神经炎症和神经退行性影响。对临床、组织病理学和实验研究的数据进行评估,以评估结核病与认知障碍之间的潜在联系。结果smtb可通过血液播散、“特洛伊木马”机制或通过嗅觉途径绕过血脑屏障(BBB)进入中枢神经系统。一旦进入大脑,结核分枝杆菌就会引起慢性神经炎症并破坏海马结构。研究表明,结核病增加了患阿尔茨海默病和帕金森病的风险,有证据表明,结核病会导致β淀粉样蛋白积累和神经元损失。此外,特定的结核分枝杆菌菌株表现出嗜神经性,并产生促进中枢神经系统侵袭的毒力因子。结论了解结核与神经认知障碍之间的相互作用对改善结核后护理至关重要。认识到HSST是CNS-TB谱系中的一种慢性疾病,可能有助于早期诊断和有针对性的干预,以减轻长期的神经系统后果。
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引用次数: 0
Reduced host cell-free DNA as a biomarker in latent tuberculosis infection among tuberculosis contacts 减少宿主无细胞DNA作为结核接触者潜伏性结核感染的生物标志物
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-05-09 DOI: 10.1016/j.tube.2025.102651
Jia-Yih Feng , Yen-Han Tseng , Chih-Jung Chang , Yu-Hsun Chiang , Sheng-Wei Pan , Wei-Juin Su , Yuh-Min Chen

Objectives

Circulating cell-free DNA (cfDNA), including mitochondrial cfDNA (mt-cfDNA) and nuclear cfDNA (nu-cfDNA), are potential biomarkers for infectious diseases. However, cfDNA variations in TB contacts with latent tuberculosis infection (LTBI) and their potential link to a predominance of M1 monocyte polarization in LTBI remain unexplored.

Methods

Contacts of TB patients were screened for LTBI using the Interferon gamma (IFN-γ) release assay. Blood cfDNA was extracted, and mt-cfDNA and nu-cfDNA copy numbers were quantified by qPCR. cfDNA levels in the supernatant of M1-polarized THP-1-derived macrophages were measured.

Results

Levels of mt-cfDNA and nu-cfDNA were lower in the LTBI group (n = 76) than in the uninfected group (n = 58) (p = 0.012, and p < 0.001). The results were consistent in an age- and sex-matched analysis (n = 41 pairs). mt-cfDNA and nu-cfDNA levels were negatively associated with the TB-specific IFN-γ response (p = 0.009, p < 0.001). In the LTBI group, mt-cfDNA was negatively associated with the index case's bacterial burden (p = 0.045). In cell model, mt-cfDNA and nu-cfDNA levels in the supernatant from M1-polarized macrophage were lower than those from M2-polarized cells (p = 0.030, p = 0.045).

