Tuberculosis Treatment Strategies Research Articles

Mechanistic and dynamic insight into novel IL7 receptor activators as immunotherapy for the treatment of tuberculosis

The bacterium that causes tuberculosis (TB), Mycobacterium tuberculosis, is still a significant global public health problem due to its contagious nature and the emergence of drug-resistant variants. This study leverages network pharmacology and computational drug discovery to identify genes linked to TB using the GSE54992 and GSE62525 datasets. In active tuberculosis patients, it identifies 162 DEGs that are not present in healthy people. The research includes an investigation of gene ontology (GO) and protein–protein interaction (PPI) networks to provide a comprehensive understanding of these DEGs. Crucially, it identifies ten hub genes: IL7R, CCR7, CXCR5, CCR6, CCR9, S1PR1, BACH2, CXCL5, SPIB, and EBF. The research suggests IL7R as a potential therapeutic target because of its essential role in FoxO signalling pathways and cytokine-cytokine receptor interaction. IL7 and its receptor (IL7R) are vital for T cell functionality and essential in combating TB. The study explores novel small-molecule activators for IL7R (IL7Rα), aiming to boost the immune response against TB. The following four compounds were found using molecular dynamics simulation, virtual screening, computational pharmacophore modelling, and MM/GBSA analytical techniques: ZINC02131028, ZINC02135418, ZINC46007405, and ZINC59273354. These activators may enhance the IL7 signalling pathway, potentially strengthening the immune fight against M. tuberculosis. Among these ZINC02131028 showed the best results to activate IL7 by binding to its active site, stabilizing its active conformation and enhancing its interaction with the IL7 receptor (IL7R). The findings encourage experimental validation of these IL7 activators, marking a significant step towards innovative TB treatment strategies.

Transcriptome analysis and molecular characterization of novel small RNAs in Mycobacterium tuberculosis Lineage 1.

Mycobacterium tuberculosis (Mtb), the tuberculosis-causing agent, exhibits diverse genetic lineages, with known links to virulence. While genomic and transcriptomic variations between modern and ancient Mtb lineages have been explored, the role of small non-coding RNA (sRNA) in post-translational gene regulation remains largely uncharted. In this study, Mtb Lineage 1 (L1) Sabahan strains (n = 3) underwent sRNA sequencing, revealing 351 sRNAs, including 23 known sRNAs and 328 novel ones identified using ANNOgesic. Thirteen sRNAs were selected based on the best average cut-off value of 300, with RT-qPCR revealing significant expression differences for sRNA 1 (p = 0.0132) and sRNA 29 (p = 0.0012) between Mtb L1 and other lineages (L2 and L4, n = 3) (p > 0.05). Further characterization using RACE (rapid amplification of cDNA ends), followed by target prediction with TargetRNA3 unveils that sRNA 1 (55 base pairs) targets Rv0506, Rv0697, and Rv3590c, and sRNA 29 (86 base pairs) targets Rv33859c, Rv3345c, Rv0755c, Rv0107c, Rv1817, Rv2950c, Rv1181, Rv3610c, and Rv3296. Functional characterization with Mycobrowser reveals these targets involved in regulating intermediary metabolism and respiration, cell wall and cell processes, lipid metabolism, information pathways, and PE/PPE. In summary, two novel sRNAs, sRNA 1 and sRNA 29, exhibited differential expression between L1 and other lineages, with predicted roles in essential Mtb functions. These findings offer insights into Mtb regulatory mechanisms, holding promise for the development of improved tuberculosis treatment strategies in the future.

