Efficacy of anti-tuberculosis therapy with INH, RIF and Bedaquiline in mice with different genetic susceptibility to the infection

<b>Objective:</b> to study the efficacy of anti-tuberculosis (TB) therapy in dependence of genetics of the host. <b>Introduction:</b> Dependence of anti-TB drugs’ performance upon genetics of the host remains very poorly studied, and the question about possible influence of genetic susceptibility to infection on the efficacy of treatment remains unanswered. <b>Methods:</b> Highly TB susceptible I/St, resistant C57BL/6 and (I/St x C57BL/6) F1 female mice were infected via aerosol with M. tuberculosis H37Rv. Three or 8 weeks after infection of mice we initiated therapy with isoniazid (INH), rifampicin or Bedaquiline. Treatment duration was 2 months. Efficacy of therapy was evaluated by CFU counts in lungs and spleens as well as by lung pathology. <b>Results:</b> All 3 drugs were more effective in genetically susceptible I/St mice if treatment was initiated in 3 weeks of infection. When therapy was initiated at week 8 of infection the picture was the opposite - the least effect was achieved in I/St mice. Unlike other mouse strains, I/St mice by week 8 of infections develop necrotic and hypoxic granulomas in the lungs. This may be the cause of reduced metabolic state of mycobacteria in such granulomas and difficult access of drugs to them. <b>Conclusions:</b> Efficacy of TB-drug therapy depends on genetic susceptibility of the host to TB infection. Necrotic and hypoxic lung granuloma in susceptible host can significantly abrogate drug efficacy.