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Therapeutic effect of recombinant adenovirus encoding interferon-gamma in a murine model of progressive pulmonary
Dulce A Mata-Espinosa1, Valentin Mendoza-Rodríguez, Diana Aguilar-León
1Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
Abstract:
We constructed recombinant adenoviruses encoding murine interferon-gamma (AdIFNgamma) and tested its therapeutic efficiency in a well characterized model of progressive pulmonary tuberculosis (TB) in Balb/c mice, infected through the trachea with the laboratory drug-susceptible H37Rv strain or multidrug-resistant (MDR) clinical isolate. When the disease was in a late phase, 2 months after infection, we administered by intratracheal cannulation a single dose [1.7 x 10(9) plaque forming units (pfu)] of AdIFNgamma or the control adenovirus. Groups of mice were killed at different time-points and the lungs were examined to determine bacilli colony forming units (CFU), cytokine/chemokine gene expression, and CD4/CD8 subpopulations, and also subjected to automated histomorphometry. In comparison with the control group, after 2 weeks of treatment and during the next 6 months, AdIFNgamma-treated animals infected with either the H37Rv strain or the MDR strain showed significantly lower bacilli loads and tissue damage (pneumonia), higher expressions of IFN-gamma, tumor necrosis factor (TNF), and inducible nitric oxide synthase (iNOS), and bigger granulomas. When compared with the results from conventional chemotherapy or AdIFNgamma treatment alone, the combined treatment with AdIFNgamma plus conventional chemotherapy shortened the time taken for reduction of bacillary load. This shows that gene therapy with AdIFNgamma efficiently reconstituted the protective immune response and controlled the progress of pulmonary TB produced by MDR or non-MDR strains.
Insights
Gene therapy using adenovirus encoding interferon-gamma (AdIFNgamma) effectively treated pulmonary tuberculosis (TB) in mice. This approach reduced bacterial load and tissue damage for both drug-susceptible and multidrug-resistant TB strains.
Area of Science:
- Immunology
- Gene Therapy
- Pulmonary Medicine
Background:
- Tuberculosis (TB) remains a significant global health challenge, particularly with the rise of multidrug-resistant (MDR) strains.
- Current treatment regimens for TB can be lengthy and are less effective against MDR strains.
- Developing novel therapeutic strategies is crucial for combating TB progression.
Purpose of the Study:
- To evaluate the therapeutic efficacy of recombinant adenoviruses encoding murine interferon-gamma (AdIFNgamma) in a murine model of pulmonary tuberculosis.
- To assess the impact of AdIFNgamma on bacterial load, immune responses, and lung pathology in both drug-susceptible and MDR TB infections.
- To compare the efficacy of AdIFNgamma monotherapy and combination therapy with conventional chemotherapy.
Main Methods:
- Construction of recombinant adenoviruses encoding murine interferon-gamma (AdIFNgamma).
- Intratracheal administration of AdIFNgamma or control adenovirus in Balb/c mice infected with H37Rv or MDR TB strains.
- Assessment of bacilli colony forming units (CFU), cytokine/chemokine gene expression (IFN-gamma, TNF, iNOS), CD4/CD8 subpopulations, and histomorphometry at various time points.
Main Results:
- AdIFNgamma treatment led to significantly lower bacilli loads and reduced lung tissue damage (pneumonia) compared to controls.
- Treated animals exhibited higher gene expression of IFN-gamma, TNF, and iNOS, along with larger granulomas.
- Combination therapy of AdIFNgamma and conventional chemotherapy shortened the time to bacillary load reduction.
Conclusions:
- Gene therapy with AdIFNgamma effectively reconstitutes protective immune responses against pulmonary TB.
- AdIFNgamma demonstrates therapeutic potential in controlling both drug-susceptible and MDR TB strains.
- Combined AdIFNgamma and conventional chemotherapy offers an accelerated treatment approach for TB.
