Tuberculosis is a worldwide health problem with 2 billion people infected with Mycobacterium tuberculosis (Mtb, the bacteria causing TB). The hallmark of infection is the emergence of organized structures of immune cells forming primarily in the lung in response to infection. Granulomas physically contain and immunologically restrain bacteria that cannot be cleared. We have developed several models that spatially characterize the dynamics of the host-mycobacterial interaction, and identified mechanisms that control granuloma formation and development. In particular, we published several agent-based models (ABMs) of granuloma formation in TB that include many subtypes of T cell populations, macrophages as well as key cytokine and chemokine effector molecules. These ABM studies emphasize the important role of T-cell related mechanisms in infection progression, such as magnitude and timing of T cell recruitment, and macrophage activation. In these models, the priming and recruitment of T cells from the lung draining lymph node (LN) was captured phenomenologically. In addition to these ABM studies, we have also developed several multi-organ models using ODEs to examine trafficking of cells between, for example, the lung and LN. While we can predict temporal dynamic behaviors, those models are not coupled to the spatial aspects of granuloma. To this end, we have developed a multi-organ model that is hybrid: an ABM for the lung compartment and a non-linear system of ODE representing the lymph node compartment. This hybrid multi-organ approach to study TB granuloma formation in the lung and immune priming in the LN allows us to dissect protective mechanisms that cannot be achieved using the single compartment or multi-compartment ODE system. The main finding of this work is that trafficking of important cells known as antigen presenting cells from the lung to the lymph node is a key control mechanism for protective immunity: the entire spectrum of infection outcomes can be regulated by key immune cell migration rates. Our hybrid multi-organ implementation suggests that effector CD4+ T cells can rescue the system from a persistent infection and lead to clearance once a granuloma is fully formed. This could be effective as an immunotherapy strategy for latently infected individuals.
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