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1.
Mol Biol Rep ; 51(1): 1091, 2024 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-39446249

RESUMEN

BACKGROUND: Mono-resistance to rifampicin/isoniazid increases poor treatment outcomes and the risk of multi-drug resistance (MDR) in tuberculosis (TB) patients. Limited information exists about mono-resistance status of TB patients in Uttar Pradesh, North India. This study aimed to estimate the burden of rifampicin and isoniazid mono-resistance in Western Uttar Pradesh. METHODS AND RESULTS: 153 sputum samples of suspected pulmonary tuberculosis patients were processed to isolate Mycobacterium tuberculosis using the Lowenstein-Jensen (L-J) culture medium. The isolates were identified using an immuno-chromatographic test and IS6110 PCR. The confirmed Mycobacterium tuberculosis isolates were tested for drug susceptibility testing against rifampicin and isoniazid anti-tuberculosis drugs. The results of the drug susceptibility testing were compared with demographic information and analyzed statistically. Out of 153 sputum samples, 83 (54.24%) samples were positive for growth on L-J medium, including 82 (98.79%) Mycobacterium tuberculosis isolates. Of the 82 Mycobacterium tuberculosis isolates, 16 (19.51%), 7 (8.54%), and 5 (6.10%) isolates were MDR, mono-resistant to rifampicin and isoniazid, respectively. The occurrence of RIF/INH mono-resistant-TB was higher in patients of male gender, age above 45 years, living in rural conditions, history of weight loss, and previous anti-TB treatment, but the effect was not statistically significant. CONCLUSIONS: The study reported the status of rifampicin and isoniazid mono-resistance among TB patients and highlighted the need for continuous monitoring and improved intervention for the initial detection of mono-drug-resistant cases. This will improve clinical treatment outcomes and decrease the rate of drug-resistant TB in Uttar Pradesh, North India.


Asunto(s)
Antituberculosos , Isoniazida , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis Pulmonar , Humanos , Rifampin/farmacología , Rifampin/uso terapéutico , India/epidemiología , Isoniazida/farmacología , Isoniazida/uso terapéutico , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiología , Masculino , Femenino , Adulto , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Persona de Mediana Edad , Prevalencia , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Esputo/microbiología , Farmacorresistencia Bacteriana/genética , Anciano , Adulto Joven
2.
Indian J Med Res ; 159(2): 163-180, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38577857

RESUMEN

ABSTRACT: From an initial thought of being used as a cellular garbage bin to a promising target for liquid biopsies, the role of exosomes has drastically evolved in just a few years of their discovery in 1983. Exosomes are naturally secreted nano-sized vesicles, abundant in all types of body fluids and can be isolated intact even from the stored biological samples. Being stable carriers of genetic material (cellular DNA, mRNA and miRNA) and having specific cargo (signature content of originating cells), exosomes play a crucial role in pathogenesis and have been identified as a novel source of biomarkers in a variety of disease conditions. Recently exosomes have emerged as a promising 'liquid biopsy tool'and have shown great potential in the field of non-invasive disease diagnostics, prognostics and treatment response monitoring in both communicable as well as non-communicable diseases. However, there are certain limitations to overcome which restrict the use of exosome-based liquid biopsy as a gold standard testing procedure in routine clinical practices. The present review summarizes the current knowledge on the role of exosomes as the liquid biopsy tool in diagnosis, prognosis and treatment response monitoring in communicable and non-communicable diseases and highlights the major limitations, technical advancements and future prospects of the utilization of exosome-based liquid biopsy in clinical interventions.


