However, the exact mechanism underlying this Mtb strain depend ant differential response is not fully understood. To bet ter understand the interaction between specific infecting Mtb strains and host protective immunity, we established a rabbit model of Mtb infection that mimics the full www.selleckchem.com/products/kpt-330.html range of disease manifestations seen in humans. In rabbits, the nature of the infecting Mtb strain Inhibitors,Modulators,Libraries signifi cantly influences the host pathogen interactions and de termines the outcome of infection. We have used the clinical Mtb strain CDC1551, which is highly immuno genic in animals, to infect rabbits by aerosol expos ure. Infection with CDC1551 results in early transient limited bacillary growth, followed by spontaneous clear ance of organisms, as manifested Inhibitors,Modulators,Libraries by an absence of detect able colony forming units in the lungs, liver and spleen by 12 to 16 weeks post infection, depending on the initial inoculum.

This phenomenon rep resents true LTBI rather than tissue sterilization, since reactivation Inhibitors,Modulators,Libraries of the infection is achieved with immune suppression of rabbits with triamcinolone, a synthetic corticosteroid. In CDC1551 infected rabbits, control of infection is associated with small, well differentiated lung granulomas and robust activation of the host antimicro bial response, characterized by peak activation of mono cytes and CD4 T cells by 4 weeks, that gradually declines over the next 4 to 8 weeks in parallel with de clining CFU numbers. Concurrent with bacillary clear ance, the granulomatous lesions resorb with time, and the lungs regain a normal appearance.

Inhibitors,Modulators,Libraries In contrast, infection of rabbits with the less immunogenic, but more virulent, clinical Mtb strain HN878 Inhibitors,Modulators,Libraries leads to progressive granulomatous TB. In the lungs of these animals, diverse lesions are observed, including small, cellular granulomas and larger ones with necrotic centers, as well as liquefied lesions that eventually cavitate with extensive etc bacillary growth at the luminal surface, similar to those seen in human pulmonary disease. HN878 infection is as sociated with lung inflammation, followed by a slow and sub optimal activation of the host innate and adaptive immune responses and the sustained presence of acti vated CD4 and CD8 T cells throughout the course of infection, which seems to be driven by the bacillary load in the lungs. To gain insight into the host response that culminates in the progression of infection to active TB disease ver sus establishment of LTBI, we investigated the early and 4 week response to HN878 and CDC1551 following equivalent implantation of each Mtb strain into the lungs of rabbits. Leukocyte recruitment and granuloma development in response to Mtb infection were determined by histological analysis of lung tissue.