Allele-specific induction of IL-1β expression by C/EBPβ and PU.1 contributes to increased tuberculosis susceptibility.
Allele-specific induction of IL-1β expression by C/EBPβ and PU.1 contributes to increased tuberculosis susceptibility.
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DOI：
10.1371/journal.ppat.1004426
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发表时间：
2014-10
期刊：
影响因子：
6.7
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Zhang G;Zhou B;Li S;Yue J;Yang H;Wen Y;Zhan S;Wang W;Liao M;Zhang M;Zeng G;Feng CG;Sassetti CM;Chen X
结核分枝杆菌感染与一系列临床结果相关，从长期潜伏感染到疾病进展的不同表现。促炎途径，例如由IL-1β控制的那些，具有通过限制细菌复制来预防疾病和通过造成组织损伤来促进疾病的对比潜力。因此，单个炎症通路对M.结核病感染仍然不明确。在这项研究中，我们确定了人IL-1B启动子区的天然多态性，该多态性改变了C/EBPβ和PU.1转录因子的结合，并控制Mtb诱导的IL-1β产生。IL-1β高表达基因型与活动性肺结核的发生、肺部疾病的严重程度和治疗效果差相关。较高的IL-1β表达并不抑制产生IFN-γ的T细胞的活性，而是与肺中的中性粒细胞积聚相关。这些观察结果支持IL-1β和粒细胞炎症作为人类TB疾病进展的驱动因素的特定作用，并提出了预防和治疗结核病的新策略。IL-1β对于抗菌适应性免疫的初始建立是重要的，但IL-1β表达延长也可导致M.肺结核感染。IL-1β在促进抗分枝杆菌免疫和慢性组织损伤方面的矛盾活性使得该细胞因子对人群中TB进展的最终贡献尚不清楚。在这项工作中，我们使用人类遗传学和分子生物学的组合来解决IL-1β介导的炎症的作用，并表明旺盛的IL-1β应答与人类的TB进展和不良治疗结果有因果关系。这项工作进一步加深了我们对结核病免疫因素的理解，并为开发特异性抗炎治疗提供了强有力的理论基础，这些抗炎治疗可以改善结核病治疗的长期结果。此外，这些见解为未来结核病控制工作的设计提供了信息，包括合理设计疾病预防疫苗和结核病化疗的基因型靶向治疗。
Mycobacterium tuberculosis infection is associated with a spectrum of clinical outcomes, from long-term latent infection to different manifestations of progressive disease. Pro-inflammatory pathways, such as those controlled by IL-1β, have the contrasting potential both to prevent disease by restricting bacterial replication, and to promote disease by inflicting tissue damage. Thus, the ultimate contribution of individual inflammatory pathways to the outcome of M. tuberculosis infection remains ambiguous. In this study, we identified a naturally-occurring polymorphism in the human IL1B promoter region, which alters the association of the C/EBPβ and PU.1 transcription factors and controls Mtb-induced IL-1β production. The high-IL-1β expressing genotype was associated with the development of active tuberculosis, the severity of pulmonary disease and poor treatment outcome in TB patients. Higher IL-1β expression did not suppress the activity of IFN-γ-producing T cells, but instead correlated with neutrophil accumulation in the lung. These observations support a specific role for IL-1β and granulocytic inflammation as a driver of TB disease progression in humans, and suggest novel strategies for the prevention and treatment of tuberculosis. IL-1β is important for the initial establishment of antimicrobial adaptive immunity, but prolonged IL-1β expression can also cause progressive immunopathology during M. tuberculosis infection. The paradoxical activities of IL-1β in promoting both antimycobacterial immunity and chronic tissue damage have left the ultimate contribution of this cytokine to TB progression in human populations unclear. In this work, we address the role of IL-1β-mediated inflammation using a combination of human genetics and molecular biology, and suggest that exuberant IL-1β responses are causatively associated with TB progression and poor treatment outcome in humans. This work furthers our understanding of the immunological factors that underlie TB disease and provide a strong rationale for the development of specific anti-inflammatory adjunctive therapies that could improve the long-term outcome of TB treatment. In addition, these insights inform the design of future TB control efforts that include the rational design of disease-preventing vaccines and genotype-targeted delivery of TB chemotherapy.
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影响因子：
--
作者：
El Baghdadi, J.;Grant, A-V;Sabri, A.;El Azbaoui, S.;Zaidi, H.;Cobat, A.;Schurr, E.;Boisson-Dupuis, S.;Casanova, J-L;Abel, L.
通讯作者：
Abel, L.
DOI：
10.1179/096805105x58706
发表时间：
2005-01-01
期刊：
JOURNAL OF ENDOTOXIN RESEARCH
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作者：
Awomoyi, AA;Charurat, M;Newport, MJ
通讯作者：
Newport, MJ
影响因子：
5.5
作者：
Jurado, Javier O.;Pasquinelli, Virginia;Garcia, Veronica E.
通讯作者：
Garcia, Veronica E.
影响因子：
5.4
作者：
Caccamo, Nadia;Guggino, Giuliana;Dieli, Francesco
通讯作者：
Dieli, Francesco
DOI：
10.1084/jem.20090067
发表时间：
2010-04-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dorhoi A;Desel C;Yeremeev V;Pradl L;Brinkmann V;Mollenkopf HJ;Hanke K;Gross O;Ruland J;Kaufmann SH
通讯作者：
Kaufmann SH