Asunto(s)
Exosomas , Enfermedades no Transmisibles , Humanos , Exosomas/genética , Exosomas/patología , Biopsia Líquida/métodos , Pronóstico , Biomarcadores
3.
BMC Immunol ; 24(1): 49, 2023 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-38036985

RESUMEN

BACKGROUND: Tumor necrosis factor (TNF) is known to promote T cell migration and increase the expression of vascular endothelial growth factor (VEGF) and chemokines. The administration of Xpro-1595, a dominant-negative TNF (DN-TNF) engineered to selectively inactivate soluble TNF (solTNF), has been extensively studied and proven effective in reducing TNF production without suppressing innate immunity during infection. The literature also supports the involvement of glutamic acid-leucine-arginine (ELR+) chemokines and VEGF in angiogenesis and the spread of infections. MATERIALS AND METHODS: In this study, we administered Xpro-1595 to guinea pigs to selectively inhibit solTNF, aiming to assess its impact on Mycobacterium tuberculosis (M.tb) dissemination, bacterial growth attenuation, and immunological responses. We conducted immunohistochemical analyses, immunological assays, and colony enumeration to comprehensively study the effects of Xpro-1595 by comparing with anti-TB drugs treated M.tb infected guinea pigs. Throughout the infection and treatment period, we measured the levels of Interleukin-12 subunit alpha (IL-12), Interferon-gamma (IFN-γ), TNF, Tumor growth factor (TGF), and T lymphocytes using ELISA. RESULTS: Our findings revealed a reduction in M.tb dissemination and inflammation without compromising the immune response during Xpro-1595 treatment. Notably, Xpro-1595 therapy effectively regulated the expression of VEGFA and ELR + chemokines, which emerged as key factors contributing to infection dissemination. Furthermore, this treatment influenced the migration of CD4 T cells in the early stages of infection, subsequently leading to a reduced T cell response and controlled proinflammatory signalling, thus mitigating inflammation. CONCLUSION: Our study underscores the pivotal role of solTNF in the dissemination of M.tb to other organs. This preliminary investigation sheds light on the involvement of solTNF in the mechanisms underlying M.tb dissemination, although further in-depth research is warranted to fully elucidate its role in this process.


Asunto(s)
Productos Biológicos , Mycobacterium tuberculosis , Animales , Cobayas , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular , Quimiocinas , Inflamación
4.
Indian J Med Res ; 156(1): 21-30, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-36510895

RESUMEN

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a leading cause of human deaths due to any infectious disease worldwide. However, infection of Mycobacterium bovis, primarily an animal pathogen, also leads to the development of 'human tuberculosis'. Infected animals have been considered the major source of M. bovis infection and humans get exposed to M. bovis through close contact with infected animals or consumption of contaminated milk, unpasteurized dairy products and improperly cooked contaminated meat. The information on the global distribution of bovine TB (bTB) is limited, but the disease has been reported from all the livestock-producing middle- and low-income countries of the world. In recent years, there is a renewed interest for the control of bTB to minimize human infection worldwide. In India, while the sporadic presence of M. bovis has been reported in domestic animals, animal-derived food products and human beings from different geographical regions of the country, the information on the national prevalence of bTB and transmission dynamics of zoonotic TB is, however, not available. The present article reviewed published information on the status of M. bovis-induced zoonotic TB to highlight the key challenges and opportunities for intervention to minimize the risk of M. bovis infection in humans and secure optimum animal productivity in India.


Asunto(s)
Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculosis Bovina , Tuberculosis , Bovinos , Animales , Humanos , Tuberculosis Bovina/epidemiología , Tuberculosis Bovina/microbiología , Tuberculosis Bovina/prevención & control , Tuberculosis/epidemiología , Tuberculosis/microbiología , Leche/microbiología
5.
BMC Microbiol ; 21(1): 123, 2021 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-33879047