Trend of pulmonary tuberculosis and rifampicin-resistance among tuberculosis presumptive patients in Central Tigray, Ethiopia; 2018 -2023: a six-year retrospective study

BackgroundTuberculosis (TB) is a major public health concern in the developing countries. Moreover, the emergence of multidrug-resistant tuberculosis is challenging. However, there are no organized data on the trends of pulmonary tuberculosis and rifampicin-resistant Mycobacterium tuberculosis in the study area.MethodsA retrospective cross-sectional study was conducted to fill the information gap in Central Tigray at St. Mary General Hospital between 2018 and 2023. Data were collected from the GeneXpert™ tuberculosis registration logbooks using standard checklists and analyzed using Statistical Package for Social Science version 22. After performing logistic regression, a p-value < 0.05 with a corresponding 95% confidence interval was considered statistically significant. Moreover, chi square test for trend was performed to assess the percentage of annual detection of pulmonary tuberculosis and rifampicin-resistant Mycobacterium tuberculosis during the study years.ResultPresumptive pulmonary tuberculosis patients with complete data (n = 3696) were included in the study. The overall prevalence of pulmonary tuberculosis was 11.7%, of which 8.1% were resistant to rifampicin. The study revealed that the incidence of pulmonary tuberculosis has been increasing, mainly in the recent four years. Likewise, an increase in rifampicin-resistant Mycobacterium tuberculosis was observed with considerable fluctuations. Age, human immunodeficiency virus infection, and presumptive rifampicin-resistant Mycobacterium tuberculosis infection were significantly associated with the presence of pulmonary tuberculosis. Moreover, pulmonary tuberculosis was more prevalent among participants in the productive-age group.ConclusionAlthough there have been fluctuations, an increasing of pulmonary tuberculosis and rifampicin-resistant Mycobacterium tuberculosis has been observed in recent years. Hence, prevention and treatment strategies for tuberculosis should be strengthened to alleviate the burden of pulmonary tuberculosis and rifampicin-resistant Mycobacterium tuberculosis in the study area.

The Practice and Modalities of African Traditional Medicine in Tuberculosis Treatment - A Traditional Medical Practitioners’ Perspective

Aims: This study sought to explore the role of the traditional medical practitioner (TMP) and document the modalities of tuberculosis (TB) treatment in traditional medicine (TM) in Harare, Zimbabwe. Study design: An ethnographic research survey of TMPs in Harare urban. Place and Duration of Study: Harare’s southern suburbs of Warren Park, Mufakose, Budiriro, Belvedere, Mbare (Mupedzanhamo) and Harare central business district, between April and June 2021. Methodology: Fourteen (14) experienced TB practitioners, registered with the Zimbabwe National Traditional Healers Association (ZINATHA) were recruited for the study. These included exclusive herbalists (36%), spiritualists (14%) and those who used a combination of spiritualism and herbalism (50%) in their practice. Data was collected through semi-structured in-person interviews. The practices and treatment modalities in the traditional treatment of TB were documented; and any linkages with the conventional medical system were identified. Results: Forty-six (46) plant species from 28 families were prescribed in various polyherbal combinations for a maximum of 6 months in difficult cases. TMPs were found to be relevant and knowledgeable in the treatment of TB. In addition to offering alternative or complementary treatment options to patients, TMPs were also agents of health education promotion, and collaborated to some extent with allopathic healthcare providers across the service delivery system from diagnosis to treatment of patients. Conclusion: If formalized, TMPs have the potential to make considerable contributions to TB treatment strategies and help improve treatment outcome in TB patients.

Evaluation of factors associated with acceptance of adherence and toxicity levels in the treatment of tuberculosis infection and effectiveness of the treatment

Tuberculosis treatment remains a challenge due to the need to consider, when approaching it, the context of individual and collective health. In addition, social and economic issues have been shown to be variables that need to be considered when it comes to treatment effectiveness. In a small proportion of cases, the bacillus is transmitted to humans from infected cows through drinking non-sterilized milk. This mode of transmission plays only a minor role in the natural history of the disease in humans. This study explores factors influencing acceptance of adherence and toxicity levels in tuberculosis treatment, aiming to assess their impact on treatment effectiveness. Through comprehensive evaluation, aim to identify key variables contributing to patient compliance and potential barriers to successful outcomes, shedding light on optimizing tuberculosis treatment strategies.

Analysis on time delay of tuberculosis among adolescents and young adults in Eastern China.

