Bonser Luke R, Eckalbar Walter L, Rodriguez Lauren, Shen Jiangshan, Koh Kyung Duk, Zlock Lorna T, Christenson Stephanie, Woodruff Prescott G, Finkbeiner Walter E, Erle David J
Lung Biology Center, Critical Care, Allergy and Sleep Medicine, Department of Medicine; University of California, San Francisco.
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine; University of California, San Francisco.
bioRxiv. 2021 Feb 25:2021.02.25.432762. doi: 10.1101/2021.02.25.432762.
Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown.
We sought to discover how IL-13 and other cytokines affect expression of genes encoding SARS-CoV-2-associated host proteins in human bronchial epithelial cells (HBECs) and determine whether IL-13 stimulation alters susceptibility to SARS-CoV-2 infection.
We used bulk and single cell RNA-seq to identify cytokine-induced changes in SARS-CoV-2-associated gene expression in HBECs. We related these to gene expression changes in airway epithelium from individuals with mild-moderate asthma and chronic obstructive pulmonary disease (COPD). We analyzed effects of IL-13 on SARS-CoV-2 infection of HBECs.
Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples). 41 (12%) of these mRNAs were regulated by IL-13 (>1.5-fold change, FDR < 0.05). Many IL-13-regulated SARS-CoV-2-associated genes were also altered in type 2 high asthma and COPD. IL-13 pretreatment reduced viral RNA recovered from SARS-CoV-2 infected cells and decreased dsRNA, a marker of viral replication, to below the limit of detection in our assay. Mucus also inhibited viral infection.
IL-13 markedly reduces susceptibility of HBECs to SARS-CoV-2 infection through mechanisms that likely differ from those activated by type I interferons. Our findings may help explain reports of relatively low prevalence of asthma in patients diagnosed with COVID-19 and could lead to new strategies for reducing SARS-CoV-2 infection.
哮喘与气道上皮的慢性变化有关，而气道上皮是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的关键靶标。许多上皮变化由2型细胞因子白细胞介素-13（IL-13）驱动，但IL-13对SARS-CoV-2感染的影响尚不清楚。
我们试图发现IL-13和其他细胞因子如何影响人支气管上皮细胞（HBECs）中编码SARS-CoV-2相关宿主蛋白的基因表达，并确定IL-13刺激是否会改变对SARS-CoV-2感染的易感性。
我们使用批量和单细胞RNA测序来鉴定细胞因子诱导的HBECs中SARS-CoV-2相关基因表达的变化。我们将这些变化与轻度至中度哮喘和慢性阻塞性肺疾病（COPD）患者气道上皮中的基因表达变化相关联。我们分析了IL-13对HBECs感染SARS-CoV-2的影响。
在HBECs中检测到342种（97%）SARS-CoV-2相关蛋白中332种的编码转录本（在50%的样本中≥1转每百万映射读取数）。其中41种（12%）mRNA受IL-13调节（变化>1.5倍，错误发现率<0.05）。许多受IL-13调节的SARS-CoV-2相关基因在2型高哮喘和COPD中也发生了改变。IL-13预处理减少了从感染SARS-CoV-2的细胞中回收的病毒RNA，并将病毒复制标志物双链RNA降低到我们检测方法的检测限以下。黏液也抑制病毒感染。
IL-13通过可能不同于I型干扰素激活的机制，显著降低HBECs对SARS-CoV-2感染的易感性。我们的发现可能有助于解释COVID-19诊断患者中哮喘患病率相对较低的报道，并可能导致减少SARS-CoV-2感染的新策略。