RESUMEN

BACKGROUND: Information on the genetic variability of drug resistant isolates of Mycobacterium tuberculosis is of paramount importance to understand transmission dynamics of disease and to improve TB control strategies. Despite of largest number of multidrug-resistant (MDR) tuberculosis cases (1, 30,000; 27% of the global burden), strains responsible for the expansion or development of drug-resistant Mycobacterium tuberculosis infections have been poorly characterized in India. Present study was aimed to investigate the genetic diversity in MDR isolates of Mycobacterium tuberculosis in North India. RESULTS: Spacer oligonucleotide typing (spoligotyping) was performed on 293 clinical MDR isolates of Mycobacterium tuberculosis recovered from cases of pulmonary tuberculosis from North India. Spoligotyping identified 74 distinct spoligotype patterns. Comparison with an international spoligotype database (spoldb4 database) showed that 240 (81.91%) and 32 (10.92%) strains displayed known and shared type patterns, while 21 (7.16%) strains displayed unique spoligotype patterns. Among the phylogeographic lineages, lineage 3 (East African-Indian) was found most predominant lineage (n = 159, 66.25%), followed by lineage 2 (East Asian; n = 34, 14.16%), lineage 1 (Indo-Oceanic; n = 30, 12.50%) and lineage 4 (Euro American; n = 17, 7.08%). Overall, CAS1_DEL (60.41%; SITs 2585, 26, 2694, 309, 381, 428, 1401, 141, 25, 1327) was found most pre-dominant spoligotype pattern followed by Beijing (14.16%; SITs255, 260, 1941, 269) and EAI3_IND (5.00%; SITs 298, 338, 11). The demographic and clinical characteristics were not found significantly associated with genotypic lineages of MDR-M.tuberculosis isolates recovered from pulmonary TB patients of North India. CONCLUSIONS: Present study reveals high genetic diversity among the Mycobacterium tuberculosis isolates and highlights that SIT141/CAS1_Del followed by SIT26/ Beijing lineage is the most common spoligotype responsible for the development and transmission of MDR-TB in North India. The high presence of shared type and unique spoligotype patterns of MDR strains indicates epidemiological significance of locally evolved strains in ongoing transmission of MDR-TB within this community which needs to be further monitored using robust molecular tools with high discriminatory power.


Asunto(s)
Variación Genética , Mycobacterium tuberculosis/genética , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Pulmonar/microbiología , Técnicas de Tipificación Bacteriana , Genotipo , Humanos , India , Mycobacterium tuberculosis/clasificación
6.
Microb Pathog ; 115: 343-352, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29197526

RESUMEN

The immune signalling genes during the challenge of bovine macrophages with bacterial products derived from tuberculosis causing bacteria in cattle were investigated in the present study. An in-vitro cell culture model of bovine monocyte-derived macrophages were challenged to Mycobacterium bovis. Macrophages from healthy and already infected animals can both be fully activated during M. bovis infection. Analysis of mRNA abundance in peripheral blood mononuclear cells from M. bovis infected and non-infected cattle were performed as a controls. Cells of treatment were challenged after six days for six hours incubation at 37 °C, with 5% CO2, to total RNA was extracted then cDNA labelling, hybridization and scanning for microarray methods have been developed for microarray based immune related gene expression analysis. The differential expressions twenty genes (IL1, CCL3, CXCR4, TNF, TLR2, IL12, CSF3, CCR5, CCR3, MAPT, NFKB1, CCL4, IL6, IL2, IL23A, CCL20, IL8, CXCL8, TRIP10, CXCL2 and IL1B) implicated in M. bovis response were examined Agilent Bovine_GXP_8 × 60 K microarray platform. Cells of treatment were challenged after six days for six hours incubation then pathways analysis of Toll like receptor and Chemokine signalling pathway study of responsible genes in bovine tuberculosis. The PBMC from M. bovis infected cattle exhibit different transcriptional profiles compared with PBMC from healthy control animals in response to M. bovis antigen stimulation, providing evidence of a novel genes expression program due to M. bovis exposure. It will guide future studies, regarding the complex macrophage specific signalling pathways stimulated upon phagocytosis of M. bovis and role of signalling pathways in creating the host immune response to cattle tuberculosis.