Tuberculosis (TB) is recognized as a significant global public health concern. Still, there remains a dearth of comprehensive evaluation regarding the specific indicators and their influencing factors of delay for adolescents and young adults. All notified pulmonary TB (PTB) patients in Jiaxing City were collected between 2005 and 2022 from China's TB Information Management System. Logistic regression models were conducted to ascertain the factors that influenced patient and health system delays for PTB cases, respectively. Furthermore, the impact of the COVID-19 pandemic on local delays has been explored. From January 1, 2005 to December 31, 2022, a total of 5,282 PTB cases were notified in Jiaxing City, including 1,678 adolescents and 3,604 young adults. For patient delay, female (AOR: 1.18, 95%CI: 1.05-1.32), PTB complicated with extra-pulmonary TB (AOR: 1.70, 95% CI: 1.28-2.26), passive case finding (AOR: 1.46, 95% CI: 1.07-1.98) and retreatment (AOR: 1.52, 95% CI: 1.11-2.09) showed a higher risk of delay. For health system delay, minorities (AOR: 0.69, 95% CI: 0.53-0.90) and non-students (AOR: 0.83, 95% CI: 0.71-0.98) experienced a lower delay. Referral (AOR: 1.46, 95% CI: 1.29-1.65) had a higher health system delay compared with clinical consultation. Furthermore, county hospitals (AOR: 1.47, 95% CI: 1.32-1.65) and etiological positive results (AOR: 1.46, 95% CI: 1.30-1.63) were associated with comparatively high odds of patient delay. Contrarily, county hospitals (AOR: 0.88, 95% CI: 0.78-1.00) and etiological positive results (AOR: 0.67, 95% CI: 0.59-0.74) experienced a lower health system delay. Besides, the median of patient delay, health system delay, and total delay during the COVID-19 pandemic were significantly lower than that before. In general, there has been a noteworthy decline in the notification rate of PTB among adolescents and young adults in Jiaxing City while the declining trend was not obvious in patient delay, health system delay, and total delay, respectively. It also found factors such as gender, case-finding method, and the hospital level might influence the times of seeking health care and diagnosis in health agencies. These findings will provide valuable insights for refining preventive and treatment strategies for TB among adolescents and young adults.

Pharmacogenetic Study of Drugs Affecting Mycobacterium tuberculosis.

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. 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. 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). 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.

Genetic diversities of Mycobacterium tuberculosis complex species in Western Kenya.

Tuberculosis (TB) remains a high-burden infectious disease worldwide. Mycobacterium tuberculosis complex (MTBC) is the aetiological agent of TB. The TB burden is significantly linked to the development of drug-resistant strains. Thus, there is an urgent need for close surveillance of MTBC circulating in a given region, such as Western Kenya, for treatment of TB. To determine the proportion of MTBC species, strains and genetic diversities in circulation in HIV/AIDS-prevalent regions, and Western Kenya in particular. The clinical MTBC isolates were collected from Moi Teaching and Referral Hospital (MTRH) at Eldoret-Kenya during 2013-14. All clinical MTBC isolates were confirmed by the gold standard method (Löwenstein-Jensen medium culture) before inclusion in the investigation. Twelve-loci mycobacterium interspersed repetitive unit - variable-number tandem repeats (MIRU-VNTR) genotyping was performed to determine the circulating species/strains of MTBC using the www.miru-vntrplus.org web platform. Allelic diversity was calculated using the Hunter-Gaston diversity index (HGDI). The species M. tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium pinnipedii, Mycobacterium microti, Mycobacterium caprae and Mycobacterium canetti were identified in the MTBC population. These strains were found in the Beijing, Latin American Mediterranean, Uganda 1/2, East African Indian, Ilama, West African 1/2, Harlem, URAL, Ghana, Seal, Cameroon and Vole etc. regions of Western Kenya. Notably, some isolates had unknown (new/unassigned) species. The strains were grouped into nine clusters with a clustering rate of 31.18 % and a high allelic diversity index of 0.53 was observed. The present findings suggest that there is an urgent need for more awareness among healthcare professionals and stakeholders concerning the existence of foreign MTBC species/strains in Kenya. Furthermore, 12-loci MIRU-VNTR may not be suitable for the surveillance of MTBC strains in circulation in Kenya. Thus, high-resolution techniques such as whole-genome sequencing need to be adopted to resolve the genetic diversity and establish evolutionary trends for future and archived samples. This knowledge will be crucial in restraining TB, providing insights into new drug development, and developing prevention, control and treatment strategies for TB.

