The adaptor molecule CARD9 is essential for tuberculosis control.
The adaptor molecule CARD9 is essential for tuberculosis control.
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DOI：
10.1084/jem.20090067
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发表时间：
2010-04-12
期刊：
影响因子：
--
通讯作者：
Kaufmann SH
中科院分区：
文献类型：
--
作者：
Dorhoi A;Desel C;Yeremeev V;Pradl L;Brinkmann V;Mollenkopf HJ;Hanke K;Gross O;Ruland J;Kaufmann SH
宿主和病原体之间的串扰始于通过模式识别受体（PRR）识别细菌特征，所述模式识别受体动员下游信号级联。我们研究了胞质衔接caspase募集结构域家族成员9（CARD 9）在结核病中的作用。这种衔接子通过汇聚多个PRR下游的信号，对先天免疫的完全激活至关重要。Card 9 −/−小鼠在气溶胶感染后早期死亡，具有较高的分枝杆菌负荷，脓肉芽肿性肺炎，加速粒细胞募集，血清和肺中促炎细胞因子和粒细胞集落刺激因子（G-CSF）丰度较高。G-CSF中和和中性粒细胞耗竭显著延长了生存期，表明加重的全身性炎症性疾病引发了Card 9 −/−小鼠的致死性。CARD 9缺陷对T细胞应答没有明显影响，但对造血区室有显著影响。Card 9 −/−粒细胞在结核分枝杆菌感染后不能产生IL-10，这表明缺乏IL-10反馈回路导致了粒细胞主导的病理学，不受控制的细菌复制，以及最终导致感染的Card 9 −/−小鼠死亡。我们的数据提供了证据表明，先天性反应失调引发了过度的肺部炎症，并证明了CARD 9信号传导在自主先天宿主防御结核病中的关键作用。
The cross talk between host and pathogen starts with recognition of bacterial signatures through pattern recognition receptors (PRRs), which mobilize downstream signaling cascades. We investigated the role of the cytosolic adaptor caspase recruitment domain family, member 9 (CARD9) in tuberculosis. This adaptor was critical for full activation of innate immunity by converging signals downstream of multiple PRRs. Card9−/− mice succumbed early after aerosol infection, with higher mycobacterial burden, pyogranulomatous pneumonia, accelerated granulocyte recruitment, and higher abundance of proinflammatory cytokines and granulocyte colony-stimulating factor (G-CSF) in serum and lung. Neutralization of G-CSF and neutrophil depletion significantly prolonged survival, indicating that an exacerbated systemic inflammatory disease triggered lethality of Card9−/− mice. CARD9 deficiency had no apparent effect on T cell responses, but a marked impact on the hematopoietic compartment. Card9−/− granulocytes failed to produce IL-10 after Mycobaterium tuberculosis infection, suggesting that an absent antiinflammatory feedback loop accounted for granulocyte-dominated pathology, uncontrolled bacterial replication, and, ultimately, death of infected Card9−/− mice. Our data provide evidence that deregulated innate responses trigger excessive lung inflammation and demonstrate a pivotal role of CARD9 signaling in autonomous innate host defense against tuberculosis.
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DOI：
10.1084/jem.20070608
发表时间：
2008-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Di Liberto D;Locati M;Caccamo N;Vecchi A;Meraviglia S;Salerno A;Sireci G;Nebuloni M;Caceres N;Cardona PJ;Dieli F;Mantovani A
通讯作者：
Mantovani A
影响因子：
3.2
作者：
Badewa, AP;Quinton, LJ;Mason, CM
通讯作者：
Mason, CM
影响因子：
64.8
作者：
Gross, Olaf;Gewies, Andreas;Ruland, Juergen
通讯作者：
Ruland, Juergen
影响因子：
4.8
作者：
Bertin, J;Guo, Y;Alnemri, ES
通讯作者：
Alnemri, ES
影响因子：
4.4
作者：
Fielding, Ceri A.;McLoughlin, Rachel M.;Jenkins, Brendan J.
通讯作者：
Jenkins, Brendan J.