An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.
An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.
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作者：
结核病（TB），由结核分枝杆菌（M.结核病（TB）是世界范围内发病率和死亡率的主要原因，并且控制TB的努力受到诊断、预防和治疗困难的阻碍。大多数感染M.结核病仍然是无症状的，称为潜伏性结核病，有10%的终生风险发展为活动性结核病，但目前的测试不能确定哪些人会发展为疾病。免疫反应的M。结核病很复杂，特征不完全，阻碍了新的诊断、治疗和疫苗的开发。我们在中等和高负荷环境中鉴定了活动性TB的全血393转录物特征，其与疾病的放射学程度相关，并在治疗后恢复到健康对照的水平。潜伏性结核病患者的一个子集具有与活动性结核病患者相似的特征。我们还确定了一个特定的86转录本签名，区分活动性结核病与其他炎症和感染性疾病。模块和途径分析显示，TB特征由嗜中性粒细胞驱动的干扰素（IFN）诱导型基因谱主导，由IFN-γ和I型IFNαβ信号传导组成。与纯化细胞和流式细胞仪分析中的转录签名比较，表明该TB签名反映了细胞组成和基因表达改变的变化。尽管在系统性红斑狼疮（SLE）患者的全血中也观察到IFN签名，但其完整的模块签名与TB不同，浆细胞转录物的丰度增加。我们的研究证明了迄今为止未被充分认识的I型IFNαβ信号传导在TB发病机制中的作用，这对疫苗和治疗开发具有意义。我们的研究还提供了广泛的转录生物标志物，有可能作为诊断和预后工具，以打击结核病的流行。
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is a major cause of morbidity and mortality worldwide and efforts to control TB are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease, but current tests cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. We identified a whole blood 393 transcript signature for active TB in intermediate and high burden settings, correlating with radiological extent of disease and reverting to that of healthy controls following treatment. A subset of latent TB patients had signatures similar to those in active TB patients. We also identified a specific 86-transcript signature that discriminated active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and Type I IFNαβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis, suggest that this TB signature reflects both changes in cellular composition and altered gene expression. Although an IFN signature was also observed in whole blood of patients with Systemic Lupus Erythematosus (SLE), their complete modular signature differed from TB with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto under-appreciated role of Type I IFNαβ signalling in TB pathogenesis, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.
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DOI：
10.1084/jem.20021553
发表时间：
2003-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bennett L;Palucka AK;Arce E;Cantrell V;Borvak J;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
4.7
作者：
Jacobsen, Marc;Repsilber, Dirk;Kaufmann, Stefan H. E.
通讯作者：
Kaufmann, Stefan H. E.
影响因子：
29.7
作者：
Cooper AM
通讯作者：
Cooper AM
影响因子：
15.3
作者：
Allantaz, Florence;Chaussabel, Damien;Pascual, Virginia
通讯作者：
Pascual, Virginia
影响因子：
3.1
作者：
Cooper, AM;Pearl, JE;Orme, IM
通讯作者：
Orme, IM