A model to predict cell-mediated immune regulatory mechanisms during humaninfection with Mycobacterium tuberculosis

A key issue for the study of tuberculosis infection (TB) is to understand w hy individuals infected with Mycobacterium tuberculosis experience differen t clinical outcomes. Elaborating the immune mechanisms that determine wheth er an infected individual will suffer active Tn or latent infection can aid in developing treatment and prevention strategies. To better understand th e dynamics of M. tuberculosis infection and immunity, we have developed a v irtual human model that qualitatively and quantitatively characterizes the cellular and cytokine control network operational during TB infection. Usin g this model, we identify key regulatory elements in the host response. In particular, factors affecting cell functions, such as macrophage activation and bactericidal capabilities, and effector T cell functions such as cytot oxicity and cytokine production can each be determinative. The model indica tes, however, that even if latency is achieved, it may come at the expense of tissue damage if the response is not properly regulated. A balance in Th 1 and Th2 immune responses governed by IFN-gamma, IL-10, and IL-4 facilitat e this down-regulation. These results are further explored through virtual deletion and depletion experiments.