Lymph node granulomas in the persistence and dissemination of pulmonary tuberculosis disease

Kathryn Krupinsky

University of Michigan Medical School

"Lymph node granulomas in the persistence and dissemination of pulmonary tuberculosis disease"

Tuberculosis (TB) is a disease of major public health concern with an estimated one fourth of the world currently infected with M. tuberculosis (Mtb). The hallmark structure of TB is the granuloma, a highly organized immune cell structure that both sequesters bacteria, helping prevent further infection progression but also allows a niche for persistence. While primarily studied within lungs, granulomas are also found within the lymph nodes (LNs). Both lung and LN granulomas vary in ability to control infection, ranging from completely clearing to persisting for decades. Many questions remain surrounding the impact of LN infection such as: development of LN granulomas effects on pulmonary infection, causes for heterogeneity of LN granulomas, and differences between within-host clearance strategies and control between LN and lung granulomas. To address these questions, we developed a non-linear ODE model of LNs allowing for development of granulomas to occur within lymph nodes. We connect this model within the context of an infected whole-host model of Mtb infection, we call HostSim. We calibrate our model, which represents both LN and multiple lung granulomas, and blood using data derived from necropsy from cynomolgus macaques, a nonhuman primate which closely mimics human TB pathology. Our calibrated model reproduces general kinetics of macrophages and bacteria observed within LN granulomas over time. With this model, we will determine cellular mechanisms driving heterogeneity in LN granulomas and the impacts of LN granulomas on pulmonary infection, reactivation and dissemination using sensitivity analysis and in silico experimentation.
Additional authors: Joshua Mattila (Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh and Center for Vaccine Research, University of Pittsburgh); JoAnne Flynn (Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh and Center for Vaccine Research, University of Pittsburgh); Denise Kirschner (Department of Microbiology and Immunology, School of Medicine, University of Michigan)

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