The mechanisms by which viruses cause exacerbations of chronic airways diseases are not precisely known. MicroRNAs (miRNAs) are small non-coding RNA molecules that silence the expression of specific genes, either by inhibiting transcription or translation. In pilot studies, we determined the effect of RV infectionon nasal aspirate miRNA expression patterns in five children with asthma and two controls. miRNAs were measured in nasal aspirates obtained before and during natural colds. Of 754 miRNAs tested, RV significantly decreased the expression of 82 miRNAs. Several of the RV-downregulated miRNAs (miRs-192, -200a, -205, -200c, -141, -429 and -200b) directly target ZEB1 and ZEB2, transcriptional repressors of E-cadherin expression. Another set of miRNAs (miR-17, -20a and -106b) regulate E-cadherin expression and distribution by targeting Stat3 and p38 MAP kinase. Inhibition of these miRNAs by viral infection would be expected to reduce E-cadherin expression, diminish epithelial barrier function and induce epithelial-to-mesenchymal cell transition. These data suggest a novel mechanism by which RV infection could increase translocation of allergens and bacteria across the epithelial barrier, thereby augmenting airway mucosal sensitization, inflammation and responsiveness.
Two aims are proposed.
Specific Aim 1. Determine the effects of RV infection on miRNA expression in asthmatic children. We hypothesize that: 1) RV infection alters the expression of miRNAs in nasal aspirates from children with asthma, with the predominant effect being downregulation; 2) miRs-192, -200a, -205, -141, -429, -17, -20a and -106b, each of which target E-cadherin transcriptional repressors, are specifically downregulated by RV infection.
Specific Aim 2. Determine the effects of miRNA downregulation on the expression of relevant target mRNAs. We hypothesize that: 1) RV-induced miRNA downregulation will be associated with increased expression of associated target genes; and 2) ZEB1, ZEB2, Stat3 and p38 MAP kinase mRNA and protein expression will be increased following RV infection, leading to reduced expression of E-cadherin. This early-stage work is a critical first step in our understanding of the role of miRNA in the viral exacerbation of asthma. Further understanding of this novel mechanism may lead to new therapeutic interventions for patients with asthma and other chronic airways diseases.
Micro RNAs (miRNAs) are small non-coding RNA molecules that 'silence' the expression of specific genes, either by inhibiting transcription or translation. This exploratory R21 application seeks to understand viral-induced asthma exacerbations by examining, for the first time, rhinovirus-induced changes in nasal secretion miRNAs. Our project will investigate a novel mechanism by which viral infection, via changes in miRNA expression, could diminish airway epithelial barrier function, thereby augmenting airway mucosal sensitization, inflammation and responsiveness.
| Lewis, Toby C; Metitiri, Ediri E; Mentz, Graciela B et al. (2018) Influence of viral infection on the relationships between airway cytokines and lung function in asthmatic children. Respir Res 19:228 |
| Lewis, Toby C; Metitiri, Ediri E; Mentz, Graciela B et al. (2018) Impact of community respiratory viral infections in urban children with asthma. Ann Allergy Asthma Immunol : |
