Priority Research Centre GrowUpWell, Experimental and Translational Respiratory Medicine Group, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
Airway Disease Infection Section, National Heart and Lung Institute, Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.
JCI Insight. 2021 Apr 8;6(7):127933. doi: 10.1172/jci.insight.127933.
Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the cause of approximately 80% of common colds, are detected in nearly half of all infants with bronchiolitis and the majority of children with an asthma exacerbation. Bronchiolitis in early life is a strong risk factor for the development of asthma. Here, we found that RV infection induced the expression of miRNA 122 (miR-122) in mouse lungs and in human airway epithelial cells. In vivo inhibition specifically in the lung reduced neutrophilic inflammation and CXCL2 expression, boosted innate IFN responses, and ameliorated airway hyperreactivity in the absence and in the presence of allergic lung inflammation. Inhibition of miR-122 in the lung increased the levels of suppressor of cytokine signaling 1 (SOCS1), which is an in vitro-validated target of miR-122. Importantly, gene silencing of SOCS1 in vivo completely reversed the protective effects of miR-122 inhibition on RV-induced lung disease. Higher miR-122 expression in nasopharyngeal aspirates was associated with a longer time on oxygen therapy and a higher rate of treatment failure in 87 infants hospitalized with moderately severe bronchiolitis. These results suggest that miR-122 promotes RV-induced lung disease via suppression of its target SOCS1 in vivo. Higher miR-122 expression was associated with worse clinical outcomes, highlighting the potential use of anti-miR-122 oligonucleotides, successfully trialed for treatment of hepatitis C, as potential therapeutics for RV-induced bronchiolitis and asthma exacerbations.
病毒引起的呼吸道感染是儿童健康的主要负担，现有的治疗方法主要是支持性的，而不是针对疾病的。鼻病毒（RV）是引起普通感冒的主要原因，约占所有毛细支气管炎婴儿的近一半，也是大多数哮喘加重儿童的主要病因。婴儿期毛细支气管炎是发展为哮喘的一个强烈危险因素。在这里，我们发现 RV 感染会在小鼠肺部和人类气道上皮细胞中诱导 microRNA 122（miR-122）的表达。体内特异性抑制肺部 miR-122 的表达，可减少中性粒细胞炎症和 CXCL2 的表达，增强先天 IFN 反应，并在不存在和存在过敏性肺炎症的情况下改善气道高反应性。抑制肺部的 miR-122 增加了细胞因子信号转导抑制因子 1（SOCS1）的水平，SOCS1 是 miR-122 的体外验证靶标。重要的是，体内 SOCS1 基因沉默完全逆转了 miR-122 抑制对 RV 诱导的肺部疾病的保护作用。鼻咽抽吸物中较高的 miR-122 表达与 87 例中度严重毛细支气管炎住院婴儿的吸氧时间延长和治疗失败率较高相关。这些结果表明，miR-122 通过体内抑制其靶标 SOCS1 促进 RV 诱导的肺部疾病。较高的 miR-122 表达与更差的临床结局相关，这突显了抗 miR-122 寡核苷酸的潜在用途，抗 miR-122 寡核苷酸已成功用于丙型肝炎的治疗，可作为治疗 RV 诱导的毛细支气管炎和哮喘加重的潜在疗法。
