Airway Secretory microRNAome Changes during Rhinovirus Infection in Early Childhood.

Maria J Gutierrez,Geovanny F Perez,Sarah Ferrante,Krishna Pancham,Stephanie Val,Dinesh K Pillai,Mary C Rose,Gustavo Nino,Robert Freishtat,Jose L Gomez,Mamta Giri,Diego Preciado

doi:10.1371/journal.pone.0162244

Maria J Gutierrez, Geovanny F Perez + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0162244

Copy DOI

Abstract

BackgroundInnate immune responses are fine-tuned by small noncoding RNA molecules termed microRNAs (miRs) that modify gene expression in response to the environment. During acute infections, miRs can be secreted in extracellular vesicles (EV) to facilitate cell-to-cell genetic communication. The purpose of this study was to characterize the baseline population of miRs secreted in EVs in the airways of young children (airway secretory microRNAome) and examine the changes during rhinovirus (RV) infection, the most common cause of asthma exacerbations and the most important early risk factor for the development of asthma beyond childhood.MethodsNasal airway secretions were obtained from children (≤3 yrs. old) during PCR-confirmed RV infections (n = 10) and age-matched controls (n = 10). Nasal EVs were isolated with polymer-based precipitation and global miR profiles generated using NanoString microarrays. We validated our in vivo airway secretory miR data in an in vitro airway epithelium model using apical secretions from primary human bronchial epithelial cells (HBEC) differentiated at air-liquid interface (ALI). Bioinformatics tools were used to determine the unified (nasal and bronchial) signature airway secretory miRNAome and changes during RV infection in children.ResultsMultiscale analysis identified four signature miRs comprising the baseline airway secretory miRNAome: hsa-miR-630, hsa-miR-302d-3p, hsa- miR-320e, hsa-miR-612. We identified hsa-miR-155 as the main change in the baseline miRNAome during RV infection in young children. We investigated the potential biological relevance of the airway secretion of hsa-mir-155 using in silico models derived from gene datasets of experimental in vivo human RV infection. These analyses confirmed that hsa-miR-155 targetome is an overrepresented pathway in the upper airways of individuals infected with RV.ConclusionsComparative analysis of the airway secretory microRNAome in children indicates that RV infection is associated with airway secretion of EVs containing miR-155, which is predicted in silico to regulate antiviral immunity. Further characterization of the airway secretory microRNAome during health and disease may lead to completely new strategies to treat and monitor respiratory conditions in all ages.

Highlights

Immune responses are fine-tuned by small RNA molecules termed microRNAs that modify gene expression in response to the environment. miRs comprise a large family of highly conserved, short, non-coding RNAs that regulate post-transcriptional gene-silencing through inhibition of translation or promotion of mRNA degradation.[1] miRs regulate approximately 60% of protein encoding genes.[2]
We investigated the potential biological relevance of the airway secretion of hsamir-155 using in silico models derived from gene datasets of experimental in vivo human RV infection
Comparative analysis of the airway secretory microRNAome in children indicates that RV infection is associated with airway secretion of extracellular vesicles (EVs) containing miR-155, which is predicted in silico to regulate antiviral immunity

Summary

Introduction

Immune responses are fine-tuned by small RNA molecules termed microRNAs (miRs) that modify gene expression in response to the environment. miRs comprise a large family of highly conserved, short, non-coding RNAs that regulate post-transcriptional gene-silencing through inhibition of translation or promotion of mRNA degradation.[1] miRs regulate approximately 60% of protein encoding genes.[2]. Immune responses are fine-tuned by small RNA molecules termed microRNAs (miRs) that modify gene expression in response to the environment. Respiratory immune responses are fine-tuned by miRs. Resident and migrating lung immune cells such as macrophages, dendritic cells (DC), lymphocytes and airway epithelium and smooth muscle cells undergo post-translational regulation of immune-related genes via miRs.[5] Numerous miRs have been reported to have physiological roles in maintaining tissue homeostasis and normal development in the airways and the lung.[6, 7] There is compelling evidence demonstrating that several miRs play pivotal roles in fine-tuning important pathogenic pathways including the regulation of the effector function of T helper (Th) 2 cells in allergic asthma,[8] the regulation of host defense immune responses,[9] and the repair and remodeling of the airways.[5] Despite the importance of miRs in the genetic regulation of the respiratory system, there is paucity of data describing the baseline population of miRs secreted in EV in the human airways (airway secretory miRNAome). The purpose of this study was to characterize the baseline population of miRs secreted in EVs in the airways of young children (airway secretory microRNAome) and examine the changes during rhinovirus (RV) infection, the most common cause of asthma exacerbations and the most important early risk factor for the development of asthma beyond childhood

Objectives

Methods

Results

Conclusion