A Multi-Compartment Hybrid Computational Model Predicts Key Roles for Dendritic Cells in Tuberculosis Infection.

Simeone Marino,Denise Kirschner

doi:10.3390/computation4040039

Simeone Marino, Denise Kirschner

Open Access

https://doi.org/10.3390/computation4040039

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Abstract

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 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.ResultsThe model was calibrated using experimental data from the lungs and blood of NHPs. The addition of DCs allowed us to investigate in greater detail mechanisms of recruitment, trafficking and antigen presentation and their role in tuberculosis infection.ConclusionThe 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.

Highlights

Tuberculosis (TB) remains one of the main causes of death world-wide and the leading cause due to an infectious disease [1]
We focus on the role of dendritic cells as they serve as the link between physiological compartments of lungs and lymph nodes (LNs) that generate activated immune cells that can traffic to lung granulomas to aid in infection control
We calibrated the current model to Non-Human Primates (NHPs) experimental data in the lung and blood

Summary

Introduction

Tuberculosis (TB) remains one of the main causes of death world-wide and the leading cause due to an infectious disease [1]. For such an ancient disease, it is surprising that so little is still known about what provides a protective response against infection with Mycobacterium tuberculosis (Mtb), the causative agent. When infection occurs with Mtb, two main outcomes are observed. This occurs when the host controls infection, which remains clinically latent even though bacteria are still harbored (about 90% of infected) [2]. Latent infection can become reactivated if the host is compromised in some way leading to active disease. There is still no efficacious vaccine against Mtb, ~30 vaccines are in various stages of testing and clinical trials (http://www.aeras.org/)

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