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| Status |
Public on Aug 02, 2018 |
| Title |
Host-directed adjunctive therapy with pravastatin against chronic TB in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Mycobacterium tuberculosis (Mtb) is known to subvert immune responses to establish infection and cause disease. Thus, host-directed therapy (HDT), as adjunctive treatment to traditional antitubercular regimens, is an attractive strategy. Statins are a class of drugs used to lower cholesterol levels by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a crucial enzyme in the cholesterol biosynthesis pathway. Here, we conducted a preclinical animal study aimed at comparing the bactericidal activities of the standard TB regimen (rifampin, isoniazid, pyrazinamide and ethambutol; RHZE) with or without escalating doses of pravastatin against chronic TB in BALB/c mice. Antibiotics were given five times weekly for 8 weeks (continuous phase) beginning 6 weeks after infection. Treatment with RHZE plus pravastatin at doses ranging from 30 mg/kg to 180 mg/kg demonstrated a dose-dependent increase in bactericidal activity, reducing lung bacillary counts by 0.2–0.6 log10, 0.3–0.6 log10 and 0.3–0.8 log10 compared to RHZE alone at weeks 2, 4 and 8, respectively. After 8 weeks of treatment, the degree of lung inflammation correlated with the bactericidal activity of each drug regimen.
In order to gain insight into the anti-TB mechanism of action of pravastatin in vivo, the lungs of mice treated with pravastatin adjunctive therapy and those treated with RHZE alone were analyzed by whole-genome microarrays and RT-PCR. Mouse sera were studied by multiplex enzyme-linked immunosorbent assays. Treatment with pravastatin for 1 month had a profound effect on the global transcription in mouse lungs.
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| Overall design |
Mtb-infected BALB/c mice were treated with the standard TB regimen (RHZE= rifampicin 10 mg/kg+ isoniazid 10 mg/kg + pyrazinamide 150 mg/kg+ ethambutol 100 mg/kg) with or without increasing doses of pravastatin (30, 90, 180 mg/kg). Treatment was given orally five times weekly for 4 weeks (continuous phase) beginning 6 weeks after infection
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| Contributor(s) |
Dutta NK, Karakousis PC |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Jun 02, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Noton K Dutta |
| E-mail(s) |
[email protected]
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| Organization name |
Johns Hopkins University
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| Department |
Medicine
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| Lab |
Center for Tuberculosis Research
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| Street address |
1550 Orleans Street, Room 110
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| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21287 |
| Country |
USA |
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| Platforms (1) |
| GPL11202 |
Agilent-026655 Whole Mouse Genome Microarray 4x44K v2 (Probe Name version) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA389105 |
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