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Antitubercular activity of 2-mercaptobenzothiazole derivatives targeting type II NADH dehydrogenase.RSC Medicinal Chemistry May 2024() type II NADH dehydrogenase (NDH-2) transports electrons into the mycobacterial respiratory pathway at the cost of reduction of NADH to NAD and is an attractive drug...
() type II NADH dehydrogenase (NDH-2) transports electrons into the mycobacterial respiratory pathway at the cost of reduction of NADH to NAD and is an attractive drug target. Herein, we have synthesised a series of 2-mercaptobenzothiazoles (C1-C14) and evaluated their anti-tubercular potential as NDH-2 inhibitors. The synthesised compounds C1-C14 were evaluated for MIC and ATP depletion against H37Ra, , and H37Rv mc 6230. Compounds C3, C4, and C11 were found to be the active molecules in the series and were further evaluated for their MIC against -resistant strains and for their bactericidal potential against H37Rv mc6230. The Peredox-mCherry-expressing strain was used to examine whether C3, C4, and C11 possess NDH-2 inhibitory potential. Furthermore, cytotoxicity analysis against HepG2 displayed a safety index (SI) of >10 for C3 and C4. To get an insight into the mode of interaction at NDH-2, we have performed computational analysis of our active compounds.
PubMed: 38784457
DOI: 10.1039/d4md00118d -
Veterinary Research May 2024Zoonotic diseases represent a significant societal challenge in terms of their health and economic impacts. One Health approaches to managing zoonotic diseases are... (Review)
Review
Zoonotic diseases represent a significant societal challenge in terms of their health and economic impacts. One Health approaches to managing zoonotic diseases are becoming more prevalent, but require novel thinking, tools and cross-disciplinary collaboration. Bovine tuberculosis (bTB) is one example of a costly One Health challenge with a complex epidemiology involving humans, domestic animals, wildlife and environmental factors, which require sophisticated collaborative approaches. We undertook a scoping review of multi-host bTB epidemiology to identify trends in species publication focus, methodologies, and One Health approaches. We aimed to identify knowledge gaps where novel research could provide insights to inform control policy, for bTB and other zoonoses. The review included 532 articles. We found different levels of research attention across episystems, with a significant proportion of the literature focusing on the badger-cattle-TB episystem, with far less attention given to tropical multi-host episystems. We found a limited number of studies focusing on management solutions and their efficacy, with very few studies looking at modelling exit strategies. Only a small number of studies looked at the effect of human disturbances on the spread of bTB involving wildlife hosts. Most of the studies we reviewed focused on the effect of badger vaccination and culling on bTB dynamics with few looking at how roads, human perturbations and habitat change may affect wildlife movement and disease spread. Finally, we observed a lack of studies considering the effect of weather variables on bTB spread, which is particularly relevant when studying zoonoses under climate change scenarios. Significant technological and methodological advances have been applied to bTB episystems, providing explicit insights into its spread and maintenance across populations. We identified a prominent bias towards certain species and locations. Generating more high-quality empirical data on wildlife host distribution and abundance, high-resolution individual behaviours and greater use of mathematical models and simulations are key areas for future research. Integrating data sources across disciplines, and a "virtuous cycle" of well-designed empirical data collection linked with mathematical and simulation modelling could provide additional gains for policy-makers and managers, enabling optimised bTB management with broader insights for other zoonoses.
