| 1. |
- Abuzeid, Nadir, et al.
(författare)
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Antimycobacterial activity of selected medicinal plants traditionally used in Sudan to treat infectious diseases
- 2014
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Ingår i: Journal of Ethnopharmacology. - : Elsevier. - 0378-8741 .- 1872-7573. ; 157, s. 134-139
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Tidskriftsartikel (refereegranskat)abstract
- Ethnopharmacological relevance: The emergence of multidrug-resistant strains of Mycobacterium tuberculosis underscores the need for continuous development of new and efficient methods to determine the susceptibility of isolates of Mycobacterium tuberculosis in the search for novel antimycobacterial agents. Natural products constitute an important source of new drugs, and design and implementation of antimycobacterial susceptibility testing methods are necessary to evaluate the different extracts and compounds. In this study we have explored the antimycobacterial properties of 50 ethanolic extracts from different parts of 46 selected medicinal plants traditionally used in Sudan to treat infectious diseases. Materials and methods: Plants were harvested and ethanolic extracts were prepared. For selected extracts, fractionation with hydrophilic and hydrophobic solvents was undertaken. A luminometry-based assay was used for determination of mycobacterial growth in broth cultures and inside primary human macrophages in the presence or absence of plant extracts and fractions of extracts. Cytotoxicity was also assessed for active fractions of plant extracts. Results: Of the tested extracts, three exhibited a significant inhibitory effect on an avirulent strain of Mycobacterium tubercluosis (H37Ra) at the initial screening doses (125 and 6.25 mu g/ml). These were bark and leaf extracts of Khaya senegalensis and the leaf extract of Rosmarinus officinalis L. Further fractions of these plant extracts were prepared with n-hexane, chloroform, ethyl acetate, n-butanol, ethanol and water, and the activity of these extracts was retained in hydrophobic fractions. Cytotoxicity assays revealed that the chloroform fraction of Khaya senegalensis bark was non-toxic to human monocyte-derived macrophages and other cell types at the concentrations used and hence, further analysis, including assessment of IC50 and intracellular activity was done with this fraction. Conclusion: These results encourage further investigations to identify the active compound(s) within the chloroform fraction of Khaya senegalensis bark. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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| 2. |
- Elkington, Paul, et al.
(författare)
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In Vitro Granuloma Models of Tuberculosis: Potential and Challenges
- 2019
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Ingår i: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613. ; 219:12, s. 1858-1866
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Forskningsöversikt (refereegranskat)abstract
- Despite intensive research efforts, several fundamental disease processes for tuberculosis (TB) remain poorly understood. A central enigma is that host immunity is necessary to control disease yet promotes transmission by causing lung immunopathology. Our inability to distinguish these processes makes it challenging to design rational novel interventions. Elucidating basic immune mechanisms likely requires both in vivo and in vitro analyses, since Mycobacterium tuberculosis is a highly specialized human pathogen. The classic immune response is the TB granuloma organized in three dimensions within extracellular matrix. Several groups are developing cell culture granuloma models. In January 2018, NIAID convened a workshop, entitled "3-D Human in vitro TB Granuloma Model" to advance the field. Here, we summarize the arguments for developing advanced TB cell culture models and critically review those currently available. We discuss how integrating complementary approaches, specifically organoids and mathematical modeling, can maximize progress, and conclude by discussing future challenges and opportunities.
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| 3. |
- Idh, Jonna, et al.
