scholarly journals Activity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis Infection

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Sandeep Tyagi ◽  
Vikram Saini ◽  
Iwan Vervoort ◽  
...  
Keyword(s):  
Mouse Model ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Positive Control ◽  
Negative Control ◽  
Tuberculosis Infection ◽  
Content Type ◽  
Control Regimen ◽  
Long Acting ◽  
Aerosol Infection

ABSTRACT The potent antituberculosis activity and long half-life of bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: an untreated negative-control regimen; positive-control regimens of daily rifampin (10 mg/kg of body weight), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily bedaquiline at 2.67 mg/kg (B2.67), 5.33 mg/kg (B5.33), or 8 mg/kg (B8) to deliver the same total amount of bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative- and positive-control regimens performed as expected. One, two, and three doses of BLAI-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively, by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.

scholarly journals Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection

2019 ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Sandeep Tyagi ◽  
Vikram Saini ◽  
Iwan Vervoort ◽  
...  
Keyword(s):  
Mouse Model ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Positive Control ◽  
Negative Control ◽  
Tuberculosis Infection ◽  
Sustained Activity ◽  
Short Course ◽  
Long Acting ◽  
Aerosol Infection

ABSTRACTThe potent anti-tuberculosis activity and long half-life of bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: untreated negative control; positive controls of daily rifampin (10 mg/kg), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily bedaquiline at 2.67 (B2.67), 5.33 (B5.33), or 8 (B8) mg/kg to deliver the same total bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative and positive control regimens performed as expected. One, two, and three doses of BLA-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.

scholarly journals MicroRNA-889 Inhibits Autophagy To Maintain Mycobacterial Survival in Patients with Latent Tuberculosis Infection by Targeting TWEAK

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Der-Yuan Chen ◽  
Yi-Ming Chen ◽  
Chin-Fu Lin ◽  
Che-Min Lo ◽  
Hung-Jen Liu ◽  
...  
Keyword(s):  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Granuloma Formation ◽  
Tuberculosis Infection ◽  
Renal Diseases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antibody Treatment ◽  
Content Type ◽  
Tnf Α

ABSTRACT Autophagy plays an important role in protecting the host against pathogens. Mycobacterium tuberculosis can suppress autophagy and then remain dormant and survive within the host for an extended period, which is responsible for latent tuberculosis infection (LTBI). Here, we explored the role of microRNAs (miRNAs) in LTBI. The miRNA profiles were explored using the next-generation sequencing approach, followed by quantitative reverse transcription-PCR validation. The biological function of candidate miRNA was evaluated using immunoblotting, immunofluorescence techniques, and enzyme-linked immunosorbent assay in an in vitro human TB granuloma model. An increased miR-889 expression was observed in patients with LTBI compared with that in patients without infection. The reporter assay identified tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) as the target of miR-889. Mycobacterial infection induced TWEAK upregulation in the early phase. TWEAK induced autophagy and promoted mycobacterial autophagosome maturation through activation of AMP-activated protein kinase (AMPK). Upon entry to LTBI status, elevated miR-889 levels were associated with TNF alpha (TNF-α) and granuloma formation/maintenance. MiR-889 inhibited autophagy via posttranscriptional suppression of TWEAK expression to maintain mycobacterial survival in granulomas. Adalimumab (anti-TNF-α monoclonal antibody) treatment reduced levels of both TNF-α and miR-889 and caused granuloma destruction and LTBI reactivation. The circulating miR-889 and TWEAK levels were correlated with LTBI and subsequently associated with anti-TNF-α-related LTBI reactivation in patients. We propose that miR-889 and TWEAK can act as targets that can be manipulated for antimycobacterial therapeutic purposes and act as candidate biomarkers for LTBI and LTBI reactivation, respectively. IMPORTANCE TB remains a leading cause of morbidity and mortality worldwide. Approximately one-quarter of the world’s population has latent TB infection. TWEAK is a multiple-function cytokine and may be used as a target for the treatment of rheumatic diseases, cardiovascular diseases, and renal diseases. Here, we demonstrated a novel relationship between TWEAK and activation of the autophagic machinery which promotes antimycobacterial immunity. Additionally, TB infection is highly dynamic and determined by the interaction between the host and mycobacterium. We demonstrated a mechanism of fine-tuned balance between the mycobacterium and host for granuloma formation and/or maintenance in LTBI status. Once patients entered LTBI status, the upregulation of miR-889 was associated with TNF-α levels and granuloma formation to maintain mycobacterial survival. Adalimumab (a TNF-α inhibitor) reduced both TNF-α and miR-889 levels and caused LTBI reactivation and, thus, TWEAK enhancement. MiR-889 and TWEAK may become potential diagnostic biomarkers or therapeutic targets for LTBI and LTBI reactivation, respectively.

