Sarah Djeddi, Daniela Fernandez-Salinas, George X Huang, Vitor R C Aguiar, Chitrasen Mohanty, Christina Kendziorski, Steven Gazal, Joshua A Boyce, Carole Ober, James E Gern, Nora A Barrett, Maria Gutierrez-Arcelus
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引用次数: 0
摘要
哮喘是一种由遗传和环境因素引起的复杂疾病。研究表明,鼻病毒感染时的喘息与儿童哮喘的发生有关。目前已发现 150 多种哮喘的非编码风险变异,其中许多影响 T 细胞的基因调控,但大多数风险变异的影响仍然未知。鉴于气道上皮细胞是抵御呼吸道病毒和过敏原的第一道防线,我们假设气道上皮细胞也可能介导哮喘的遗传易感性。我们将遗传数据与受到不同刺激的气道上皮细胞的转录组学进行了整合。我们证明,鼻病毒感染会显著上调儿童期发病的哮喘相关基因,尤其是在非纤毛细胞中。在感染流感时也能观察到这种富集现象,但在感染严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)或细胞因子激活时却观察不到。总之,我们的研究结果表明,鼻病毒感染是一种环境因素,它通过非纤毛气道上皮细胞与遗传风险因素相互作用,导致儿童发病型哮喘。
Rhinovirus infection of airway epithelial cells uncovers the non-ciliated subset as a likely driver of genetic risk to childhood-onset asthma.
Asthma is a complex disease caused by genetic and environmental factors. Studies show that wheezing during rhinovirus infection correlates with childhood asthma development. Over 150 non-coding risk variants for asthma have been identified, many affecting gene regulation in T cells, but the effects of most risk variants remain unknown. We hypothesized that airway epithelial cells could also mediate genetic susceptibility to asthma given they are the first line of defense against respiratory viruses and allergens. We integrated genetic data with transcriptomics of airway epithelial cells subject to different stimuli. We demonstrate that rhinovirus infection significantly upregulates childhood-onset asthma-associated genes, particularly in non-ciliated cells. This enrichment is also observed with influenza infection but not with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or cytokine activation. Overall, our results suggest that rhinovirus infection is an environmental factor that interacts with genetic risk factors through non-ciliated airway epithelial cells to drive childhood-onset asthma.