Asunto(s)
Regulación de la Expresión Génica/inmunología , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Mycobacterium bovis/inmunología , Tuberculosis Bovina/inmunología , Animales , Bovinos , Células Cultivadas , Macrófagos/microbiología , Fagocitosis/genética , ARN Mensajero/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Tuberculosis Bovina/microbiología
7.
Microb Pathog ; 113: 480-489, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29170044

RESUMEN

A functional genomics approach was used to examine the immune response for transcriptional profiling of PBMC M. bovis infected cattle and healthy control cattle to stimulation with bovine tuberculin (purified protein derivative PPD-b). Total cellular RNA was extracted from non-challenged control and M. bovis challenged MDM for all animals at intervals of 6 h post-challenge, in response to in-vitro challenge with M. bovis (multiplicity of infection 2:1) and prepared for global gene expression analysis using the Agilent Bovine (V2) Gene Expression Microarray, 8 × 60 K. The pattern of expression of these genes in PPD bovine stimulated PBMC provides the first description of an M. bovis specific signature of infection that may provide insights into the molecular basis of the host response to infection. Analysis of these mapped reads showed 2450 genes (1291 up regulated and 1158 down regulated) 462 putative natural antisense transcripts (354 up-regulated and 108 down regulated) that were differentially expressed based on sense and antisense strand data, respectively (adjusted P-value ≤ 0.05). The results provided enrichment for genes involved top ten up regulated and down regulated panel of genes, including transcription factors proliferation of T and B lymphocytes. The highest differentially-expressed genes were associated to immune and inflammatory responses, immunity, differentiation, cell growth, apoptosis, cellular trafficking and regulation of lipolysis and thermogenesis. Microarray results were confirmed in infected cattle by RT qPCR to identify potential biomarkers TLR2, CD80, NFKB1, IL8, CXCL6 and ADORA3 of bovine tuberculosis.


Asunto(s)
Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Macrófagos/fisiología , Mycobacterium bovis/inmunología , Tuberculina/inmunología , Tuberculina/farmacología , Animales , Antígeno B7-1/análisis , Biomarcadores , Bovinos , Proliferación Celular/efectos de los fármacos , Quimiocina CXCL6/análisis , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica/veterinaria , Regulación de la Expresión Génica , Interleucina-8/análisis , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Macrófagos/microbiología , Mycobacterium bovis/patogenicidad , Subunidad p50 de NF-kappa B/análisis , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptor de Adenosina A3/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Receptor Toll-Like 2/análisis , Factores de Transcripción , Tuberculosis Bovina/microbiología , Regulación hacia Arriba
9.
Indian J Med Res ; 144(5): 661-671, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28361818

RESUMEN

Mycobacterium avium subspecies paratuberculosis (MAP) has emerged as a major health problem for domestic livestock and human beings. Reduced per animal productivity of domestic livestock seriously impacts the economics of dairy farming globally. High to very high bioload of MAP in domestic livestock and also in the human population has been reported from north India. Presence of live MAP bacilli in commercial supplies of raw and pasteurized milk and milk products indicates its public health significance. MAP is not inactivated during pasteurization, therefore, entering into human food chain daily. Recovery of MAP from patients with inflammatory bowel disease or Crohn's disease and animal healthcare workers suffering with chronic gastrointestinal problems indicate a close association of MAP with a number of chronic and other diseases affecting human health. Higher bioload of MAP in the animals increases the risk of exposure to the human population with MAP. This review summarizes the current status of MAP infection in animals as well as in human beings and also highlights the prospects of effective management and control of disease in animals to reduce the risk of exposure to human population.