Comparative proteome analysis revealed the differences in response to both Mycobacterium tuberculosis and Mycobacterium bovis infection of bovine alveolar macrophages.

Tuberculosis (TB), attributed to the Mycobacterium tuberculosis complex, is one of the most serious zoonotic diseases worldwide. Nevertheless, the host mechanisms preferentially leveraged by Mycobacterium remain unclear. After infection, both Mycobacterium tuberculosis (MTB) and Mycobacterium bovis (MB) bacteria exhibit intimate interactions with host alveolar macrophages; however, the specific mechanisms underlying these macrophage responses remain ambiguous. In our study, we performed a comparative proteomic analysis of bovine alveolar macrophages (BAMs) infected with MTB or MB to elucidate the differential responses of BAMs to each pathogen at the protein level. Our findings revealed heightened TB infection susceptibility of BAMs that had been previously infected with MTB or MB. Moreover, we observed that both types of mycobacteria triggered significant changes in BAM energy metabolism. A variety of proteins and signalling pathways associated with autophagy and inflammation-related progression were highly activated in BAMs following MB infection. Additionally, proteins linked to energy metabolism were highly expressed in BAMs following MTB infection. In summary, we propose that BAMs may resist MTB and MB infections via different mechanisms. Our findings provide critical insights into TB pathogenesis, unveiling potential biomarkers to facilitate more effective TB treatment strategies. Additionally, our data lend support to the hypothesis that MTB may be transmitted via cross-species infection.

Role Of Plant-Based Bioflavonoids in Combating Tuberculosis

Innovative strategies are required to address the ongoing threat of tuberculosis (TB), which continues to be a serious worldwide health issue. Growing interest has been paid to plant-based bioflavonoids because of their potential as TB adjunctive treatments. This chapter offers a thorough examination of the varied function of bioflavonoids in TB treatment. The first sections highlight bioflavonoids' natural defense roles in plants while describing their chemical diversity and origins. We study the mechanisms of action of bioflavonoids on Mycobacterium TB, including how they interfere with biofilm development, virulence factors, and host immunological responses. Notably, the potential for decreased drug resistance and shortened treatment durations is highlighted when discussing the synergistic effects between bioflavonoids and traditional TB medications. The anti-inflammatory properties of bioflavonoids are examined in the context of TB pathogenesis, addressing their role in modulating inflammatory responses and mitigating tissue damage. Clinical studies evaluating bioflavonoid efficacy, safety, and bioavailability are reviewed, providing insights into their therapeutic potential. Challenges associated with bioavailability and formulation are also discussed, highlighting strategies to optimize drug delivery.Incorporating ethnobotanical perspectives, we explore historical plant-based remedies for TB and the integration of traditional knowledge with modern research. The abstract concludes by outlining future directions, emphasizing promising bioflavonoid candidates for TB treatment, targeting latent infections, and advocating for collaborative, interdisciplinary research efforts. Ultimately, this chapter underscores the promising role of plant-based bioflavonoids as a potential avenue for enhancing the efficacy and resilience of TB treatment strategies, offering hope for improved outcomes in TB management.

Herp regulates intracellular survival of Mycobacterium tuberculosis H37Ra in macrophages by regulating reactive oxygen species-mediated autophagy.

