The roles of immune memory and aging in protective immunity and endogenous reactivation of tuberculosis.
The roles of immune memory and aging in protective immunity and endogenous reactivation of tuberculosis.
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DOI：
10.1371/journal.pone.0060425
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kirschner D
中科院分区：
文献类型：
--
作者：
Guzzetta G;Kirschner D
寻找更有效的结核病疫苗和改进的预防性治疗方法，以防止潜伏结核病的内源性再激活，对于阻断传播和实现世卫组织到2050年消除结核病的目标具有战略意义。结核病研究中的关键相关开放问题包括：i）原发感染后强烈记忆反应的决定因素是什么？ii）细胞因子对继发感染的保护性记忆反应的作用是什么？iii）老年人再激活风险增加的机制是什么？为了解决这些问题，我们探讨了一个计算模型的免疫反应结核分枝杆菌，包括数学描述的免疫衰老和免疫记忆的产生和维持。敏感性分析技术，以及广泛的模型表征和计算机模拟实验，被应用于确定控制结核病再激活和免疫记忆的关键机制。本研究的主要发现通过以下模型预测总结：i）记忆保护的强度和持续时间增加与原发感染期间肿瘤坏死因子（TNF）的较高水平相关; ii）记忆T细胞在继发感染期间产生TNF而不是干扰素是有效保护的主要决定因素; iii）CD 4 + T细胞的募集受损可能促进衰老宿主中潜伏性TB感染的再活化。这项研究是第一次尝试考虑免疫动力学的持续感染的整个生命周期的主机，考虑到免疫衰老和记忆。虽然该模型是结核病特异性的，但其结果适用于其他持续性细菌感染，并有助于结核病治疗和/或疫苗方案的开发、评估和改进。
Finding more effective vaccines against tuberculosis (TB) and improved preventive treatments against endogenous reactivation of latent TB is strategic to block transmission and reach the WHO goal of eliminating TB by 2050. Key related open questions in TB research include: i) what are the determinants of a strong memory response upon primary infection? ii) what is the role of cytokines towards protective memory response against a secondary infection? iii) what are the mechanisms responsible for the increased risk of reactivation in elderly individuals? To address these questions, we explored a computational model of the immune response to Mycobacterium tuberculosis including a mathematical description of immunosenescence and the generation and maintenance of immune memory. Sensitivity analysis techniques, together with extensive model characterization and in silico experiments, were applied to identify key mechanisms controlling TB reactivation and immunological memory. Key findings of this study are summarized by the following model predictions: i) increased strength and duration of memory protection is associated with higher levels of Tumor Necrosis Factor- (TNF) during primary infection; ii) production of TNF, but not of interferon-, by memory T cells during secondary infection is a major determinant of effective protection; iii) impaired recruitment of CD4+ T cells may promote reactivation of latent TB infections in aging hosts. This study is a first attempt to consider the immune dynamics of a persistent infection throughout the lifetime of the host, taking into account immunosenescence and memory. While the model is TB specific, the results are applicable to other persistent bacterial infections and can aid in the development, evaluation and refinement of TB treatment and/or vaccine protocols.
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影响因子：
3.7
作者：
Caccamo N;Guggino G;Meraviglia S;Gelsomino G;Di Carlo P;Titone L;Bocchino M;Galati D;Matarese A;Nouta J;Klein MR;Salerno A;Sanduzzi A;Dieli F;Ottenhoff TH
通讯作者：
Ottenhoff TH
影响因子：
29.4
作者：
Dahari H;Layden-Almer JE;Kallwitz E;Ribeiro RM;Cotler SJ;Layden TJ;Perelson AS
通讯作者：
Perelson AS
影响因子：
15.9
作者：
Bruns, Heiko;Meinken, Christoph;Stenger, Steffen
通讯作者：
Stenger, Steffen
DOI：
10.1111/j.1749-6632.2010.05830.x
发表时间：
2011-01-01
期刊：
YEAR IN IMMUNOLOGY
影响因子：
--
作者：
Gerlach, Carmen;van Heijst, Jeroen W. J.;Schumacher, Ton N. M.
通讯作者：
Schumacher, Ton N. M.
影响因子：
4.4
作者：
Ely, KH;Cookenham, T;Woodland, DL
通讯作者：
Woodland, DL