Conclusions

TB contacts with LTBI had lower cfDNA levels, which correlated with index case infectivity. Reduced cfDNA in M1-polarized macrophages warrants further investigation into the mechanisms of cfDNA reduction in LTBI.
目的循环游离细胞DNA (cfDNA),包括线粒体cfDNA (mt-cfDNA)和核cfDNA (nu-cfDNA),是潜在的传染病生物标志物。然而,cfDNA在结核接触者潜伏性结核感染(LTBI)中的变异及其与LTBI中M1单核细胞极化优势的潜在联系仍未被探索。方法采用干扰素γ (IFN-γ)释放法对接触者进行LTBI筛查。提取血cfDNA,用qPCR法定量mt-cfDNA和nu-cfDNA拷贝数。检测m1极化thp -1衍生巨噬细胞上清液中cfDNA水平。结果LTBI组(n = 76) mt-cfDNA和nu-cfDNA水平低于未感染组(n = 58) (p = 0.012, p <;0.001)。在年龄和性别匹配分析(n = 41对)中,结果是一致的。mt-cfDNA和nu-cfDNA水平与结核病特异性IFN-γ反应呈负相关(p = 0.009, p <;0.001)。在LTBI组中,mt-cfDNA与指示病例的细菌负担呈负相关(p = 0.045)。在细胞模型中,m1极化巨噬细胞上清中mt-cfDNA和nu-cfDNA水平低于m2极化细胞(p = 0.030, p = 0.045)。结论stb与LTBI接触者cfDNA水平较低,与指示病例感染相关。m1极化巨噬细胞中cfDNA的减少值得进一步研究cfDNA减少在LTBI中的机制。
{"title":"Reduced host cell-free DNA as a biomarker in latent tuberculosis infection among tuberculosis contacts","authors":"Jia-Yih Feng ,&nbsp;Yen-Han Tseng ,&nbsp;Chih-Jung Chang ,&nbsp;Yu-Hsun Chiang ,&nbsp;Sheng-Wei Pan ,&nbsp;Wei-Juin Su ,&nbsp;Yuh-Min Chen","doi":"10.1016/j.tube.2025.102651","DOIUrl":"10.1016/j.tube.2025.102651","url":null,"abstract":"<div><h3>Objectives</h3><div>Circulating cell-free DNA (cfDNA), including mitochondrial cfDNA (mt-cfDNA) and nuclear cfDNA (nu-cfDNA), are potential biomarkers for infectious diseases. However, cfDNA variations in TB contacts with latent tuberculosis infection (LTBI) and their potential link to a predominance of M1 monocyte polarization in LTBI remain unexplored.</div></div><div><h3>Methods</h3><div>Contacts of TB patients were screened for LTBI using the Interferon gamma (IFN-γ) release assay. Blood cfDNA was extracted, and mt-cfDNA and nu-cfDNA copy numbers were quantified by qPCR. cfDNA levels in the supernatant of M1-polarized THP-1-derived macrophages were measured.</div></div><div><h3>Results</h3><div>Levels of mt-cfDNA and nu-cfDNA were lower in the LTBI group (n = 76) than in the uninfected group (n = 58) (p = 0.012, and p &lt; 0.001). The results were consistent in an age- and sex-matched analysis (n = 41 pairs). mt-cfDNA and nu-cfDNA levels were negatively associated with the TB-specific IFN-γ response (p = 0.009, p &lt; 0.001). In the LTBI group, mt-cfDNA was negatively associated with the index case's bacterial burden (p = 0.045). In cell model, mt-cfDNA and nu-cfDNA levels in the supernatant from M1-polarized macrophage were lower than those from M2-polarized cells (p = 0.030, p = 0.045).</div></div><div><h3>Conclusions</h3><div>TB contacts with LTBI had lower cfDNA levels, which correlated with index case infectivity. Reduced cfDNA in M1-polarized macrophages warrants further investigation into the mechanisms of cfDNA reduction in LTBI.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"153 ","pages":"Article 102651"},"PeriodicalIF":2.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943226","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}
引用次数: 0
Analysis of the cross-study replicability of tuberculosis gene signatures using 49 curated human transcriptomic datasets 利用49个整理的人类转录组数据集分析结核基因特征的交叉研究可重复性
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-05-08 DOI: 10.1016/j.tube.2025.102649
Xutao Wang , Katie Harper , Pranay Sinha , W. Evan Johnson , Prasad Patil

Background

Tuberculosis (TB) is the leading cause of infectious disease mortality worldwide. Numerous host blood-based gene expression signatures have been proposed in the literature as alternative tools for diagnosing TB infection. However, the generalizability of these signatures to different patient contexts is not well-characterized. There is a pressing need for a well-curated database of TB gene expression studies for the systematic assessment of existing and newly developed TB gene signatures.

Results

We built curatedTBData, a manually-curated database of 49 human TB transcriptomic studies. This data resource is freely available through GitHub and as an R Bioconductor package that allows users to validate new and existing biomarkers without the challenges of harmonizing heterogeneous studies. We demonstrate the use of this data resource with cross-study comparisons for 72 human host blood-based TB gene signatures. For the comparison of subjects with active TB from healthy controls, 19 gene signatures had weighted mean AUC of 0.90 or greater, with the highest result of 0.94. In active TB disease versus latent TB infection, 7 gene signatures had weighted mean AUC of 0.90 or greater, with a maximum of 0.93.

