Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses

Abstract

Previous genetic studies on susceptibility to otitis media and airway infections have focused on immune pathways acting within the local mucosal epithelium, and outside of allergic rhinitis and asthma, limited studies exist on the overlaps at the gene, pathway or network level between the upper and lower airways. In this report, we compared [1] pathways identified from network analysis using genes derived from published genomewide family-based and association studies for otitis media, sinusitis, and lung phenotypes, to [2] pathways identified using differentially expressed genes from RNA-sequence data from lower airway, sinus, and middle ear tissues, in particular cholesteatoma tissue compared to middle ear mucosa. For otitis media, a large number of genes (n = 1,806) were identified as differentially expressed between cholesteatoma and middle ear mucosa, which in turn led to the identification of 68 pathways that are enriched in cholesteatoma. Two differentially expressed genes CR1 and SAA1 overlap in middle ear, sinus, and lower airway samples and are potentially novel genes for otitis media susceptibility. In addition, 56 genes were differentially expressed in both tissues from the middle ear and either sinus or lower airways. Pathways that are common in upper and lower airway diseases, whether from published DNA studies or from our RNA-sequencing analyses, include chromatin organization/remodeling, endocytosis, immune system process, protein folding, and viral process. Taken together, our findings from genetic susceptibility and differential tissue expression studies support the hypothesis that the unified airway theory wherein the upper and lower respiratory tracts act as an integrated unit also applies to infectious and nonallergic airway epithelial disease. Our results may be

Systems Biology Approaches to Understanding the Human Immune System

“…Indeed, IRF5 −/− and IL-10RA −/− mutant iPSDM cells were both shown to have increased susceptibility to C. trachomatis infection. These results, along with numerous other published studies [e.g., (73)(74)(75)(76)(77)], demonstrate that multi-omics integration using PPI networks can reveal novel insight into the factors that play a significant role in the host immune response to infections.…”

Identification of Macrophage Polarization-Related Genes as Biomarkers of Chronic Obstructive Pulmonary Disease Based on Bioinformatics Analyses

“…For example, the authors uploaded the GSE124180 dataset mainly compared the correlation of gene expression across COPD-relevant tissues, including large-airway epithelium, alveolar macrophage, and peripheral blood, and explored the biological functions of overlapped genes among three tissues [ 42 ]. On the other hand, Baschal et al compared the gene expressions across the lower airway, sinus, and middle ear tissues using the GSE124180 dataset and other data [ 43 ]. Different from these two researches, our study mainly focused on the role of macrophage polarization in COPD and identification of macrophage polarization-related genes as the biomarkers of COPD based on the peripheral blood of the GSE124180 dataset.…”

The Role of Respiratory Flora in the Pathogenesis of Chronic Respiratory Diseases

“…They are the main structure of the local innate immune system and the main carrier of the airway flora. There are cilia on the surface of respiratory mucosal epithelial cells, which can transport bacteria of the lower airway upwards, while the mucus secreted by goblet cells and secretory IgA antibodies produced by submucosal lymphohistiocytes can further maintain the local chemical immune barrier function of the mucosa and prevent the invasion and colonization of pathogens [ 13 , 14 ]. However, the local immune system of the airway neither equips with the strong acid and alkali on the surface of alimentary canal mucosa and the powerful germicidal mechanism of excellent enzyme system nor the extremely anaerobic environment, which determines that there is no significant difference in the species but only in the number of bacteria in the upper and lower airway.…”