A review of computational and mathematical modeling contributions to our understanding of Mycobacterium tuberculosis within-host infection and treatment

Abstract

Tuberculosis (TB) is an ancient and deadly disease characterized by complex host-pathogen dynamics playing out over multiple time and length scales and physiological compartments. Computational modeling can be used to integrate various types of experimental data and suggest new hypotheses, mechanisms, and therapeutic approaches to TB. Here, we offer a first-time comprehensive review of work on within-host TB models that describe the immune response of the host to infection, including the formation of lung granulomas. The models include systems of ordinary and partial differential equations and agent-based models as well as hybrid and multi-scale models that are combinations of these. Many aspects of M. tuberculosis infection, including host dynamics in the lung (typical site of infection for TB), granuloma formation, roles of cytokine and chemokine dynamics, and bacterial nutrient availability have been explored. Finally, we survey applications of these within-host models to TB therapy and prevention and suggest future directions to impact this global disease.

Keywords: agent-based model; antibiotic treatment; granuloma; mathematical modeling; sensitivity analysis; simulations; systems biology.

Figure

Physiological compartments involved in Mtb infection dynamics. Infection begins when Mtb are inhaled into the lung, taken up by macrophages, and begin multiplying. Antigen-presenting cells (including dendritic cells, DCs) travel through lymphatics to lung-draining lymph nodes (LNs) where priming of naïve T cells occurs. This process initiates the Mtb-specific immune response generating both CD4+ and CD8+ T cells. These T cells have phenotypes that include activated, effector, effector memory (EM), and central memory (CM). Effector and memory T cells flow out of the LN into blood to traffic to the lung to participate in granuloma formation and function. Multiple cytokines also play a role in granuloma formation and infection control. Granulomas are dynamic, can last the lifetime of a host, and fall into major categories of solid cellular, caseous (a central core of necrotic material), fibrotic (a cuff of fibrosis surrounds the granuloma) and disseminating (increasing in both size and bacteria). Orally administered antibiotics appear in the blood for distribution to lungs (pharmacokinetics). Most human data reflects the blood compartment, as it is the most easily sampled compartment, in the hope that blood data may be useful for predicting disease progression.