Topics: Animals; Tuberculosis, Bovine; Cattle; Zoonoses; Humans; Animals, Wild; One Health; Mustelidae
PubMed: 38773649
DOI: 10.1186/s13567-024-01314-w -
Veterinary Research Communications May 2024India is renowned for its complex megadiverse ecosystems and abundant biodiversity. Bovine tuberculosis (bTB) often remains synonymous with Mycobacterium bovis infection... (Review)
Review
India is renowned for its complex megadiverse ecosystems and abundant biodiversity. Bovine tuberculosis (bTB) often remains synonymous with Mycobacterium bovis infection in cattle. The domain of tuberculosis (TB) among wild animals, induced by members of the Mycobacterium tuberculosis complex organisms (MTBC), is often underexplored and underreported in India. Within this context, instances of wild animal tuberculosis (wTB) have manifested across both captive and free-roaming animals. The sources contributing to wTB in animals can be human, animal, or environmental factors, thus illuminating the complex transmission pathways. The diagnosis of wTB continues to pose a formidable challenge, a consequence of the expansive taxonomic diversity in both the host and the pathogen. Complications inherent in acquiring samples from wildlife, the absence of standardized diagnostic protocols, limited insights into infection prevalence, and resource constraints compound diagnosis. Amidst these, adopting the comprehensive One Health paradigm surfaces as an imperative, accentuating the interconnectedness bridging human, animal, and environmental health. Recognizing key stakeholders and fostering intersectoral collaboration to provide enhanced diagnostic techniques driven by skilled personnel and advanced infrastructure play pivotal roles in a comprehensive strategy. Additionally, leveraging vaccination efforts contributes to effective control. A national wTB surveillance program is a cornerstone, ensuring an integrated and holistic approach to disease management. Through this review, we delve into the current landscape of wTB in India, unveiling its multifaceted challenges, and further explore the multifarious strategies that the One Health approach proffers in this dynamic endeavor.
PubMed: 38771446
DOI: 10.1007/s11259-024-10401-4 -
Microbiology Spectrum Jul 2024causes animal tuberculosis in livestock and wildlife, with an impact on animal health and production, wildlife management, and public health. In this work, we sampled a...
UNLABELLED
causes animal tuberculosis in livestock and wildlife, with an impact on animal health and production, wildlife management, and public health. In this work, we sampled a multi-host tuberculosis community from the official hotspot risk area of Portugal over 16 years, generating the largest available data set in the country. Using phylogenetic and ecological modeling, we aimed to reconstruct the history of circulating lineages across the livestock-wildlife interface to inform intervention and the implementation of genomic surveillance within the official eradication plan. We find evidence for the co-circulation of European 1 (Eu1), Eu2, and Eu3 clonal complexes, with Eu3 providing sufficient temporal signal for further phylogenetic investigation. The Eu3 most recent common ancestor (bovine) was dated in the 1990s, subsequently transitioning to wildlife (red deer and wild boar). Isolate clustering based on sample metadata was used to inform phylogenetic inference, unravelng frequent transmission between two clusters that represent an ecological corridor of previously unrecognized importance in Portugal. The latter was associated with transmission at the livestock-wildlife interface toward locations with higher temperature and precipitation, lower agriculture and road density, and lower host densities. This is the first analysis of Eu3 complex in Iberia, shedding light on background ecological factors underlying long-term transmission and informing where efforts could be focused within the larger hotspot risk area of Portugal.
IMPORTANCE
Efforts to strengthen surveillance and control of animal tuberculosis (TB) are ongoing worlwide. Here, we developed an eco-phylodynamic framework based on discrete phylogenetic approaches informed by whole-genome sequence data representing a multi-host transmission system at the livestock-wildlife interface, within a rich ecological landscape in Portugal, to understand transmission processes and translate this knowledge into disease management benefits. We find evidence for the co-circulation of several clades, with frequent transmission of the Eu3 lineage among cattle and wildlife populations. Most transition events between different ecological settings took place toward host, climate and land use gradients, underscoring animal TB expansion and a potential corridor of unrecognized importance for maintenance. Results stress that animal TB is an established wildlife disease without ecological barriers, showing that control measures in place are insufficient to prevent long-distance transmission and spillover across multi-host communities, demanding new interventions targeting livestock-wildlife interactions.
Topics: Portugal; Animals; Mycobacterium bovis; Cattle; Phylogeny; Animals, Wild; Livestock; Tuberculosis, Bovine; Deer; Sus scrofa; Tuberculosis
PubMed: 38771094
DOI: 10.1128/spectrum.03829-23 -
Yi Chuan = Hereditas Nov 2023Circular RNA (circRNA) is a category of non-coding RNAs characterized by the absence of a 5'-cap and 3'-poly(A) tail, and participates in the physiological processes of...
