Role of Post-transcriptional Dysregulation and Aberrant Microbiota in Obstructive Lung Disease

We leverage multi-omics approaches RNA-seq and 16S rRNA gene sequencing to characterize non-coding RNAs and microbial community changes in diseases that affect the lungs. In particular, we assess the roles of exosomal microRNAs in rhinovirus (RV)-induced asthma and the lung microbiome alterations in prophylaxis-treated infants with cystic fibrosis. Asthma symptoms are often exacerbated by the common-cold-causing RV. We characterized the temporal behavior of circulating exosomal microRNAs (ExoMiRNAs) in a longitudinal bi-phasic case-control study of mild asthmatic patients (n = 12) and matched non-atopic healthy controls (n = 12) inoculated with rhinovirus. We aimed to define clinical and immunologic characteristics associated with differentially expressed (DE) miRNAs. In total, 26 DE ExoMiRNAs, including (hsa-)let-7f-5p, let-7a-5p, miR-122-5p, miR-101-3p, and miR-126-3p, were identified between asthmatic and healthy subjects after inoculation with RV. Time series clustering identified a unique cluster of upregulated DE ExoMiRNAs with augmented mean expression and a distinct cluster of downregulated DE ExoMiRNAs with decreased mean expression in asthmatic subjects upon RV challenge. Notably, the Upregulated Cluster correlated with Th1 and interferon-induced cytokines/chemokines (IFN-γ and IFN-γ-inducible protein-10) and interleukin-10 (IL-10). Conversely, the Downregulated Cluster correlated with IL-13, a Th2 cytokine, pulmonary function measurements (FVC%, FEV1%, and PEF%), and inflammatory biomarkers (FeNO, eosinophil%, and neutrophil%). Key ExoMiRNA-target genes and anti-viral defense mechanisms of the Upregulated and Downregulated Clusters were identified by network and gene enrichment analyses. Our findings provide insight into the regulatory role of ExoMiRNAs in RV-induced asthma. Cystic fibrosis (CF) is a genetic disorder caused by the mutation of the CFTR gene. Antibiotic prophylaxis treatment has been recommended in certain countries, yet its effect on the lung microbiome and pulmonary function is not clear. In our multi-center observational study of 45 infants at two visits (∼3 and 14 months of age), we found a pulmonary microbial community shift in the prophylaxis-treated infants with CF. Other than the traditional CF bacteria Staphylocuccus and Pseudomonas, non-traditional CF bacteria such as Streptococcus, Neisseria and Gemella were among the core taxa. The prophylaxis-treated infants had a much lower alpha diversity and a higher composition of Streptococcus at the earlier visit, and the higher level of Streptococcus was associated with declined FEV0.5%. We also show that the alteration of the lung microbiota at the early CF may be linked to antimicrobial resistance. Our results suggest that prophylactic treatment may exert an adverse effect on pulmonary function and should be used with caution.