Several studies have suggested that endoplasmic reticulum (ER) stress is important in the pathogenesis of infectious diseases; however, the precise function of ER stress regulation and the role of Herp as a regulator in Mtb H37Ra-induced ER stress remain elusive. Therefore, our study investigated ER stress and autophagy associated with Herp expression in Mycobacterium tuberculosis-infected macrophages to determine the role of Herp in the pathogenesis of tuberculosis.

Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines Targeting Mycobacterium tuberculosis.

The rise in multidrug resistant tuberculosis cases underscores the urgent need to develop new treatment strategies for tuberculosis. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition of Mycobacterium tuberculosis (Mtb) growth and survival. Structure-activity relationship studies led us to identify several potent analogs displaying low micromolar to nanomolar inhibitory activity, specifically against Mtb. The potent analogs demonstrated no cytotoxicity in mammalian cells at over 100 times the effective concentration required in Mtb and were bactericidal against Mtb during infection of macrophages. In the exploratory ADME investigations, we observed suboptimal ADME characteristics, which prompted us to identify potential metabolic liabilities for further optimization. Our preliminary investigations into the mechanism of action suggest that this series is not engaging the promiscuous targets that arise from many phenotypic screens. We selected for resistant mutants with the nanomolar potent nitro-containing compound 20 and identified resistant isolates with mutations in genes required for coenzyme F420 biosynthesis and the nitroreductase Ddn. This suggests that the aromatic nitro-1,2,4-triazolyl pyridines are activated by F420-dependent Ddn activity, similar to the nitro-containing TB drug pretomanid. We were able to circumvent the requirement for F420-dependent Ddn activity using compounds that contained non-nitro groups, identifying a key feature to be modified to avoid this predominant resistance mechanism. These studies provide the foundation for the development of a new class of 1,2,4-triazole compounds for the treatment of tuberculosis.

Host-Directed Therapies for Tuberculosis.

Tuberculosis (TB) is one of the leading causes of death worldwide, consistently threatening public health. Conventional tuberculosis treatment requires a long-term treatment regimen and is associated with side effects. The efficacy of antitubercular drugs has decreased with the emergence of drug-resistant TB; therefore, the development of new TB treatment strategies is urgently needed. In this context, we present host-directed therapy (HDT) as an alternative to current tuberculosis therapy. Unlike antitubercular drugs that directly target Mycobacterium tuberculosis (Mtb), the causative agent of TB, HDT is an approach for treating TB that appropriately modulates host immune responses. HDT primarily aims to enhance the antimicrobial activity of the host in order to control Mtb infection and attenuate excessive inflammation in order to minimize tissue damage. Recently, research based on the repositioning of drugs for use in HDT has been in progress. Based on the overall immune responses against Mtb infection and the immune-evasion mechanisms of Mtb, this review examines the repositioned drugs available for HDT and their mechanisms of action.

Compliance of patients to DOTS tuberculosis treatment strategy in a South-East Nigeria Teaching Hospital.

Tuberculosis ranks the second highest cause of adult mortality after HIV in the world. The Directly Observed Treatment Short course (DOTS) strategy is aimed at following up on patients' adherence to treatment regimen. To assess the level of compliance of patients to the DOTS strategy. A retrospective study of patients seen at the University of Nigeria Teaching Hospital from January, 2013 to April, 2015. Relevant information was collected from patients' folders. Data analysis was with the SPSS and results represented in tables. 111 (50%) patients were compliant with their DOTS treatment plan while 107 (41.3%) were non-compliant. Ninety-two patients (41.4%) were successfully treated and discharged home, 7 patients (3.2%) referred to other centres. The proportion of patients regarding their marital status, occupation, educational level and address that was compliant to the DOTS TB reflected varied patterns. The study reflected poor to average compliance to DOTS. There is a need for creation of more DOTS centres; regular surveys and updates on DOTS TB strategy should be the norm rather than the exception.

