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RHINOVIRUS INFECTION OF THE AIRWAY EPITHELIUM ENHANCES MAST CELL IMMUNE RESPONSES VIA EPITHELIAL-DERIVED INTERFERONS

ABSTRACT: Rationale: Mast cells (MCs) within the airway epithelium in asthma are closely related to airway dysfunction, but crosstalk between airway epithelial cells (AECs) and MCs in asthma remains incompletely understood. Human rhinovirus (HRV) infections are key triggers for asthma progression and AECs from individuals with asthma may have dysregulated anti-viral responses. Objectives: We utilize primary phenotyped AECs in an ex vivo coculture model system to examine crosstalk between AECs and MCs following epithelial HRV infection. Methods: Primary AECs were obtained from children with asthma (n=11) and healthy children (n=10), differentiated at air-liquid interface, and cultured in the presence of laboratory of allergic diseases-2 (LAD2) MCs. AECs were infected with HRV serogroup A 16 (HRV16) for 48 hours. RNA isolated from both AECs and MCs underwent RNA-sequencing (RNAseq) analysis. Direct effects of epithelial-derived interferons on LAD2 MCs were examined by qPCR. Results: MCs increased expression of pro-inflammatory and anti-viral genes in AECs. AECs demonstrated a robust antiviral response following HRV16 infection that resulted in significant changes in MC gene expression, including upregulation of genes involved in anti-viral responses, leukocyte activation, and type-2 (T2) inflammation. Subsequent ex vivo modeling demonstrated that IFN-β induces MC IL13 expression. The effects of AEC phenotype were small relative to the effects of viral infection and the presence of MCs. Conclusions: There is significant crosstalk between AECs and MCs, which are present in the epithelium in asthma. Epithelial-derived interferons not only play a role in viral suppression, but further alter MC immune responses including specific T2 genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206680 | GEO | 2022/06/22

REPOSITORIES: GEO

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Project description:Monkey disease models, which are comparable to humans in terms of genetic, anatomical, and physiological characteristics, are important for understanding disease mechanisms and evaluating the efficiency of biological treatments. Here, we established an A.suum-induced model of asthma in cynomolgus monkeys to profile airway inflammation and remodeling in the lungs by single-cell transcriptomic sequencing (scRNA-seq). The asthma model results in airway hyperresponsiveness and remodeling, demonstrated by pulmonary function test and histological characterization. scRNA-seq reveals that the model elevates the numbers of stromal, epithelial and mesenchymal cells (MCs). Particularly, the model increases the numbers of endothelial cells (ECs), fibroblasts (Fibs) and smooth muscle cells (SMCs) in the lungs, with upregulated gene expression associated with cell functions enriched in cell migration and angiogenesis in ECs and Fibs, and VEGF-driven cell proliferation, apoptotic process and complement activation in SMCs. Interestingly, we discover a novel Fib subtype that mediates type I inflammation in the asthmatic lungs. Moreover, MCs cells in the asthmatic lungs are found to regulate airway remodeling and immunological responses, with elevated gene expression enriched in cell migration, proliferation, angiogenesis and innate immunological responses. Despite the fact that the numbers of epithelial cells in the asthma lungs do not change at the time of lung tissue collection, their gene expressions are significantly altered, with an enrichment in the biological processes of IL-17 signaling pathway and apoptosis in the majority of subtypes of epithelial cells. Moreover, the ubiquitin process and DNA repair are more prevalent in ciliated epithelial cells. Last, cell-to-cell interaction analysis reveals a complex network among stromal cells, MCs and macrophages that contribute to the development of asthma and airway remodeling. Our findings provide a critical resource for understanding the principle underlying airway remodeling and inflammation in a monkey model of asthma, as well as valuable hints for the future treatment of asthma, especially the airway remodeling-characterized refractory asthma.

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RHINOVIRUS INFECTION OF THE AIRWAY EPITHELIUM ENHANCES MAST CELL IMMUNE RESPONSES VIA EPITHELIAL-DERIVED INTERFERONS

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