Conclusions

The curatedTBData data package offers a comprehensive resource of curated human blood-based gene expression and clinically annotated data. This resource will facilitate the development of new signatures that are generalizable across cohorts or more applicable to specific subsets of patients.
背景结核病(TB)是世界范围内传染病死亡的主要原因。文献中提出了许多基于宿主血液的基因表达特征作为诊断结核病感染的替代工具。然而,这些特征在不同患者情况下的普遍性并没有很好地表征。目前迫切需要一个精心设计的结核病基因表达研究数据库,以便系统地评估现有的和新开发的结核病基因特征。我们建立了curatedTBData,这是一个人工整理的49项人类结核病转录组学研究数据库。该数据资源可以通过GitHub和R Bioconductor包免费获得,允许用户验证新的和现有的生物标志物,而无需协调异构研究的挑战。我们通过对72个基于人类宿主血液的结核病基因特征进行交叉研究比较,证明了该数据资源的使用。与健康对照的活动性结核病患者相比,19个基因特征的加权平均AUC为0.90或更高,最高结果为0.94。在活动性结核与潜伏性结核感染中,7个基因特征的加权平均AUC大于等于0.90,最大值为0.93。curatedTBData数据包提供了一个综合的人类血液基因表达和临床注释数据资源。该资源将促进新特征的开发,这些特征可在整个队列中推广,或更适用于特定的患者亚群。
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引用次数: 0
Uncharted territory: the role of mitochondrial DNA variation in macrophage-mediated host susceptibility to tuberculosis 未知领域:线粒体DNA变异在巨噬细胞介导的宿主对结核病易感性中的作用
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-05-08 DOI: 10.1016/j.tube.2025.102650
Dayna Croock , Yolandi Swart , Tomasz Janusz Sanko , Vuyo Mavumengwana , Marlo Möller , Caitlin Uren , Desiree C. Petersen
Mitochondria form an integral, yet frequently underappreciated, part of the immune response to Mycobacterium tuberculosis (M.tb), particularly within macrophages. Despite growing recognition for their role in infection and immunity, studies investigating how mitochondrial DNA (mtDNA) variation influences host susceptibility to tuberculosis (TB) are limited. Notably, there are no studies in African-based populations, although Africans possess unparalleled human genetic diversity, including the earliest diverged mitochondrial haplogroups, and a high TB burden. This underrepresentation limits the discovery of novel ancestry-specific genetic loci associated with TB. In this review article, we describe the unique characteristics of mtDNA, highlight key mitochondrial functions relevant to macrophage responses during M.tb infection, and summarise published studies that investigate the role of host mtDNA variation in TB susceptibility. We further advocate for the inclusion of African populations in future studies to identify novel TB susceptibility genetic risk loci and expand the current knowledgebase on host TB susceptibility.
线粒体在对结核分枝杆菌(M.tb)的免疫反应中,尤其是在巨噬细胞中,是一个不可缺少的,但经常被低估的组成部分。尽管人们越来越认识到线粒体DNA (mtDNA)变异在感染和免疫中的作用,但关于线粒体DNA (mtDNA)变异如何影响宿主对结核病(TB)易感性的研究有限。值得注意的是,没有针对非洲人口的研究,尽管非洲人拥有无与伦比的人类遗传多样性,包括最早分化的线粒体单倍群,以及较高的结核病负担。这种代表性不足限制了发现与结核病相关的新的祖先特异性遗传位点。在这篇综述文章中,我们描述了mtDNA的独特特征,强调了与结核分枝杆菌感染期间巨噬细胞反应相关的关键线粒体功能,并总结了研究宿主mtDNA变异在结核易感性中的作用的已发表研究。我们进一步提倡在未来的研究中纳入非洲人群,以确定新的结核病易感性遗传风险位点,并扩大目前关于宿主结核病易感性的知识库。
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引用次数: 0
IL-27 signaling limits the diversity of antigen-specific T cells and interferes with protection induced by BCG vaccination IL-27信号限制抗原特异性T细胞的多样性并干扰卡介苗接种诱导的保护作用
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-04-23 DOI: 10.1016/j.tube.2025.102641
Ashley M. Divens , Kenneth J. Ryan , Alessandro Sette , Cecilia S. Lindestam Arlehamn , Cory M. Robinson
