Synergy between individual TNF-dependent functions determines granuloma performance for controlling Mycobacterium tuberculosis infection.
Synergy between individual TNF-dependent functions determines granuloma performance for controlling Mycobacterium tuberculosis infection.
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DOI：
10.4049/jimmunol.0802297
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发表时间：
2009-03-15
期刊：
影响因子：
--
通讯作者：
Kirschner DE
中科院分区：
文献类型：
--
作者：
Ray JC;Flynn JL;Kirschner DE
结核分枝杆菌是世界上最致命的人类病原体之一;全面了解它如何在宿主中成功存活对于开发新的治疗策略至关重要。感染M.结核病是肉芽肿的形成，肉芽肿是免疫细胞的聚集体，其结构和功能可以反映宿主控制感染的成功或失败。多效细胞因子肿瘤坏死因子-α（TNF）是宿主对感染反应（包括肉芽肿形成）的一个中心调节因子。实验工作已经表征了TNF在巨噬细胞活化中的作用;细胞凋亡的调节;趋化因子和细胞因子的产生;以及通过跨内皮迁移调节细胞募集。分离这些功能的影响目前在体内是困难的或不可能的。为此，我们应用一个计算模型来了解TNF在单个肉芽肿中控制结核病的特定作用。在该模型中，细胞被表示为空间网格上的离散实体，通过遵循从已发表的实验研究确定的编程规则来响应环境刺激。模拟肉芽肿出现作为这些规则的结果。在确认TNF在该模型中的重要性后，我们评估了个体TNF功能的影响。该模型预测多种TNF活性有助于控制肉芽肿内的感染，巨噬细胞活化是控制细菌生长的关键效应机制。结果表明，细菌数量是TNF肉芽肿结构的一个重要因素。最后，肿瘤坏死因子依赖的细胞凋亡可能会减少炎症的代价是损害分枝杆菌清除。
Mycobacterium tuberculosis is one of the world's most deadly human pathogens; an integrated understanding of how it successfully survives in its host is crucial to developing new treatment strategies. One notable characteristic of infection with M. tuberculosis is the formation of granulomas, aggregates of immune cells whose structure and function may reflect success or failure of the host to contain infection. One central regulator of host responses to infection, including granuloma formation, is the pleiotropic cytokine tumor necrosis factor-α (TNF). Experimental work has characterized roles for TNF in macrophage activation; regulation of apoptosis; chemokine and cytokine production; and regulation of cellular recruitment via trans-endothelial migration. Separating the effects of these functions is presently difficult or impossible in vivo. To this end, we applied a computational model to understand specific roles of TNF in control of tuberculosis in a single granuloma. In the model, cells are represented as discrete entities on a spatial grid responding to environmental stimuli by following programmed rules determined from published experimental studies. Simulated granulomas emerge as a result of these rules. After confirming the importance of TNF in this model, we assessed the effects of individual TNF functions. The model predicts that multiple TNF activities contribute to control of infection within the granuloma, with macrophage activation as a key effector mechanism for controlling bacterial growth. Results suggest that bacterial numbers are a strong contributing factor to granuloma structure with TNF. Finally, TNF-dependent apoptosis may reduce inflammation at the cost of impairing mycobacterial clearance.
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