Background

Respiratory viral infection in early childhood, including that from respiratory syncytial virus (RSV), has been previously associated with the development of asthma.

Objective

We aimed to determine whether ex vivo RSV infection of bronchial epithelial cells (BECs) from children with asthma would induce specific gene expression patterns and whether such patterns were associated with lung function among BEC donors.

Methods

Primary BECs from carefully characterized children with asthma (n = 18) and matched healthy children without asthma (n = 8) were differentiated at an air-liquid interface for 21 days. Air-liquid interface cultures were infected with RSV for 96 hours and RNA was subsequently isolated from BECs. In each case, we analyzed gene expression using RNA sequencing and assessed differences between conditions by linear modeling of the data. BEC donors completed spirometry to measure lung function.

Results

RSV infection of BECs from subjects with asthma, compared with uninfected BECs from subjects with asthma, led to a significant increase in expression of 6199 genes. There was significantly greater expression of 195 genes in BECs from children with asthma and airway obstruction (FEV₁/forced vital capacity < 0.85 and FEV₁ < 100% predicted) than in BECs from children with asthma without obstruction, or in BECs from healthy children. These specific genes were found to be highly enriched for viral response genes induced in parallel with types I and III interferons.

Conclusions

BECs from children with asthma and with obstructive physiology exhibit greater expression of types I and III interferons and interferon-stimulated genes than do cells from children with normal lung function, and expression of interferon-associated genes correlates with the degree of airway obstruction. These findings suggest that an exaggerated interferon response to viral infection by airway epithelial cells may be a mechanism leading to lung function decline in a subset of children with asthma.

中文翻译：

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哮喘儿童支气管上皮对呼吸道合胞病毒的干扰素反应与肺功能呈负相关

背景

儿童早期的呼吸道病毒感染，包括呼吸道合胞病毒（RSV）引起的呼吸道感染，以前与哮喘的发展有关。

客观的

我们旨在确定哮喘儿童支气管上皮细胞（BEC）的离体RSV感染是否会诱导特定的基因表达模式，以及这种模式是否与BEC供体之间的肺功能相关。

方法

在气液界面上区分了经过仔细表征的哮喘儿童（n = 18）和匹配的健康儿童（哮喘）（n = 8）的原发性BEC。气液界面培养物被RSV感染96小时，随后从BEC中分离出RNA。在每种情况下，我们使用RNA测序分析基因表达，并通过数据的线性建模评估条件之间的差异。BEC供体完成肺活量测定以测量肺功能。

结果

与来自哮喘受试者的未感染BEC相比，来自哮喘受试者的BEC的RSV感染导致6199基因表达的显着增加。哮喘和气道阻塞患儿的BECs（FEV ₁ /强迫肺活量<0.85，FEV ₁  <预测的100％）中195个基因的表达明显高于无阻塞患儿的BECs或健康儿童的BECs 。发现这些特异性基因高度富集与I型和III型干扰素平行诱导的病毒反应基因。

结论

与患有正常肺功能的儿童的细胞相比，患有哮喘和具有阻塞性生理功能的儿童的BEC表现出更高的I型和III型干扰素和干扰素刺激基因的表达，并且干扰素相关基因的表达与气道阻塞程度相关。这些发现表明，气道上皮细胞对病毒感染的过度干扰素反应可能是导致一部分哮喘儿童肺功能下降的机制。