Tuberculosis (TB) is the leading cause of death due to a pathogen. The live-attenuated BCG vaccine is the only approved vaccine to prevent TB, but it fails to confer long-term protection. We hypothesize that the immunosuppressive cytokine IL-27 may contribute to the inefficacies of the BCG vaccine. IL-27 is elevated in neonates, the population most commonly administered BCG, and levels increase further upon vaccination. IL-27 interferes with the phagolysosomal pathway, suggesting it may limit the diversity of antigens processed and presented to T cells. We hypothesized that in the absence of IL-27 signaling, BCG vaccination induces antigen-specific T cells that recognize a greater number of antigens and provide enhanced protection during M. tuberculosis (Mtb) challenge. CD3+ T cells isolated from IL-27Rα KO mice vaccinated with BCG as neonates were more responsive to BCG and a Mtb peptide pool than T cells from vaccinated WT mice. Adoptive transfer of IL-27Rα KO T cells provided more consistent protection against Mtb than WT, but this was not observed in TCRα−/− mice. A principal component analysis suggested a more consistent multifunctional cytokine response was associated IL-27Rα KO T cells. These findings enhance our understanding of IL-27 during neonatal vaccination and development of protective immunity.
结核病(TB)是由病原体导致死亡的主要原因。减毒卡介苗是唯一被批准用于预防结核病的疫苗,但它不能提供长期保护。我们推测免疫抑制因子IL-27可能是卡介苗无效的原因之一。IL-27在最常接种卡介苗的新生儿中升高,接种后水平进一步升高。IL-27干扰吞噬溶酶体途径,表明它可能限制抗原加工并呈递给T细胞的多样性。我们假设,在缺乏IL-27信号的情况下,卡介苗接种诱导抗原特异性T细胞识别更多的抗原,并在结核分枝杆菌(Mtb)攻击期间提供增强的保护。新生期接种卡介苗的IL-27Rα KO小鼠分离的CD3+ T细胞对卡介苗和结核分枝杆菌肽库的反应强于接种WT小鼠的T细胞。IL-27Rα KO T细胞的过继转移比WT对Mtb具有更一致的保护作用,但在TCRα−/−小鼠中没有观察到这一点。主成分分析表明,更一致的多功能细胞因子反应与IL-27Rα KO T细胞有关。这些发现增强了我们对新生儿免疫接种和保护性免疫发展过程中IL-27的理解。
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引用次数: 0
Customized MHC Class I & II restricted peptides from clinical isolates of Mycobacterium tuberculosis tweak strong cellular immune response in Healthy individuals and Pulmonary Tuberculosis patients: A potential candidate in vaccine design 从结核分枝杆菌临床分离株中定制的MHC I类和II类限制性肽在健康个体和肺结核患者中改变了强烈的细胞免疫反应:疫苗设计的潜在候选物
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-04-15 DOI: 10.1016/j.tube.2025.102640
Niharika Sharma , Beenu Joshi , Bhawna Sharma , Santosh Kumar , Keshar Kunja Mohanty , Hridayesh Prakash
Tuberculosis (TB) remains a global health challenge as annual mortality rate due to drug resistant TB is increasing exponentially. This is mostly associated with the delayed diagnosis of Multidrug-resistant (MDR) or latent TB. Effective management of TB demands development of novel immunological strategies, such as peptide-based/subunit vaccines that can stimulate specific immune responses. In this context, we evaluated the immunogenic potential of two Major Histocompatibility Complex (MHC) Class I/II-restricted peptides from Mycobacterium tuberculosis (M. tuberculosis): Rv2588c and Rv0148. The peptides were tested on T and monocyte populations from healthy donors and pulmonary TB (PTB) patients. Flow cytometry analysis revealed significant T cell activation in peripheral blood mononuclear cells (PBMC) from both groups. Enzyme-linked immunosorbent assay (ELISA) demonstrated a strong IFN-γ response, confirming effective T cell activation. Additionally, these peptides induced increased nitric oxide (NO) production in macrophages, indicating their role in activating the innate immune system. Overall, Rv2588c and Rv0148 peptides exhibited robust immunogenicity, stimulating both adaptive and innate immune responses in PBMCs from healthy and PTB individuals. These findings highlight their potential as promising TB vaccine candidates, paving the way for improved TB treatment and prevention strategies.
