A human-like TB in genetically susceptible mice followed by the true dormancy in a Cornell-like model.

Mouse tuberculosis (TB) models that utilize genetically susceptible mouse strains demonstrate many features of human lung disease. In the present study, pathology caused by progressive M. tuberculosis H37Rv infection in TB-susceptible I/St mice following the low-dose aerosol challenge showed close similarity to human TB, with formation of necrotic granuloma with adjusting B-cell-rich follicles. A remarkable feature was the development of hypoxic zones around TB lesions by day 60 of infection. Necrotizing inflammatory foci were abundantly infiltrated with Ly-6G+ neutrophils. The levels of mRNA for neutrophil-recruiting factors (KC, MIP-2, IL-17 and IL-6) were all significantly increased in infected compared to naïve animals. A profound elevation of the mRNA level for IFN-gamma resulted neither in mycobacterial growth inhibition, nor in IL-17 response counter-regulation. Three-month therapy with RIF and INH resulted in eradication of culturable mycobacteria (at least 9 months following withdrawal), recovery of the lung tissue structure, and normalization of inflammatory genes expression. However, stable mycobacterial DNA (M. tuberculosis-specific insertion IS6110 detected by the qrt-PCR) was retained in the lungs for a long time after culturable bacilli were eliminated, and combination of lung homogenate liquid cultures with auramine staining demonstrated the presence of acid-fast bacilli with unaltered mycobacterial morphology. The lack of mycobacterial growth on agar, their microscopic detection in concentrated liquid cultures, and the increase in numbers of IS6110 copies in vivo at late stages of cured infection suggest that in our model dormant M. tuberculosis survived in the host.