Mathematical Biology Seminar: Mohammad Fallahi-Sichani

Abstract:

Tuberculosis (TB) granulomas are organized collections of immune cells that form in the lung as a result of immune response to Mycobacterium tuberculosis (Mtb) infection. Formation and maintenance of granulomas are essential for control of Mtb infection and are regulated in part by a pro‐inflammatory cytokine, tumor necrosis factor‐α (TNF). We have developed a multi‐scale computational model that includes molecular, cellular and tissue scale events that occur during TB granuloma formation. At the molecular scale, we focus on TNF. TNF receptor internalization kinetics are predicted to play a critical role in infection outcome, controlling whether there is clearance of bacteria, excessive inflammation, containment of bacteria in a stable granuloma, or uncontrolled growth of bacteria. Our results suggest that there is an inter‐play between TNF and bacterial levels in a granuloma that is controlled by the combined effects of both molecular and cellular scale processes. We also use the model to explain what mechanisms lead to differential effects of TNF-neutralizing drugs (generally used to treat anti-inflammatory diseases) on reactivation of TB. Ultimately, these results can help to elaborate relevant features of the immune response to Mtb infection, identifying new strategies for therapy and prevention.