由于耐药结核病每年造成的死亡率呈指数级增长,结核病仍然是全球卫生挑战。这主要与耐多药(MDR)或潜伏性结核病的诊断延迟有关。结核病的有效管理需要开发新的免疫策略,例如可以刺激特异性免疫反应的肽基/亚单位疫苗。在这种情况下,我们评估了结核分枝杆菌(M. tuberculosis)的两种主要组织相容性复合体(MHC) I/ ii类限制性肽的免疫原性潜力:Rv2588c和Rv0148。这些肽在健康供体和肺结核患者的T细胞和单核细胞群体中进行了测试。流式细胞术分析显示两组外周血单个核细胞(PBMC) T细胞活化显著。酶联免疫吸附试验(ELISA)显示了强烈的IFN-γ反应,证实了有效的T细胞激活。此外,这些肽诱导巨噬细胞中一氧化氮(NO)的产生增加,表明它们在激活先天免疫系统中的作用。总的来说,Rv2588c和Rv0148肽表现出强大的免疫原性,在健康和肺结核患者的pbmc中刺激适应性和先天免疫反应。这些发现突出了它们作为有希望的结核病候选疫苗的潜力,为改进结核病治疗和预防战略铺平了道路。
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引用次数: 0
Characterization of the global bovine microRNAome of peripheral blood mononuclear cells isolated from Mycobacterium bovis exposed cattle 暴露牛分枝杆菌分离的牛外周血单个核细胞的整体microRNAome特征
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-04-04 DOI: 10.1016/j.tube.2025.102639
Anna E. Karagianni , Lindert Benedictus , Sabine Steinbach , Femke Broere , Elisabeth M.D.L. van der Heijden
Accurate diagnostics are urgently needed for bovine TB – an economically devastating disease posing a re-emerging threat to veterinary and public health worldwide. MicroRNAs, post-transcriptional gene regulators involved in a range of biological processes and immunological pathways, have emerged as promising diagnostic biomarkers for numerous diseases. In human TB, microRNAs have been widely studied, but not much is currently known about their role in bovine TB. This study aimed to investigate the diagnostic potential of microRNAs in bTB through comprehensive analysis of their expression profiles in disparate states of M. bovis exposure. We used RNA-sequencing to characterize the global microRNAome of peripheral blood mononuclear cells from cattle that were either unvaccinated, BCG-vaccinated, unprotected or protected. A total of 468 microRNAs were detected across all samples, none of which were uniquely expressed in any group. Significant differential expression was observed for bta-miR-6122–3p, bta-miR-3533 and bta-miR29b in various comparisons. Subsequent target analysis of bta-miR-29b, a candidate biomarker in human tuberculosis, revealed that several genes (ACVR2A, PIK3R1, TBX21, TGFBR1 and TGFBR2) involved in a number of relevant T-cell and immune signaling pathways, were amongst the predicted targets. Overall, this study provides evidence that microRNAs could be promising novel biomarkers for bovine TB diagnostics.
牛结核病是一种经济上具有破坏性的疾病,对全世界的兽医和公共卫生构成了重新出现的威胁,迫切需要准确的诊断。microrna是参与一系列生物过程和免疫途径的转录后基因调控因子,已成为许多疾病的有希望的诊断生物标志物。在人类结核病中,microrna已经得到了广泛的研究,但是目前对它们在牛结核病中的作用知之甚少。本研究旨在通过综合分析microrna在牛分枝杆菌暴露不同状态下的表达谱,探讨microrna在bTB中的诊断潜力。我们使用rna测序来表征未接种、接种bcg、未接种或保护的牛外周血单个核细胞的全局microRNAome。在所有样本中共检测到468个microrna,其中没有一个在任何组中唯一表达。在各种比较中,bta-miR-6122-3p、bta-miR-3533和bta-miR29b的表达存在显著差异。随后对人类结核病候选生物标志物bta-miR-29b的靶标分析显示,参与许多相关t细胞和免疫信号通路的几个基因(ACVR2A, PIK3R1, TBX21, TGFBR1和TGFBR2)是预测的靶标之一。总的来说,这项研究提供了证据,证明microrna可能是牛结核病诊断中有希望的新型生物标志物。
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引用次数: 0
Response to “Prevalence of non-tuberculous mycobacteria by Line-Probe Assay” 对“线探针法检测非结核分枝杆菌患病率”的回应
IF 2.8 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-04-02 DOI: 10.1016/j.tube.2025.102637
Elizna Maasdorp , Monique J. Williams
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引用次数: 0
期刊
Tuberculosis
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