Activation of STAT3-mediated ciliated cell survival protects against severe infection by respiratory syncytial virus.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Caiqi Zhao, Yan Bai, Wei Wang, Gaurang M Amonkar, Hongmei Mou, Judith Olejnik, Adam J Hume, Elke Mühlberger, Nicholas W Lukacs, Rachel Fearns, Paul H Lerou, Xingbin Ai
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Abstract

Respiratory syncytial virus (RSV) selectively targets ciliated cells in human bronchial epithelium and can cause bronchiolitis and pneumonia, mostly in infants. To identify molecular targets of intervention during RSV infection in infants, we investigated how age regulates RSV interaction with the bronchial epithelium barrier. Employing precision-cut lung slices and air-liquid interface cultures generated from infant and adult human donors, we found robust RSV virus spread and extensive apoptotic cell death only in infant bronchial epithelium. In contrast, adult bronchial epithelium showed no barrier damage and limited RSV infection. Single nuclear RNA-Seq revealed age-related insufficiency of an antiapoptotic STAT3 activation response to RSV infection in infant ciliated cells, which was exploited to facilitate virus spread via the extruded apoptotic ciliated cells carrying RSV. Activation of STAT3 and blockade of apoptosis rendered protection against severe RSV infection in infant bronchial epithelium. Lastly, apoptotic inhibitor treatment of a neonatal mouse model of RSV infection mitigated infection and inflammation in the lung. Taken together, our findings identify a STAT3-mediated antiapoptosis pathway as a target to battle severe RSV disease in infants.

激活 STAT3 介导的纤毛细胞存活可防止呼吸道合胞病毒的严重感染。
呼吸道合胞病毒(RSV)选择性地针对人类支气管上皮的纤毛细胞,可引起支气管炎和肺炎,主要发生在婴儿身上。为了确定婴儿感染 RSV 期间的分子干预目标,我们研究了年龄如何调节 RSV 与支气管上皮屏障的相互作用。通过使用精确切割的肺切片和从婴儿和成人供体中产生的气液界面培养物,我们发现只有在婴儿支气管上皮中才会出现强大的 RSV 病毒传播和广泛的细胞凋亡。相比之下,成人支气管上皮细胞未出现屏障损伤,RSV 感染也很有限。单核 RNA-Seq 发现,婴儿纤毛细胞对 RSV 感染的抗凋亡 STAT3 激活反应与年龄有关,而婴儿纤毛细胞对 RSV 感染的抗凋亡 STAT3 激活反应不足,从而导致病毒通过携带 RSV 的凋亡纤毛细胞扩散。激活 STAT3 和阻止细胞凋亡可保护婴儿支气管上皮免受严重的 RSV 感染。最后,凋亡抑制剂治疗新生小鼠 RSV 感染模型可减轻肺部感染和炎症。综上所述,我们的研究结果确定了 STAT3 介导的抗细胞凋亡途径是抗击婴儿严重 RSV 疾病的靶点。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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