Segovia-Juarez Jose L, Ganguli Suman, Kirschner Denise
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
J Theor Biol. 2004 Dec 7;231(3):357-76. doi: 10.1016/j.jtbi.2004.06.031.
Infection with Mycobacterium tuberculosis is a major world health problem. An estimated 2 billion people are presently infected and the disease causes approximately 3 million deaths per year. After bacteria are inhaled into the lung, a complex immune response is triggered leading to the formation of multicellular structures termed granulomas. It is believed that the collection of host granulomas either contain bacteria resulting in a latent infection or are unable to do so, leading to active disease. Thus, understanding granuloma formation and function is essential for improving both diagnosis and treatment of tuberculosis. Granuloma formation is a complex spatio-temporal system involving interactions of bacteria, specific immune cells, including macrophages, CD4+ and CD8+ T cells, as well as immune effectors such as chemokine and cytokines. To study this complex dynamical system we have developed an agent-based model of granuloma formation in the lung. This model combines continuous representations of chemokines with discrete agent representations of macrophages and T cells in a cellular automata-like environment. Our results indicate that key host elements involved in granuloma formation are chemokine diffusion, prevention of macrophage overcrowding within the granuloma, arrival time, location and number of T cells within the granuloma, and an overall host ability to activate macrophages. Interestingly, a key bacterial factor is its intracellular growth rate, whereby slow growth actually facilitates survival.
结核分枝杆菌感染是一个重大的全球健康问题。目前估计有20亿人受到感染，该疾病每年导致约300万人死亡。细菌被吸入肺部后，会引发复杂的免疫反应，导致形成称为肉芽肿的多细胞结构。据信，宿主肉芽肿的集合要么含有导致潜伏感染的细菌，要么无法做到这一点，从而导致活动性疾病。因此，了解肉芽肿的形成和功能对于改善结核病的诊断和治疗至关重要。肉芽肿的形成是一个复杂的时空系统，涉及细菌、特定免疫细胞（包括巨噬细胞、CD4+和CD8+ T细胞）以及免疫效应物（如趋化因子和细胞因子）之间的相互作用。为了研究这个复杂的动态系统，我们开发了一个基于主体的肺部肉芽肿形成模型。该模型在类似细胞自动机的环境中，将趋化因子的连续表示与巨噬细胞和T细胞的离散主体表示相结合。我们的结果表明，参与肉芽肿形成的关键宿主因素包括趋化因子扩散、防止巨噬细胞在肉芽肿内过度拥挤、T细胞在肉芽肿内的到达时间、位置和数量，以及宿主激活巨噬细胞的整体能力。有趣的是，一个关键的细菌因素是其细胞内生长速率，即缓慢生长实际上有助于生存。