Novel heterocyclic hydroxamates as inhibitors of the mycobacterial zinc metalloprotease Zmp1 to probe its mechanism of function

Mycobacterial zinc metalloprotease-1 (Zmp1) is an essential enzyme for intracellular survival and pathogenicity of Mycobacterium tuberculosis. However, the exact mechanism of function of this enzyme remains unclear. This paper examines the effect of novel organic molecules on the inhibition of Zmp1. We followed our previous results and synthesised three libraries of new hydroxamates. All compounds were studied for their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis by MALDI-TOF MS. Furthermore, a macrophage infection assay was performed to evaluate intracellular antimycobacterial activity. In the whole-cell assay, no direct activity of synthesised heterocyclic hydroxamates was observed against Mycobacterium tuberculosis and Mycobacterium bovis. No acute cellular toxicity was observed against the murine RAW 264.7 macrophage cell line and human MRC-5 lung fibroblast cell line. However, thiazolidinediones 2 showed the dose-dependent inhibition of intracellular survival of Mycobacterium tuberculosis H37Ra. The inhibition was structure-dependent, with the most active derivative 2f inducing an 83.2% reduction of bacterial survival within the macrophage host cell. The promising biological activity confirmed thiazolidinediones 2 as Zmp1 inhibitors that can be used as tool compounds for further exploration of the role of Zmp1 for in vivo pathogenicity. In the long run, thiazolidinediones 2 show the potential to act as a scaffold for Zmp1 inhibitors to target intracellular Mtb as a novel tuberculosis treatment strategy.

High-throughput fluorescent screening of β-lactamase inhibitors to improve antibiotic treatment strategies for tuberculosis

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which is a major threat to global public health. Currently, β-lactam antibiotics are rarely used in the treatment of TB, since Mtb naturally expresses β-lactamase (Blac) which renders Mtb resistant to such antibiotics due to β-lactam cleavage. Fortunately, antibiotic resistance can be overcome when β-lactam antibiotics are combined with a Blac inhibitor. With the current research, a near-infrared fluorescent probe LXMB was developed for the real-time detection and imaging of endogenous Blac activity in Mtb. Furthermore, a high-throughput screening platform was established using LXMB to screen Blac inhibitors from herbal medicines. Guided by the visual bioassay, Tannic acid was isolated from Galla Chinensis as a potential Blac inhibitor and was further evaluated in combination with several β-lactam antibiotics which resulted in an enhanced inhibitory effect toward M. tuberculosis H37Ra. Finally, LXMB was used to label live M. tuberculosis H37Ra phagocytosed within macrophages. Consequently, LXMB was a useful fluorescent tool to explore the mechanism of drug resistance based on Blac and can assist in the development of new tuberculosis treatments.

Comparing the Treatment Outcomes of Tuberculosis Patients in a Private Clinic with a Governmental Health Center in Jimma City, Ethiopia: Retrospective Study.

BackgroundTuberculosis (TB) is a common and often deadly infectious disease caused by various strains of mycobacterium, usually mycobacterium tuberculosis in humans. The disease has major causes of morbidity and mortality, particularly where the diagnostic and control program is not far extended.ObjectiveTo compare the treatment outcomes of tuberculosis patients in a private clinic with a governmental health center in Jimma city, Ethiopia.MethodsA 10-year cross-sectional retrospective systemic record review was conducted to compare the treatment outcomes, and to describe the socio-demographic factors associated with the outcome in a private clinic with a governmental health center in Jimma city, Jimma, Ethiopia from September 12, 2007, to September 10, 2017. Finally, SPSS/EPI INFO analyzed data.ResultsThe present study revealed that within a 10 year duration the private clinic gives anti-TB treatment coverage for 582 patients whereas the governmental health center treats 510 patients. The treatment success rate of the private clinic is 98.1% which is 1.03-fold that of the governmental health center (95.3%); while the treatment failure of the private clinic was 0.2%, but there was no treatment failure in the governmental health center.ConclusionBoth sectors achieved the expected WHO targets by newly recommended strategy for TB treatment, DOTS (Directly Observed Treatment Short Course) and treatment success is much better to standard. This shows good progress of DOTS strategy and a decrease of noncompliance in this area. Age, educational level, and the types of TB diagnosis and treatment outcome of the patients were statistically associated in both sectors. Better counseling and awareness about the disease should have to be given for every anti-TB treatment receiving patients, despite their educational level and occupational status in both sectors.