scholarly journals Elevated Circulating Concentrations of Interferon-Gamma in Latent Tuberculosis Infection

2016 ◽  
Vol 1 (2) ◽  
pp. 291 ◽  
Author(s):  
Moises Arturo Huaman ◽  
George S. Deepe, Jr. ◽  
Carl J. Fichtenbaum
Keyword(s):  
Interferon Gamma ◽  
Immune Activation ◽  
Propensity Scores ◽  
Latent Tuberculosis Infection ◽  
Plasma Concentrations ◽  
Latent Tuberculosis ◽  
Negative Control ◽  
Tuberculosis Infection ◽  
Hiv Status

Background: Latent tuberculosis infection (LTBI) has been associated with increased immune activation. We assessed circulating concentrations of interferon-gamma in persons with LTBI.Methods: We used the 2011-2012 National Health Nutritional Examination Survey (NHANES) to identify adults with and without LTBI by QuantiFERON®-TB Gold In-Tube (QFT) results. Non-LTBI persons were 1:1 age-, gender- and race-matched to LTBI persons using propensity scores. We compared the plasma concentrations of interferon-gamma measured from the unstimulated, negative control QFT tube between LTBI and non-LTBI persons. We used Mann-Whitney tests and ordered logistic regressions for comparisons.Results: There were 430 LTBI and 430 non-LTBI matched persons included in the analysis. LTBI was associated with higher circulating concentrations of interferon-gamma (median, 3 pg/mL; IQR, 2 – 5) compared to non-LTBI (median, 2.5 pg/mL; IQR, 1.5 – 3.5), P<0.001. LTBI remained associated with higher interferon-gamma concentrations after adjusting for age, gender, race, diabetes, hypertension, tobacco use, HIV status, body mass index, lipid profile and lymphocyte count (odds ratio, 1.79, 95% CI, 1.26 – 2.53). Results remained similar when LTBI was defined by tuberculin skin testing.Conclusions: LTBI was associated with increased circulating interferon-gamma concentrations. Future studies are needed to further characterize immune activation in LTBI and its potential long-term consequences. 

scholarly journals Analysis of Rifapentine for Preventive Therapy in the Cornell Mouse Model of Latent Tuberculosis

1999 ◽  
Vol 43 (9) ◽  
pp. 2126-2130 ◽  
Author(s):  
Eishi Miyazaki ◽  
Richard E. Chaisson ◽  
William R. Bishai
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Therapy ◽  
Mouse Model ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Preventive Therapy ◽  
Load Reduction ◽  
Short Course ◽  
Drug Regimens ◽  
Long Acting

ABSTRACT Rifapentine is a long-acting rifamycin which may be useful for intermittent drug therapy against tuberculosis. In this study we measured the efficacies of rifapentine-containing intermittent drug regimens for preventive therapy using the Cornell mouse model of latent tuberculosis. We infected groups of mice intravenously withMycobacterium tuberculosis and then treated them with isoniazid and pyrazinamide for 12 weeks according to the Cornell latency development protocol. After a 4-week interval of no treatment, experimental preventive therapy was administered by esophageal gavage for 12 or 18 weeks. After equilibration and dexamethasone amplification treatment, mouse organs were analyzed by quantitative colony counts to measure the effectiveness of therapy. Our results showed that once-weekly isoniazid plus rifapentine combination therapy for 18 weeks was an effective preventive regimen with sterilizing potency and bacillary load reduction comparable to those of daily isoniazid therapy for 18 weeks. Monotherapy with rifapentine weekly or fortnightly or with rifampin twice weekly for up to 18 weeks did not offer advantages in reducing bacillary load or in sterilizing organs compared to the effects of a placebo. These results with the Cornell mouse model indicate that once-weekly, short-course preventive therapy with isoniazid plus rifapentine is effective and may warrant investigation in humans with latent tuberculosis infection.

scholarly journals A Mouse Model of Latent Tuberculosis Infection to Study Intervention Strategies to Prevent Reactivation

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0158849 ◽  
Author(s):  
Andreas Kupz ◽  
Ulrike Zedler ◽  
Manuela Stäber ◽  
Stefan H. E. Kaufmann
Keyword(s):  
Mouse Model ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Intervention Strategies ◽  
Tuberculosis Infection ◽  
Study Intervention

LATENT TUBERCULOSIS INFECTION IN CHILDREN AS A PREREQUISITE FOR THE TUBERCULOSIS DEVELOPMENT IN ADULTS

2019 ◽  
Vol 98 (5) ◽  
pp. 179-181
Author(s):  
Yu.P. Chugaev ◽  
◽  
A.I. Tsvetkov ◽  
I.A. Chernyaev ◽  
N.G. Kamaeva ◽  
...  
Keyword(s):  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Tuberculosis Infection
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