Upper Airway Gene Expression in Hospitalized Children with Rhinovirus-induced Respiratory Illnesses

Abstract

Background: The precise mechanisms underlying rhinovirus (RV)-induced respiratory illnesses are not completely known.

Objective: We sought to obtain nasal transcriptomic data from hospitalized children with respiratory viral infections.

Methods: We obtained nasal swabs from 46 children with RV (16 RV-A, 30 RV-C). For comparison, we examined swabs from 12 children with RSV and six controls. Subjects ranged in age from 1 month to 18 years. Viral detection, genotyping and copy number were determined by PCR. RNA transcripts were measured by next generation sequencing and differences in gene expression calculated using DESeq2.

Results: Compared to controls, 1232 transcripts were upregulated (adjusted p<0.05, fold change >1.5) by all three viruses, including genes regulating granulocyte chemotaxis, cysteinyl leukotriene production, epithelial remodeling and antiviral responses. Cilium-related genes were downregulated. Compared to RSV, RV induced greater expression of 207 genes including those regulating eosinophilic inflammation, mucus secretion and mast cell function.RSV induced greater upregulation of 674 genes including those regulating neutrophilic inflammation and type 1 IFN response. Computational deconvolution of RNA-seq profiles revealed that viral infection decreased ciliated cells while increasing neutrophils, natural killer cells, monocytes (all viral species) and goblet cells (RV only). RV-C infections increased mast cells and IFN-λ mRNA expression. RV copy number correlated with the expression of mast cell proteases and numerous pro-inflammatory and IFN-stimulated genes.

Conclusion: Children hospitalized with RV and RSV infections mount robust inflammatory responses, but virus-specific differences exist.

Clinical implication: These data provide insight into mechanisms by which RV, and in particular, RV-C, trigger respiratory illnesses.

Capsule summary: Nasal transcriptomics demonstrate that RV infections in hospitalized children induce expression of genes regulating eosinophilic inflammation, mucus secretion and mast cell function, with RV-C in particular increasing IFN-λ expression.