Modeling pathogen and host: in vitro, in vivo and in silico models of latent Mycobacterium tuberculosis infection

Abstract

Tuberculosis remains a significant global health burden. Little is understood regarding the critical pathogen-driven factors and host immune responses that result in latent infection and reactivation. The Wayne model is an in vitro model of latent infection in which Mycobacterium tuberculosis undergoes a hypoxia induced nonreplicating persistent state of metabolism. Using this model, important findings in genomic and proteomic factors involved in newly defined metabolic pathways and drug susceptibility have been identified. The mouse remains the most popular in vivo model latent infection. The Cornell model, reflecting chronic infection altered by antibiotic treatment, and the low to moderate dose chronic infection model have been used. Studies using this model have revealed important insights regarding TNF, IFN, reactive nitrogen intermediates, IL-10, CD4 and CD8 function during latent infection. However, the immune responses in the murine model most likely reflect chronic infection rather than true latency. The non-human primate model is the only animal model in which a true latent state occurs. However, its limited availability, high cost and support required are impractical for frequent use. Disparate data from multiple studies can be used to predict complex biologic interactions through mathematical simulations (in silico model). Mathematical modeling can be use to foresee important insights into host–pathogen interactions that can then be confirmed by in vivo experiments. Since no single perfect model of latent infection exists, the use of multiple models has and will continue to provide significant contributions in our understanding of latency and reactivation of tuberculosis.