Therapeutic effect of recombinant adenovirus encoding interferon-gamma in a murine model of progressive pulmonary tuberculosis.
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.
Mata-Espinosa
Dulce A
DA
Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
Mendoza-Rodríguez
Valentin
V
Aguilar-León
Diana
D
Rosales
Ricardo
R
López-Casillas
Fernando
F
Hernández-Pando
Rogelio
R
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D018450:Disease Progression; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics*; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D013234:Stem Cells; D014397:Tuberculosis, Pulmonary / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II