Circular RNA (circRNA) is a category of non-coding RNAs characterized by the absence of a 5'-cap and 3'-poly(A) tail, and participates in the physiological processes of various human diseases. Nonetheless, the diagnostic and functional significance of circRNAs in active pulmonary tuberculosis (ATB) remains uncertain. Consequently, the purpose of this study is to investigate whether hsa_circ_0007460 can be employed as a potential diagnostic biomarker in ATB patients and explore its function. The result of real-time quantitative fluorescent PCR (RT-qPCR) validated a notable increase in the expression of hsa_circ_0007460 in the peripheral blood of 32 ATB patients, as well as in THP-1 human macrophages infected with Bacillus Calmette Guerin (BCG) which is an attenuated strain of Mycobacterium bovis. Additionally, the receiver operating curve (ROC) illustrated that the area under the ROC curve (AUC), sensitivity and specificity were 0.7474, 76.67%, and 78.13% respectively. RNase R, Actinomycin D and other experiments confirmed that hsa_circ_0007460 was stabler than its linear mRNA, indicating that hsa_circ_0007460 has potential as a diagnostic biomarker of ATB. Furthermore, Western blot (WB), Cell Counting Kit-8 (CCK-8), plate counting, and immunofluorescence experiments revealed that hsa_circ_0007460 could regulate apoptosis and autophagy of macrophages. The downstream miRNAs and mRNAs were subsequently predicted using bioinformatics, and the hsa circ 0007460/hsa-miR-3127-5p/PATZ1 axis was built. These above results suggest that hsa_circ_0007460 is substantially up-regulated in the peripheral blood of patients with ATB and can be utilized as a potential diagnostic biomarker. In addition, hsa_circ_0007460 can promote apoptosis of macrophages and inhibit autophagy of macrophages, thereby promoting the survival of BCG.
Topics: Humans; Autophagy; RNA, Circular; Macrophages; Apoptosis; Mycobacterium tuberculosis; Female; Adult; Male; Tuberculosis, Pulmonary; THP-1 Cells; Middle Aged
PubMed: 38764269
DOI: 10.16288/j.yczz.23-160 -
Acta Tropica Aug 2024Bovine tuberculosis (bTB) is a chronic infectious-contagious disease with worldwide distribution, caused by the zoonotic pathogen Mycobacterium bovis. It is believed...
Bovine tuberculosis (bTB) is a chronic infectious-contagious disease with worldwide distribution, caused by the zoonotic pathogen Mycobacterium bovis. It is believed that the existence of wild cycles may hamper the success of bTB control strategies worldwide, where wildlife species could be reservoirs of this bacterial agent across their native (e.g., European badgers, wild boars) or non-indigenous (e.g., brushtail possum in New Zealand) ranges. However, further studies are required to understand the potential risk posed by non-native wildlife in becoming carriers of M. bovis in other neglected latitudes, such as the Southern Cone of South America. In this study, we performed a specific M. bovis-RD4 real-time PCR (qPCR) assay to detect bacterial DNA in tissues from the invasive American mink (Neogale vison) in Los Ríos region, Chile. We detected M. bovis DNA in blood samples collected from 13 out of 186 (7 %) minks with known sex and age. We did not find any significant differences in bacterial DNA detection according to mink sex and age. We found that 92 % (12/13) of specimens were positive in lung, 39 % (5/13) in mediastinal lymph node, and 15 % (2/13) in mesenteric lymph node, which suggest that both respiratory and digestive pathways as possible routes of transmission between infected hosts and minks. Our study is the first report on M. bovis molecular detection in invasive minks in an area where the largest cattle population in the country is located. Furthermore, this area is characterized by a low within-herd prevalence of M. bovis infection in cattle, with a relatively low number of infected herds, and so far, no attempts at eradicating the disease have been successful.
Topics: Animals; Mycobacterium bovis; Mink; Chile; Female; Male; Real-Time Polymerase Chain Reaction; Tuberculosis; DNA, Bacterial; Carrier State; Disease Reservoirs; Lung
PubMed: 38761833
DOI: 10.1016/j.actatropica.2024.107257 -
Microbiology Spectrum Jul 2024Currently, tuberculosis immunoprophylaxis is based solely on Bacillus Calmette-Guérin (BCG) vaccination, and some of the new potential tuberculosis vaccines are based...
