Long-term chemotherapy of C57BL/6 mice infected with epidemiologically important Mycobacterium tuberculosis strains and molecular insight into host-pathogen interplay.

In this study, we utilized a C57BL/6 mouse model to investigate the pathogenic properties of well-characterized multidrug-resistant Mycobacterium tuberculosis strains belonging to the Beijing and Latin American Mediterranean (LAM) genotypes. Control animal groups were untreated, while experimental groups received adequate chemotherapy with new-generation drugs. On days 78 and 177 post-infection, mice were euthanized and analyzed for pathological changes, bacterial load, and biochemical indicators of liver damage. Bacterial isolates cultured from the lungs were subjected to whole genome sequencing (WGS) followed by bioinformatics analysis. A complete course of anti-TB therapy reduced inflammation and extent of lung damage across all groups. Mice infected with highly virulent Beijing 396 exhibited the most severe lung damage, while those infected with less virulent Beijing 6691 and LAM 7074 strains showed the least. Treatment was most effective in mice infected with strains 6691 and 7074. However, by day 177 p.i. compared to day 78 p.i., all treated groups (except for those infected with low-virulent 7074) displayed a slight increase in the bacterial load of the lungs. WGS identified a mutation inactivating the tgs3 gene, related to lipid metabolism, tolerance, and persistence, in the lung isolates from treated animals infected with Beijing 396. To conclude, some of the found differences in inflammatory response distinguish between low-virulent (Beijing 6691 and LAM 7074) and highly-virulent (Beijing 396) strains. Some other features appear common for strains of the same genotype and might correlate with deeply rooted evolutionary changes in genomes characteristic for phylogenetically distant East-Asian and Euro-American M. tuberculosis lineages.