Abstract
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.
Highlights
Virus-induced respiratory tract infections are among the most common causes for hospital admissions during childhood, manifesting as viral bronchiolitis and pneumonia in infants and asthma exacerbations and pneumonia/pneumonitis in older children
Inhibition of miRNA 122 (miR-122) was associated with reduced CXCL2 but not CXCL1 expression (Figure 2, E and F) and the abolishment of RV-induced airway hyperreactivity (AHR) (Figure 2G)
Hepatitis C virus (HCV) may exploit miR-122 for viral replication, whereby miR-122 binds to the 5′-noncoding region of viral genomic RNA to promote viral stability and translation of viral proteins [20, 21]
Summary
Virus-induced respiratory tract infections are among the most common causes for hospital admissions during childhood, manifesting as viral bronchiolitis and pneumonia in infants and asthma exacerbations and pneumonia/pneumonitis in older children. Identifying mRNA targets and demonstrating the in vivo functional relevance of a miRNA-mRNA circuit is critical for understanding the role of these noncoding RNA species in health and complex disease settings. This is inferred by showing an inverse correlation between miRNA expression and its mRNA target in vivo. Inflammatory signaling through NF-κB underpins the immune response to RV, and infants with bronchiolitis and RV infection have a distinct nasal airway miRNA profile associated with the upregulation of NF-κB [12]. The role of miRNAs in the pathogenesis of this common infection remains elusive
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