1. ¹Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
2. ²Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
3. ³Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico

Correspondence: Rogelio Hernández-Pando, Experimental Pathology, National Institute of Medical Sciences and Nutrition "Salvador Zubirán", Calle Vasco de Quiroga 15, Tlalpan, CP14000 Mexico City, Mexico. E-mail: rhpando@quetzal.innsz.mx

Received 10 November 2006; Accepted 21 January 2008; Published online 22 April 2008.

Abstract

We constructed recombinant adenoviruses encoding murine interferon- (AdIFN) 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 [1.7 10⁹ plaque forming units (pfu)] of AdIFN 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, AdIFN-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-, tumor necrosis factor (TNF), and inducible nitric oxide synthase (iNOS), and bigger granulomas. When compared with the results from conventional chemotherapy or AdIFN treatment alone, the combined treatment with AdIFN plus conventional chemotherapy shortened the time taken for reduction of bacillary load. This shows that gene therapy with AdIFN efficiently reconstituted the protective immune response and controlled the progress of pulmonary TB produced by MDR or non-MDR strains.