Increased expression of host iron-binding proteins precedes iron accumulation and calcification of primary lung lesions in experimental tuberculosis in the guinea pig

Basaraba, Randall J.; Bielefeldt‐Ohmann, Helle; Eschelbach, E.; Reisenhauer, Claire; Tolnay, Airn E.; Taraba, Lauren C.; Shanley, Crystal A.; Smith, Erin A.; Bedwell, Cathy L.; Chlipala, Elizabeth; Orme, Ian M.

doi:10.1016/j.tube.2007.09.002

Cited by 43 publications

(35 citation statements)

References 49 publications

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“…As a consequence, intracellular mycobacteria are competing with the host for iron and zinc and to sequester metals for survival M.tb strongly upregulates the expression of EsxG and EsxH. In M.tb-infected guinea pigs, iron has been shown to accumulate within the primary lesions, but most of it accumulates as extracellular ferric iron, and it is unknown whether M.tb can exploit this source (28). ESX-5 is the most recently evolved ESX cluster and is only present in the group of slow-growing pathogenic species of mycobacteria (29).…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics

Knudsen

Nørskov-Lauritsen

Dolganov

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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A central goal in vaccine research is the identification of relevant antigens. The Mycobacterium tuberculosis chromosome encodes 23 early secretory antigenic target (ESAT-6) family members that mostly are localized as gene pairs. In proximity to five of the gene pairs are ESX secretion systems involved in the secretion of the ESAT-6 family proteins. Here, we performed a detailed and systematic investigation of the vaccine potential of five possible Esx dimer substrates, one for each of the five ESX systems. On the basis of gene transcription during infection, immunogenicity, and protective capacity in a mouse aerosol challenge model, we identified the ESX dimer substrates EsxD-EsxC, ExsG-EsxH, and ExsW-EsxV as the most promising vaccine candidates and combined them in a fusion protein, H65. Vaccination with H65 gave protection at the level of bacillus Calmette-Guérin, and the fusion protein exhibited high predicted population coverage in high endemic regions. H65 thus constitutes a promising vaccine candidate devoid of antigen 85 and fully compatible with current ESAT-6 and culture filtrate protein 10-based diagnostics.T-cell immunology | gene expression | tuberculosis

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Section: Discussionmentioning

confidence: 99%

Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics

Knudsen

Nørskov-Lauritsen

Dolganov

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Mycobacteria competes for the sources of Fe with the host, thus, one strategy of immune response would be to decrease the availability of Fe to the mycobacteria [37], [38]. Ferritin is a fundamental protein for the regulation of Fe, acting as a storage protein and managing the intracellular distribution of this element [39].…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Infection in Young Children: Analyzing the Performance of the Diagnostic Tests

et al. 2014

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ObjectiveThis study evaluated the performance of the Tuberculin Skin Test (TST) and Quantiferon-TB Gold in-Tube (QFT) and the possible association of factors which may modify their results in young children (0–6 years) with recent contact with an index tuberculosis case.Materials and MethodsA cross-sectional study including 135 children was conducted in Manaus, Amazonas-Brazil. The TST and QFT were performed and the tests results were analyzed in relation to the personal characteristics of the children studied and their relationship with the index case.ResultsThe rates of positivity were 34.8% (TST) and 26.7% (QFT), with 14.1% of indeterminations by the QFT. Concordance between tests was fair (Kappa = 0.35 P<0.001). Both the TST and QFT were associated with the intensity of exposure (Linear OR = 1.286, P = 0.005; Linear OR = 1.161, P = 0.035 respectively) with only the TST being associated with the time of exposure (Linear OR = 1.149, P = 0.009). The presence of intestinal helminths in the TST+ group was associated with negative QFT results (OR = 0.064, P = 0.049). In the TST− group lower levels of ferritin were associated with QFT+ results (Linear OR = 0.956, P = 0.036).ConclusionsConcordance between the TST and QFT was lower than expected. The factors associated with the discordant results were intestinal helminths, ferritin levels and exposure time to the index tuberculosis case. In TST+ group, helminths were associated with negative QFT results suggesting impaired cell-mediated immunity. The TST−&QFT+ group had a shorter exposure time and lower ferritin levels, suggesting that QFT is faster and ferritin may be a potential biomarker of early stages of tuberculosis infection.