Mycobacterial PPE36 Modulates Host Inflammation by Promoting E3 Ligase Smurf1-Mediated MyD88 Degradation

Mycobacterium tuberculosis (Mtb) PPE36, a cell-wall-associated protein, is highly specific and conserved for the Mtb complex group. Although PPE36 has been proven essential for iron utilization, little is known about it in regulating host immune responses. Here we exhibited that PPE36 was preferentially enriched in Mtb virulent strains and could efficiently inhibit host inflammatory responses and increase bacterial loads in infected macrophages and mice. In exploring the underlying mechanisms, we found that PPE36 could robustly inhibit the activation of inflammatory NF-κB and MAPK (Erk, p38, and Jnk) pathways by promoting E3 ligase Smurf1-mediated ubiquitination and proteasomal degradation of MyD88 protein. Our research revealed a previously unknown function of PPE36 on modulating host immune responses and provided some clues to the development of novel tuberculosis treatment strategies based on immune regulation.

An Overview on Tuberculosis and Worldwide Steps to Combat TB Including Awareness Programme in India

Objectives of current review is to collate history of Tuberculosis (TB), overview of the current literature on epidemiology, world health organisations (WHO) recent strategic plan to overcome and eliminate TB from the root, and to determine current knowledge gaps for control of TB. This study is a review, a descriptive approach of state-of-science for better treatment strategies for TB. The article finds that to reach to end TB goal, WHO, we have to follow the guideline of who about TB control, along with that the Indian government also maintained awareness program. Current findings on TB suggest that with the development of science and technology, researches being conducted to minimise the drug resistance tuberculosis, as well as WHO sets new strategy to fight against TB, which could potentially change the casual outlook of the people towards their health habits, health issues, and will help them in future to tackle from this deadly killer disease.

The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis.

Tuberculosis (TB) remains a global health challenge. Patients with drug-sensitive and drug-resistant TB undergo long, arduous, and complex treatment regimens, often involving multiple antimicrobials. While these drugs were initially implemented based on their bactericidal effects, some studies show that TB antimicrobials can also directly affect cells of the immune system, altering their immune function. As use of these antimicrobials has been the mainstay of TB therapy for over fifty years now, it is more important than ever to understand how these antimicrobials affect key pathways of the immune system. One such central pathway, which underpins the immune response to a variety of infections, is immunometabolism, namely glycolysis and oxidative phosphorylation (OXPHOS). We hypothesise that in addition to their direct bactericidal effect on Mycobacterium tuberculosis (Mtb), current TB antimicrobials can modulate immunometabolic profiles and alter mitochondrial function in primary human macrophages. Human monocyte-derived macrophages (hMDMs) were differentiated from PBMCs isolated from healthy blood donors, and treated with four first-line and six second-line TB antimicrobials three hours post stimulation with either iH37Rv-Mtb or lipopolysaccharide (LPS). 24 h post stimulation, baseline metabolism and mitochondrial function were determined using the Seahorse Extracellular Flux Analyser. The effect of these antimicrobials on cytokine and chemokine production was also assayed using Meso Scale Discovery Multi-Array technology. We show that some of the TB antimicrobials tested can significantly alter OXPHOS and glycolysis in uninfected, iH37Rv-Mtb, and LPS-stimulated hMDMs. We also demonstrate how these antimicrobial-induced immunometabolic effects are linked with alterations in mitochondrial function. Our results show that TB antimicrobials, specifically clofazimine, can modify host immunometabolism and mitochondrial function. Moreover, clofazimine significantly increased the production of IL-6 in human macrophages that were stimulated with iH37Rv-Mtb. This provides further insight into the use of some of these TB antimicrobials as potential host-directed therapies in patients with early and active disease, which could help to inform TB treatment strategies in the future.