UNLABELLED
Currently, tuberculosis immunoprophylaxis is based solely on Bacillus Calmette-Guérin (BCG) vaccination, and some of the new potential tuberculosis vaccines are based on the BCG genome. Therefore, it is reasonable to analyze the genomes of individual BCG substrains. The aim of this study was the genetic characterization of the BCG-Moreau Polish (PL) strain used for the production of the BCG vaccine in Poland since 1955. Sequencing of different BCG lots showed that the strain was stable over a period of 59 years. As a result of comparison, BCG-Moreau PL with BCG-Moreau Rio de Janeiro (RDJ) 143 single nucleotide polymorphisms (SNPs) and 32 insertion/deletion mutations (INDELs) were identified. However, the verification of these mutations showed that the most significant were accumulated in the BCG-Moreau RDJ genome. The mutations unique to the Polish strain genome are 1 SNP and 2 INDEL. The strategy of combining short-read sequencing with long-read sequencing is currently the most optimal approach for sequencing bacterial genomes. With this approach, the only available genomic sequence of BCG-Moreau PL was obtained. This sequence will primarily be a reference point in the genetic control of the stability of the vaccine strain in the future. The results enrich knowledge about the microevolution and attenuation of the BCG vaccine substrains.
IMPORTANCE
The whole genome sequence obtained is the only genomic sequence of the strain that has been used for vaccine production in Poland since 1955. Sequencing of different BCG lots showed that the strain was stable over a period of 59 years. The comprehensive genomic analysis performed not only enriches knowledge about the microevolution and attenuation of the BCG vaccine substrains but also enables the utilization of identified markers as a reference point in the genetic control and identity tests of the stability of the vaccine strain in the future.
Topics: BCG Vaccine; Mycobacterium bovis; Poland; Genome, Bacterial; Whole Genome Sequencing; Polymorphism, Single Nucleotide; Humans; Tuberculosis; INDEL Mutation; Mutation
PubMed: 38757975
DOI: 10.1128/spectrum.04259-23 -
Microbial Pathogenesis Jul 2024Tuberculosis (TB) is a major fatal infectious disease globally, exhibiting high morbidity rates and impacting public health and other socio-economic factors. However,...
Tuberculosis (TB) is a major fatal infectious disease globally, exhibiting high morbidity rates and impacting public health and other socio-economic factors. However, some individuals are resistant to TB infection and are referred to as "Resisters". Resisters remain uninfected even after exposure to high load of Mycobacterium tuberculosis (Mtb). To delineate this further, this study aimed to investigate the factors and mechanisms influencing the Mtb resistance phenotype. We assayed the phagocytic capacity of peripheral blood mononuclear cells (PBMCs) collected from Resisters, patients with latent TB infection (LTBI), and patients with active TB (ATB), following infection with fluorescent Mycobacterium bovis Bacillus Calmette-Guérin (BCG). Phagocytosis was stronger in PBMCs from ATB patients, and comparable in LTBI patients and Resisters. Subsequently, phagocytes were isolated and subjected to whole transcriptome sequencing and small RNA sequencing to analyze transcriptional expression profiles and identify potential targets associated with the resistance phenotype. The results revealed that a total of 277 mRNAs, 589 long non-coding RNAs, 523 circular RNAs, and 35 microRNAs were differentially expressed in Resisters and LTBI patients. Further, the endogenous competitive RNA (ceRNA) network was constructed from differentially expressed genes after screening. Bioinformatics, statistical analysis, and quantitative real-time polymerase chain reaction were used for the identification and validation of potential crucial targets in the ceRNA network. As a result, we obtained a ceRNA network that contributes to the resistance phenotype. TCONS_00034796-F3, ENST00000629441-DDX43, hsa-ATAD3A_0003-CYP17A1, and XR_932996.2-CERS1 may be crucial association pairs for resistance to TB infection. Overall, this study demonstrated that the phagocytic capacity of PBMCs was not a determinant of the resistance phenotype and that some non-coding RNAs could be involved in the natural resistance to TB infection through a ceRNA mechanism.
