Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis factor-α.
Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis factor-α.
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DOI：
10.1016/j.jtbi.2013.03.008
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发表时间：
2013-07-07
影响因子：
2
通讯作者：
Kirschner, D. E.
中科院分区：
文献类型：
--
作者：
El-Kebir, M.;van der Kuip, M.;van Furth, A. M.;Kirschner, D. E.
结核病是一个全球健康问题，全球每年约有150万人死亡，20亿人感染。肺外结核占所有病例的13%，其中以结核性脑膜炎最严重。它的死亡率很高，通常一旦发生不可逆转的神经损伤就会被诊断出来。诊断和治疗策略的发展需要对结核性脑膜炎的发病机制有透彻的了解。这种疾病的特点是形成大脑肉芽肿，这是试图从免疫上抑制的免疫细胞的集合，物理上含有细菌。细胞因子肿瘤坏死因子-α因其在肉芽肿形成中的重要作用而闻名。由于探索结核性脑膜炎的传统实验动物研究既困难又昂贵，因此需要另一种方法来开始解决这一重要和重大的疾病后果。在这里，我们提出了一个电子计算机模型，捕捉到了大脑独特的免疫环境，使我们能够及时研究推动肉芽肿形成的关键机制。不确定性和敏感性分析显示，肿瘤坏死因子-α对细菌负荷和免疫细胞数量的影响具有剂量依赖性，从而影响结核性脑膜炎的发病。水平不足会导致细菌过度生长，而水平过高则会导致不受控制的炎症，对宿主有害。这些研究结果对发展结核性脑膜炎的免疫调节治疗策略具有重要意义。
Tuberculosis is a global health issue with annually about 1.5 million deaths and 2 billion infected people worldwide. Extra pulmonary tuberculosis comprises 13% of all cases of which tuberculous meningitis is the most severe. It has a high mortality and is often diagnosed once irreversible neurological damage has already occurred. Development of diagnostic and treatment strategies requires a thorough understanding of the pathogenesis of tuberculous meningitis. This disease is characterized by the formation of a cerebral granuloma, which is a collection of immune cells that attempt to immunologically restrain, and physically contain bacteria. The cytokine tumor necrosis factor-α is known for its important role in granuloma formation. Because traditional experimental animal studies exploring tuberculous meningitis are difficult and expensive, another approach is needed to begin to address this important and significant disease outcome. Here, we present an in silico model capturing the unique immunological environment of the brain that allows us to study the key mechanisms driving granuloma formation in time. Uncertainty and sensitivity analysis reveal a dose-dependent effect of tumor necrosis factor-α on bacterial load and immune cell numbers thereby influencing the onset of tuberculous meningitis. Insufficient levels result in bacterial overgrowth, whereas high levels lead to uncontrolled inflammation being detrimental to the host. These findings have important implications for the development of immuno-modulating treatment strategies for tuberculous meningitis.
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