Asunto(s)
Enfermedad de Crohn/microbiología , Enfermedades Inflamatorias del Intestino/microbiología , Mycobacterium avium subsp. paratuberculosis/patogenicidad , Paratuberculosis/microbiología , Animales , Enfermedad de Crohn/epidemiología , Humanos , India , Enfermedades Inflamatorias del Intestino/epidemiología , Ganado/microbiología , Paratuberculosis/epidemiología
10.
Indian J Exp Biol ; 54(4): 229-36, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27295919

RESUMEN

Rapid and correct diagnosis is crucial for the management of multidrug resistance (MDR) in Mycobacterium tuberculosis (MTB). The present study aims at rapid diagnosis for identification of multidrug resistance tuberculosis (MDR-TB) using real-time PCR. FRET hybridization probes targeting most prominent four selected codons for rpoB526 and 531 and for katG314 and 315 genes were designed and evaluated on 143 clinical MTB isolates and paired sputa for rapid detection of MDR-TB. The results of real-time PCR were compared with gold standard L-J proportion method and further validated by DNA sequencing. Of the 143 MTB positive cultures, 85 and 58 isolates were found to be 'MDR' and 'pan susceptible', respectively by proportion L-J method. The sensitivity of real-time PCR for the detection of rifampicin (RIF) and isoniazid (INH) were 85.88 and 94.11%, respectively, and the specificity of method was found to be 98.27%. DNA sequencing of 31 MTB isolates having distinct melting temperature (Tm) as compared to the standard drug susceptible H37Rv strain showed 100% concordance with real-time PCR results. DNA sequencing revealed the mutations at Ser531Leu, His526Asp of rpoB gene and Ser315Thr, Thr314Pro of katG gene in RIF and INH resistance cases. This real-time PCR assay that targets limited number of loci in a selected range ensures direct and rapid detection of MDR-TB in Indian settings. However, future studies for revalidation as well as refinement are required to break the limitations of MDR-TB detection.


Asunto(s)
Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Antituberculosos/farmacología , ADN Bacteriano/genética , Transferencia Resonante de Energía de Fluorescencia , Humanos , Isoniazida/farmacología , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Rifampin/farmacología , Sensibilidad y Especificidad
12.
Indian J Med Res ; 141(1): 55-61, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25857495

RESUMEN

BACKGROUND & OBJECTIVES: Of the three major genotypes of Mycobacterium avium subspecies paratuberculosis (MAP), 'Bison type' is most prevalent genotype in the domestic livestock species of the country, and has also been recovered from patients suffering from Crohn's disease. Recently, a new assay based on IS1311 locus 2 PCR- restriction endonuclease analysis (REA) was designed to distinguish between 'Indian Bison type' and non-Indian genotypes. The present study investigated discriminatory potential of this new assay while screening of a panel of MAP isolates of diverse genotypes and from different geographical regions. METHODS: A total of 53 mycobacterial isolates (41 MAP and 12 mycobacterium other than MAP), three MAP genomic DNA and 36 MAP positive faecal DNA samples from different livestock species (cattle, buffaloes, goat, sheep and bison) and geographical regions (India, Canada, USA, Spain and Portugal) were included in the study. The extracted DNA samples (n=92) were analyzed for the presence of MAP specific sequences (IS900, ISMav 2 and HspX) using PCR. DNA samples were further subjected to genotype differentiation using IS1311 PCR-REA and IS1311 L2 PCR-REA methods. RESULTS: All the DNA samples (except DNA from non-MAP mycobacterial isolates) were positive for all the three MAP specific sequences based PCRs. IS1311 PCR-REA showed that MAP DNA samples of Indian origin belonged to 'Bison type'. Whereas, of the total 19 non-Indian MAP DNA samples, 2, 15 and 2 were genotyped as 'Bison type', 'Cattle type' and 'Sheep type', respectively. IS1311 L2 PCR-REA method showed different restriction profiles of 'Bison type' genotype as compared to non-Indian DNA samples. INTERPRETATION & CONCLUSIONS: IS1311 L2 PCR-REA method successfully discriminated 'Indian Bison type' from other non-Indian genotypes and showed potential to be future epidemiological tool and for genotyping of MAP isolates.