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“…In our mode of extracellular persistent communities within necrotic lesions, these bacteria survive drug therapy even though the rate of replication is low. This microenvironment contains concentrated micronutrients such as ferric and ferrous iron that may serve as a source of nutrition for extracellular bacilli similar to what has been described for intracellular bacilli in infected macrophages (5). All such processes would require a certain level of energy generation, which TMC207 specifically interferes with.…”

Section: Vol 55 2011 Rapid Therapy Of Tuberculosis In Guinea Pigs 1mentioning

confidence: 91%

Activities of TMC207, Rifampin, and Pyrazinamide against Mycobacterium tuberculosis Infection in Guinea Pigs

Shang

Shanley

Caraway

et al. 2011

Antimicrob Agents Chemother

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The experimental compound TMC207 is showing promise against infections caused by Mycobacterium tuberculosis both in a variety of animal studies and in the field. In this study, we used the guinea pig model, a species that shows several similarities to human tuberculosis, including the hallmark of primary granuloma necrosis, to determine the efficacy of a combination regimen combining TMC207 with rifampin and pyrazinamide. This drug regimen rapidly reduced the bacterial load in the lungs to undetectable levels by 8 weeks of treatment. This reduction was associated with a substantial improvement in lung pathology, but despite this effect areas of residual necrosis still remained. In the draining lymph nodes, however, tissue damage was rapid and not significantly reversed by the drug treatment. Approximately 10 to 11 months after the treatment had ended, the animals began to trigger a Karnovsky scale indicating bacterial regrowth and potential relapse, an event confirmed by the new development of both pulmonary and extrapulmonary granulomatous lesions. Interestingly, a similar rate of relapse was also seen in animals receiving 24 weeks of rifampin, pyrazinamide, and isoniazid standard chemotherapy. These data indicate that TMC207 could be a useful addition to current treatment regimens for tuberculosis.The increasing incidence of drug-resistant forms of Mycobacterium tuberculosis, now thought to exceed half a million new cases a year (8,10,11,26), further complicates the critical need to discover new antituberculosis drugs. Equally troubling, newly emerging evidence suggests that a significant percentage of new clinical isolates of M. tuberculosis are of extremely high virulence (8). Within the current drug discovery pipeline (12), a particularly attractive new candidate is the diarylquinolone TMC207 (2). This investigational drug potently inhibits the mycobacterial enzyme complex ATP synthase, thus interfering with energy production and homeostasis. As a consequence, TMC207 is highly active against both drug-sensitive and drugresistant isolates of M. tuberculosis.In animal studies, the majority of data has been obtained from the mouse model, where TMC207 has activity equivalent to, and synergizes with, standard rifampin, isoniazid, and pyrazinamide therapy (RHZ) (3,13,14,17,18,30). However, although the mouse is an excellent and cost-effective screening tool (15), it lacks elements of the disease pathogenesis in humans, including granulomatous lymphadenitis, lymphangitis, and the development of both pulmonary and extrapulmonary lesions exhibiting caseous necrosis with dystrophic calcification (15). In contrast, the guinea pig model of tuberculosis mimics multiple elements of the pathogenesis of the disease in humans (4, 6, 7).Virtually all studies evaluating drug efficacy in animal models utilize the laboratory strains M. tuberculosis H37Rv or Erdman. However, it is becoming increasingly apparent that newly emerging isolates are of very high virulence, including the W-Beijing family of M. tuberculosis, which is no...

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Increased expression of host iron-binding proteins precedes iron accumulation and calcification of primary lung lesions in experimental tuberculosis in the guinea pig

Cited by 43 publications

References 49 publications

Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics

Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics

Mycobacterium tuberculosis Infection in Young Children: Analyzing the Performance of the Diagnostic Tests

Activities of TMC207, Rifampin, and Pyrazinamide against Mycobacterium tuberculosis Infection in Guinea Pigs

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