Tuberculosis (TB) is a world-wide health problem with approximately 2 billion people infected with Mycobacterium tuberculosis (Mtb, the causative bacterium of TB).The pathologic hallmark of Mtb infection in humans and Non-Human Primates (NHPs) is the formation of spherical structures, primarily in lungs, called granulomas.Infection occurs after inhalation NIACIN NO-FLUSH of bacteria into lungs, where resident antigen-presenting cells (APCs), take up bacteria and initiate the immune response to Mtb infection.APCs traffic from the site of infection (lung) to lung-draining lymph nodes (LNs) where they prime T cells to recognize Mtb.
These T cells, circulating back through blood, migrate back to lungs to perform their immune effector functions.We have previously developed a hybrid agent-based model (ABM, labeled GranSim) describing in silico immune cell, bacterial (Mtb) and molecular behaviors during tuberculosis infection and recently linked that model to operate across three physiological compartments: lung (infection site where granulomas form), lung draining lymph node (LN, site of generation of adaptive immunity) and blood (a measurable compartment).Granuloma formation and function is captured by a spatio-temporal model (i.e.
, ABM), while LN and blood compartments represent temporal dynamics of the whole body in response to infection and are captured with ordinary differential equations (ODEs).In order to have a more mechanistic representation of APC trafficking from the lung to the lymph node, and to better capture antigen presentation in a draining LN, this current study incorporates the role of dendritic cells (DCs) in a computational fashion into GranSim.Results: The model was calibrated using experimental data from the lungs and blood of NHPs.The addition of DCs allowed BALANCED B COMPLEX us to investigate in greater detail mechanisms of recruitment, trafficking and antigen presentation and their role in tuberculosis infection.
Conclusion: The main conclusion of this study is that early events after Mtb infection are critical to establishing a timely and effective response.Manipulating CD8+ and CD4+ T cell proliferation rates, as well as DC migration early on during infection can determine the difference between bacterial clearance vs.uncontrolled bacterial growth and dissemination.