Asunto(s)
Genes Bacterianos , Mycobacterium avium subsp. paratuberculosis/clasificación , Reacción en Cadena de la Polimerasa/métodos , Animales , India , Mycobacterium avium subsp. paratuberculosis/genética
14.
J Biomed Sci ; 20: 14, 2013 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-23448104

RESUMEN

MicroRNAs (miRNAs) are evolutionarily conserved, naturally abundant, small, regulatory non-coding RNAs that inhibit gene expression at the post-transcriptional level in a sequence-specific manner. Due to involvement in a broad range of biological processes and diseases, miRNAs are now commanding considerable attention. Although much of the focus has been on the role of miRNAs in different types of cancer, recent evidence also points to a critical role of miRNAs in infectious disease, including those of bacterial origin. Now, miRNAs research is exploring rapidly as a new thrust area of biomedical research with relevance to deadly bacterial diseases like Tuberculosis (caused by Mycobacterium tuberculosis). The purpose of this review is to highlight the current developments in area of miRNAs regulation in Mycobacterial diseases; and how this might influence the diagnosis, understanding of disease biology, control and management in the future.


Asunto(s)
Regulación de la Expresión Génica , MicroARNs/genética , Mycobacterium tuberculosis/genética , Tuberculosis/genética , Humanos , MicroARNs/biosíntesis , MicroARNs/metabolismo , Mycobacterium tuberculosis/patogenicidad , Interferencia de ARN , Tuberculosis/microbiología , Tuberculosis/patología
15.
Microbiol Spectr ; : e0319722, 2023 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-36719189

RESUMEN

The majority of preclinical research has shown that Mycobacterium tuberculosis can modify host lipids in various ways. To boost its intramacrophage survival, M. tuberculosis causes host lipids to build up, resulting in the development of lipid-laden foam cells. M. tuberculosis binds to and enters the macrophage via the cell membrane cholesterol. Aggregation of cholesterol in the cell wall of M. tuberculosis and an increase in vascularity at the granuloma site reduce the permeability of rifampicin and isoniazid concentrations. However, very few studies have assessed the effect of statins on drug penetration. Here, we used atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, to observe its effect on the bacterial burden by increasing the drug concentration at the infection site. We looked into how atorvastatin could be used in conjunction with first-line drugs to promote drug permeation. In this study, we detected an accumulation of drugs at the peripheral sites of the lungs and impaired drug distribution to the diseased sites. The efficacy of antituberculosis drugs, with atorvastatin as an adjunct, on the viability of M. tuberculosis cells was demonstrated. A nontoxic statin dosage established phenotypic and normal granuloma vasculature and showed an additive effect with rifampicin and isoniazid. Our data show that statins help to reduce the tuberculosis bacterial burden. Our findings reveal that the bacterial load is connected with impaired drug permeability resulting from lipid accumulation in the bacterial cell wall. Statin therapy combined with antituberculosis medications have the potential to improve treatment in tuberculosis patients. IMPORTANCE Mycobacterium tuberculosis binds to and enters the macrophage via the cell membrane cholesterol. M. tuberculosis limits phagosomal maturation and activation without engaging in phagocytosis. Aggregation of cholesterol in the cell wall of M. tuberculosis and an increase in the vascularity at the granuloma site reduce the permeability of rifampicin and isoniazid concentrations. However, very few studies have assessed the effect of statins on drug penetration, which can be increased through a reduction in cholesterol and vascularity. Herein, we used atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, to observe its effect on bacterial burden through increasing the drug concentration at the infection site. Our main research goal is to diminish mycobacterial dissemination and attenuate bacterial growth by increasing drug permeability.

