Comparative analysis of mycobacterial infections in susceptible I/St and resistant A/Sn inbred mice

Setting: The availability and appropriate use of animal models is of significant importance for a better and more detailed understanding of the genetic, immunological and pathological mechanisms underlying the development of mycobacterial disease in humans. Objective: To define a mouse model for tuberculosis severity that can be easily adapted to genetic and immunological analysis of host repsonse to Mycobacterium tuberculosis infection. Design: We describe here two inbred strains of mice, I/St and A/Sn (both Nramp1'), that differ vastly in commonly used parameters of susceptibility to infection with virulent and attenuated strains of M. tuberculosis. Results: Following infection with a high dose of virulent H37Rv. nn. tuberculosis and compared to their resistant A/Sn counterparts, I/St mice displayed more than a 2-fold shorter mean survival time and a more rapid onset and progression of severe body weight loss (cachexia). Moreover, I/St mice supported 20-100-fold higher multiplication of M. tuberculosis following challenge with H37Rv over a large range of infectious inocula. The high susceptibility of I/St mice was also reflected by more severe lung histopathology as evidenced by larger and more numerous lung granuloma and macrophage dominated cellular infiltrates. Finally, we determined that I/St are also unable to control infection with attenuated H37Ra M. tuberculosis and two strains of M. bovis (BCG and Ravenel) indicating hyper-susceptibility of the I/St mouse strain to mycobacterial infections. Conclusions: The results of our experiments suggest that comparative analysis of resistant A/Sn and susceptible I/St mice provides an ideal way to study host dependent aspects of tuberculosis susceptibility under the controlled conditions provided by an animal model. (C) 2000 Harcourt Publishers Ltd.