Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children
Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children
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DOI：
10.1038/s41590-019-0347-8
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发表时间：
2019-05-01
影响因子：
30.5
通讯作者：
Jackson, Daniel J.
中科院分区：
文献类型：
--
作者：
Altman, Matthew C.;Gill, Michelle A.;Jackson, Daniel J.
呼吸道感染是儿童哮喘急性发作的常见前兆，但对决定感染是否以及如何导致急性发作的分子免疫反应知之甚少。通过使用系统规模的网络分析，我们确定了细胞转录途径的剧目，导致和基础的哮喘急性发作的不同模式。具体而言，在病毒相关和非病毒性急性加重中，我们展示了一组核心急性加重模块，其中上皮相关SMAD3信号传导在急性加重早期上调，淋巴细胞反应途径下调，随后效应途径包括表皮生长因子受体信号传导、细胞外基质产生、粘液分泌过多和嗜酸性粒细胞活化上调。与非病毒性急性加重相关的鳞状细胞通路相比，我们发现了一组参与病毒相关急性加重的多个炎性细胞通路。我们的工作引入了一个体内分子平台，在临床环境中研究疾病发病机制和治疗靶点，以改变病情加重。
Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.