16.
Tuberculosis (Edinb) ; 135: 102224, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35763913

RESUMEN

Pathogenic mycobacteria induce and accelerate blood vessel formation driven by extensive inflammation during granuloma formation, which is a central feature of mycobacterial pathogenesis. Tumor necrosis factor-alpha (TNF-α) enhances the expression of vascular endothelial growth factor (VEGF) and glutamic acid-leucine-arginine (ELR+) chemokines, which are potent inducers of vascularization. Most of the reported research work contends that VEGF growth factor induces neovascularization in human tuberculosis (TB) patients, but the evidence is inconclusive. Considerable ambiguity exists concerning the factors responsible for miliary tuberculosis. To identify such factors, we proposed an alternative explanation that could be found in miliary tuberculosis (MTB) cases. We performed a comparative analysis of angiogenic factors TNF-α, VEGF, and angiogenic ELR+ CXC and CC chemokine ligands in extrapulmonary tuberculosis (EPTB) and pulmonary tuberculosis (PTB) patients. To observe the relationship of these factors with the severity of bacterial burden, guinea pigs were infected with Mycobacterium tuberculosis (M.tb) and levels of the angiogenic factors were examined at different time intervals. Expression of these factors also exhibited a significant positive correlation with bacterial burden in other organs like the spleen, liver, and lymph nodes. We demonstrated statistical data on bacterial burden at different time points following the dissemination of infection in guinea pigs. In this study, we observed that there was a stimulated increase in the expression of ELR+ chemokines and VEGF in EPTB patients as compared to PTB patients. Following increased dissemination, the host immune response clears bacteria from the lungs during disease progression in guinea pigs.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Miliar , Tuberculosis Pulmonar , Proteínas Adaptadoras Transductoras de Señales , Animales , Moléculas de Adhesión Celular , Quimiocinas , Guanilato-Quinasas , Cobayas , Humanos , Factor de Necrosis Tumoral alfa , Factor A de Crecimiento Endotelial Vascular
17.
Front Immunol ; 12: 687044, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34630380

RESUMEN

Phagosome-lysosome fusion in innate immune cells like macrophages and neutrophils marshal an essential role in eliminating intracellular microorganisms. In microbe-challenged macrophages, phagosome-lysosome fusion occurs 4 to 6 h after the phagocytic uptake of the microbe. However, live pathogenic mycobacteria hinder the transfer of phagosomes to lysosomes, up to 20 h post-phagocytic uptake. This period is required to evade pro-inflammatory response and upregulate the acid-stress tolerant proteins. The exact sequence of events through which mycobacteria retards phagolysosome formation remains an enigma. The macrophage coat protein Coronin1(Cor1) is recruited and retained by mycobacteria on the phagosome membrane to retard its maturation by hindering the access of phagosome maturation factors. Mycobacteria-infected macrophages exhibit an increased cAMP level, and based on receptor stimulus, Cor1 expressing cells show a higher level of cAMP than non-Cor1 expressing cells. Here we have shown that infection of bone marrow-derived macrophages with H37Rv causes a Cor1 dependent rise of intracellular cAMP levels at the vicinity of the phagosomes. This increased cAMP fuels cytoskeletal protein Cofilin1 to depolymerize F-actin around the mycobacteria-containing phagosome. Owing to reduced F-actin levels, the movement of the phagosome toward the lysosomes is hindered, thus contributing to the retarded phagosome maturation process. Additionally, Cor1 mediated upregulation of Cofilin1 also contributes to the prevention of phagosomal acidification, which further aids in the retardation of phagosome maturation. Overall, our study provides first-hand information on Cor1 mediated retardation of phagosome maturation, which can be utilized in developing novel peptidomimetics as part of host-directed therapeutics against tuberculosis.