Topics: Humans; Phagocytes; Mycobacterium tuberculosis; Tuberculosis; Phagocytosis; MicroRNAs; Leukocytes, Mononuclear; RNA, Long Noncoding; Male; Adult; Gene Expression Profiling; Gene Regulatory Networks; Female; Transcriptome; Latent Tuberculosis; Disease Resistance; RNA, Messenger; Mycobacterium bovis; Middle Aged; Computational Biology; Young Adult; RNA, Competitive Endogenous
PubMed: 38754565
DOI: 10.1016/j.micpath.2024.106681 -
EcoHealth Mar 2024Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex (MTC) and non-tuberculous Mycobacteria (NTM), may infect wild and domestic mammals, including...
Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex (MTC) and non-tuberculous Mycobacteria (NTM), may infect wild and domestic mammals, including humans. Although cattle are the main hosts and spreaders of M. bovis, many wildlife hosts play an important role worldwide. In Argentina, wild boar and domestic pigs are considered important links in mammalian tuberculosis (mTB) transmission. The aim of this work was to investigate the presence of M. bovis in wild pigs from different regions of Argentina, to characterize isolates of M. bovis obtained, and to compare those with other previously found in vertebrate hosts. A total of 311 samples from wild pigs were obtained, and bacteriological culture, molecular identification and genotyping were performed, obtaining 63 isolates (34 MTC and 29 NTM). Twelve M. bovis spoligotypes were detected. Our findings suggest that wild pigs have a prominent role as reservoirs of mTB in Argentina, based on an estimated prevalence of 11.2 ± 1.8% (95% CI 8.0-14.8) for MTC and the frequency distribution of spoligotypes shared by cattle (75%), domestic pigs (58%) and wildlife (50%). Argentina has a typical scenario where cattle and pigs are farm-raised extensively, sharing the environment with wildlife, creating conditions for effective transmission of mTB in the wildlife-livestock-human interface.
Topics: Animals; Argentina; Animals, Wild; Tuberculosis; Mycobacterium bovis; Swine; Swine Diseases; Sus scrofa; Disease Reservoirs; Prevalence; Genotype
PubMed: 38727761
DOI: 10.1007/s10393-024-01681-y -
Veterinary Immunology and... Jun 2024The dynamics that develop between cells and molecules in the host against infection by Mycobacterium bovis, leads to the formation of granulomas mainly present in the...
The dynamics that develop between cells and molecules in the host against infection by Mycobacterium bovis, leads to the formation of granulomas mainly present in the lungs and regional lymph nodes in cattle. Cell death is one of the main features in granuloma organization, however, it has not been characterized in granulomatous lesions caused by M. bovis. In this study we aimed to identify the profiles of cell death in the granuloma stages and its relationship with the accumulation of bacteria. We identified necrosis, activated caspase-3, LC3B/p62 using immunohistochemistry and digital pathology analysis on 484 granulomatous lesions in mediastinal lymph nodes from 23 naturally infected cattle. Conclusions: greater amounts of mycobacterial antigens were identified in granulomas from calves compared with adult cattle. The highest percentage of necrosis and quantity of mycobacterial antigens were identified in granuloma stages (III/IV) from adults. The LC3B/p62 profile was heterogeneous in granulomas between adults and calves. Our data suggest that necrosis is associated with a higher amount of mycobacterial antigens in the late stages of granuloma and the development of autophagy appears to play an heterogeneous effector response against infection in adults and calves. These results represent one of the first approaches in the identification of cell death in the four stages of granulomas in bovine tuberculosis.
Topics: Animals; Cattle; Granuloma; Mycobacterium bovis; Necrosis; Tuberculosis, Bovine; Antigens, Bacterial; Lymph Nodes; Caspase 3; Immunohistochemistry
PubMed: 38723459
DOI: 10.1016/j.vetimm.2024.110757