(författare)
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Susceptibility of Clinical Strains of Mycobacterium tuberculosis to Reactive Nitrogen Species in Activated Macrophages
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Nitric oxide (NO) is produced in macrophages by the inducible NO synthase (iNOS) upon activation by pro-inflammatory cytokines. NO has been shown to be essential for the control of Mycobacterium tuberculosis infection in murine models whereas its importance in man is not as clear. There is a lack of studies regarding the susceptibility to reactive nitrogen species (RNS) in clinical strains of M. tuberculosis and the relation to first-line drug resistance, such as to isoniazid (INH). The aim of this study was to explore susceptibility to RNS and intracellular survival of clinical strains of M. tuberculosis, with or without INH resistance. Method: Seven clinical strains of M. tuberculosis were transformed with the pSMT1-plasmid encoding Vibrio harveyi luciferase. Survival was analysed by luminometry following exposure to the NO donor DETA/NO or peroxynitrite (SIN-1). Intracellular killing was studied in murine macrophages (RAW 264.7) activated with interferon gamma (IFN-γ) and lipopolysaccharide (LPS). Results: There was a significant effect on growth control of M. tuberculosis strains upon macrophage activation, which showed variability among clinical isolates. In the cell-free system, all strains showed a dose-dependent susceptibility to DETA/NO and SIN-1, and clinical strains were in general more resistant than H37Rv to DETA/NO. INH-resistant strains with an inhA mutation were significantly more tolerant to DETA/NO than inhA wild type. Conclusion: Reactive nitrogen species inhibited growth of clinical M. tuberculosis isolates both in an intra- and extracellular model with significant difference between strains. Increased tolerance to NO was associated with isoniazid resistance mediated by inhA.
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| 4. |
- Pienaar, Elsje, et al.
(författare)
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A mathematical model of the initial interaction between Mycobacterium tuberculosis and macrophages
- 2014
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Ingår i: Journal of Theoretical Biology. - : Elsevier. - 0022-5193 .- 1095-8541. ; 342, s. 23-32
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Tidskriftsartikel (refereegranskat)abstract
- There is a large body of literature describing molecular level interactions between Mycobacterium tuberculosis (Mtb) and macrophages. Macrophages initiate a range of anti-bacterial mechanisms in response to infection, and Mtb is capable of surviving and circumventing many of these responses. We apply a computational approach to ask: what are the effects on the cellular level of these opposing interactions? The model considers the interplay between bacterial killing and the pathogen's interference with macrophage function. The results reveal an oscillating balance between host and pathogen, but the balance is transient and varies in length, indicating that stochasticity in the bacterial population or host response could contribute to the diverse incubation periods observed in exposed individuals. The model captures host and strain variation and gives new insight into host-pathogen compatibility and co-evolution.
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| 5. |
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| 6. |
- Raffetseder, Johanna, et al.
(författare)
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Replication Rates of Mycobacterium tuberculosis in Human Macrophages Do Not Correlate with Mycobacterial Antibiotic Susceptibility
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:11, s. e112426-
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Tidskriftsartikel (refereegranskat)abstract
- The standard treatment of tuberculosis (TB) takes six to nine months to complete and this lengthy therapy contributes to the emergence of drug-resistant TB. TB is caused by Mycobacterium tuberculosis (Mtb) and the ability of this bacterium to switch to a dormant phenotype has been suggested to be responsible for the slow clearance during treatment. A recent study showed that the replication rate of a non-virulent mycobacterium, Mycobacterium smegmatis, did not correlate with antibiotic susceptibility. However, the question whether this observation also holds true for Mtb remains unanswered. Here, in order to mimic physiological conditions of TB infection, we established a protocol based on long-term infection of primary human macrophages, featuring Mtb replicating at different rates inside the cells. During conditions that restricted Mtb replication, the bacterial phenotype was associated with reduced acid-fastness. However, these phenotypically altered bacteria were as sensitive to isoniazid, pyrazinamide and ethambutol as intracellularly replicating Mtb. In support of the recent findings with M. smegmatis, we conclude that replication rates of Mtb do not correlate with antibiotic tolerance.
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| 7. |
- Viljoen, S, et al.
(författare)
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A state-time epidemiology model of tuberculosis: Importance of re-infection
- 2012
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Ingår i: Computational biology and chemistry (Print). - : Elsevier. - 1476-9271 .- 1476-928X. ; 36, s. 15-22
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Tidskriftsartikel (refereegranskat)abstract
- An epidemiological model is presented that considers five possible states of a population: susceptible (S), exposed (W), infectious (Y), in treatment (Z) and recovered (R). in certain instances transition rates (from one state to another) depend on the time spent in the state; therefore the states W, Y and Z depend on time and length of stay in that state - similar to age-structured models. The model is particularly amenable to describe delays of exposed persons to become infectious and re-infection of exposed persons. Other transitions that depend on state time include the case finding and diagnosis, increased death rate and treatment interruption. The mathematical model comprises of a set of partial differential and ordinary differential equations. Non-steady state solutions are first presented, followed by a bifurcation study of the stationary states.
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