Asunto(s)
Cofilina 1/metabolismo , AMP Cíclico/metabolismo , Macrófagos/microbiología , Proteínas de Microfilamentos/metabolismo , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium bovis/patogenicidad , Mycobacterium smegmatis/patogenicidad , Mycobacterium tuberculosis/patogenicidad , Fagosomas/microbiología , Tuberculosis/microbiología , Animales , Línea Celular , Interacciones Huésped-Patógeno , Concentración de Iones de Hidrógeno , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Proteínas de Microfilamentos/genética , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/metabolismo , Mycobacterium bovis/inmunología , Mycobacterium smegmatis/inmunología , Mycobacterium tuberculosis/inmunología , Fagosomas/inmunología , Fagosomas/metabolismo , Sistemas de Mensajero Secundario , Tuberculosis/inmunología , Tuberculosis/metabolismo
18.
PLoS One ; 10(4): e0122979, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25853708

RESUMEN

The tubercle complex consists of closely related mycobacterium species which appear to be variants of a single species. Comparative genome analysis of different strains could provide useful clues and insights into the genetic diversity of the species. We integrated genome assemblies of 96 strains from Mycobacterium tuberculosis complex (MTBC), which included 8 Indian clinical isolates sequenced and assembled in this study, to understand its pangenome architecture. We predicted genes for all the 96 strains and clustered their respective CDSs into homologous gene clusters (HGCs) to reveal a hard-core, soft-core and accessory genome component of MTBC. The hard-core (HGCs shared amongst 100% of the strains) was comprised of 2,066 gene clusters whereas the soft-core (HGCs shared amongst at least 95% of the strains) comprised of 3,374 gene clusters. The change in the core and accessory genome components when observed as a function of their size revealed that MTBC has an open pangenome. We identified 74 HGCs that were absent from reference strains H37Rv and H37Ra but were present in most of clinical isolates. We report PCR validation on 9 candidate genes depicting 7 genes completely absent from H37Rv and H37Ra whereas 2 genes shared partial homology with them accounting to probable insertion and deletion events. The pangenome approach is a promising tool for studying strain specific genetic differences occurring within species. We also suggest that since selecting appropriate target genes for typing purposes requires the expected target gene be present in all isolates being typed, therefore estimating the core-component of the species becomes a subject of prime importance.


Asunto(s)
Variación Genética , Mycobacterium tuberculosis/genética , Filogenia , Tuberculosis/genética , Secuencia de Bases , Hibridación Genómica Comparativa , ADN Bacteriano/genética , Genoma Bacteriano , Humanos , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/patogenicidad , Tuberculosis/microbiología , Tuberculosis/patología
19.
Biomed Res Int ; 2015: 983978, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25945351

RESUMEN

A total of 355 cows were sampled (serum, n = 315; faeces, n = 355; milk, n = 209) from dairy farms located in the Punjab state of India. Faeces and serum/milk samples were screened by acid fast staining and "indigenous ELISA," respectively. IS900 PCR was used to screen faeces and milk samples. Bio-load of MAP in dairy cows was 36.9, 15.6, 16.3, and 14.4%, using microscopy, serum ELISA, milk ELISA and milk PCR, respectively. Estimated kappa values between different test combinations: serum and milk ELISA, faecal microscopy and faecal PCR, milk ELISA and milk PCR, faecal PCR and serum ELISA were 0.325, 0.241, 0.682, and 0.677, respectively. Estimation of the relative sensitivity and specificity of different tests in the present study indicated that "serum ELISA" and "milk ELISA" were good screening tests, add "milk PCR" was "confirmatory test" for MAP infection. Combination of milk ELISA with milk PCR may be adopted as a model strategy for screening and diagnosis of JD in lactating/dairy cattle herds in Indian conditions.


Asunto(s)
Enfermedades de los Bovinos/genética , Mycobacterium avium subsp. paratuberculosis/aislamiento & purificación , Paratuberculosis/diagnóstico , Agricultura , Animales , Bovinos , Enfermedades de los Bovinos/microbiología , Industria Lechera , Heces/microbiología , Femenino , Humanos , India , Lactancia , Leche/microbiología , Mycobacterium avium subsp. paratuberculosis/genética , Mycobacterium avium subsp. paratuberculosis/patogenicidad , Paratuberculosis/microbiología
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