Highly- and Low-virulent Mycobacterium tuberculosis Strains of the Beijing Genotype Elicit Contrasting Immune Response in C57BL/6 Mice as Revealed by Inducible Nitric Oxide Synthase and Tumor Necrosis Factor-alpha Distinct Expression.

BACKGROUND

The progression of tuberculosis (TB) to active disease is heavily influenced by innate immunity. Mycobacterium tuberculosis can alter host molecular pathways, compromising immune responses and facilitating infection. We aimed to determine molecular immunohistochemical markers in the lungs of mice infected with phylogenomically and pathobiologically different M. tuberculosis strains.

METHODS

C57BL/6 male mice were infected with reference strain H37Rv (Euro-American lineage) and multidrug-resistant clinical strains 396 (highly lethal and hypervirulent subtype Beijing 14717-15) and 6691 (low-lethal and low-virulent subtype Beijing 1071-32). Lung tissues of the euthanized animals were obtained on days 14, 21, 60, and 120 after infection and were subjected to the histological and immunohistochemical analysis, including study of expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-12.

RESULTS

For strain 396, both disease progression and lung damage were associated with a highly reactive immune response and increased synthesis of iNOS and certain strain properties that may contribute to suppression of TNF-α production. In contrast, for strain 6691, a low reactivity of the immune response was detected, with statistically significantly lower values of the relative area of expression of iNOS and TNF-α at all time points.

CONCLUSIONS

The progression of the disease and damage of lung tissue in mice were associated with a highly reactive immune response, increased synthesis of iNOS, and strain properties that may reduce TNF-α production. iNOS and TNF-α can serve as molecular markers of the human immune response characterizing the differential virulence of these M. tuberculosis subtypes in a murine model.