Multiscale Computational Modeling Reveals a Critical Role for TNF-α Receptor 1 Dynamics in Tuberculosis Granuloma Formation
Multiscale Computational Modeling Reveals a Critical Role for TNF-α Receptor 1 Dynamics in Tuberculosis Granuloma Formation
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DOI：
10.4049/jimmunol.1003299
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发表时间：
2011-03-15
影响因子：
4.4
通讯作者：
Linderman, Jennifer J.
中科院分区：
文献类型：
--
作者：
Fallahi-Sichani, Mohammad;El-Kebir, Mohammed;Linderman, Jennifer J.
多种免疫因素控制宿主对结核分枝杆菌感染的反应，包括肉芽肿的形成，肉芽肿是免疫细胞的聚集体，其功能可能反映宿主控制感染的成功或失败。其中一个因素就是肿瘤坏死因子-α。实验证明，肿瘤坏死因子-α在结核分枝杆菌感染过程中具有以下活性：巨噬细胞活化、细胞凋亡、趋化因子和细胞因子的产生。肿瘤坏死因子-α在肉芽肿中的可获得性被认为在结核分枝杆菌免疫中起着关键作用。然而，在体内测量肉芽肿内的肿瘤坏死因子-α浓度梯度和活性在实验上是不可行的。此外，肉芽肿中控制肿瘤坏死因子-α浓度和活性的过程仍然未知。我们开发了一个多尺度计算模型，包括在肺部肉芽肿形成和维持过程中发生的分子、细胞和组织尺度事件。我们使用我们的模型来确定调节肿瘤坏死因子-α浓度和细胞行为的过程，从而影响肉芽肿内感染的结果。我们的模型预测，肿瘤坏死因子-αR1内化动力学在控制肉芽肿内的感染控制中发挥关键作用，控制是否有细菌清除、过度炎症、在稳定的肉芽肿内遏制细菌或细菌的不受控制的生长。我们的结果表明，在肉芽肿中，肿瘤坏死因子-α和细菌水平之间存在相互作用，这是由分子和细胞尺度过程的共同影响控制的。最后，我们的模型阐明了与结核分枝杆菌免疫有关的过程，这些过程可能是治疗的新靶点。免疫学杂志，2011,186：3472-3483。
Multiple immune factors control host responses to Mycobacterium tuberculosis infection, including the formation of granulomas, which are aggregates of immune cells whose function may reflect success or failure of the host to contain infection. One such factor is TNF-alpha. TNF-alpha has been experimentally characterized to have the following activities in M. tuberculosis infection: macrophage activation, apoptosis, and chemokine and cytokine production. Availability of TNF-alpha within a granuloma has been proposed to play a critical role in immunity to M. tuberculosis. However, in vivo measurement of a TNF-alpha concentration gradient and activities within a granuloma are not experimentally feasible. Further, processes that control TNF-alpha concentration and activities in a granuloma remain unknown. We developed a multiscale computational model that includes molecular, cellular, and tissue scale events that occur during granuloma formation and maintenance in lung. We use our model to identify processes that regulate TNF-alpha concentration and cellular behaviors and thus influence the outcome of infection within a granuloma. Our model predicts that TNF-alpha R1 internalization kinetics play a critical role in infection control within a granuloma, controlling whether there is clearance of bacteria, excessive inflammation, containment of bacteria within a stable granuloma, or uncontrolled growth of bacteria. Our results suggest that there is an interplay between TNF-alpha and bacterial levels in a granuloma that is controlled by the combined effects of both molecular and cellular scale processes. Finally, our model elucidates processes involved in immunity to M. tuberculosis that may be new targets for therapy. The Journal of Immunology, 2011, 186: 3472-3483.