LPS binding protein and activation signatures are upregulated during asthma exacerbations in children

• Published in: Respiratory research Vol. 24; no. 1; p. 184
• Main Authors: Jones, Anya C, Leffler, Jonatan, Laing, Ingrid A, Bizzintino, Joelene, Khoo, Siew-Kim, LeSouef, Peter N, Sly, Peter D, Holt, Patrick G, Strickland, Deborah H, Bosco, Anthony
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 12.07.2023; BioMed Central; BMC
• Subjects: Allergens; Analysis; Asthma; Asthma - diagnosis; Asthma - genetics; Asthma in children; Atopic asthma; Atopy; Binomial distribution; Bulk RNA-Seq; Care and treatment; Cell migration; Cell Movement; Child; Children; Clustering; Composition; Convalescence; Corticosteroids; Diagnosis; Dosage and administration; Emergency medical care; Flow cytometry; Gene expression; Genetic aspects; Genomics; Glucocorticoids; Humans; Hypersensitivity, Immediate; Immune response; Immune system; Inflammation; Innate immunity; Leukocytes, Mononuclear; Lipopolysaccharides; LPS; Network analysis; Networks; Pathogenesis; Peripheral blood; Peripheral blood mononuclear cells; Priming; Protein binding; Proteins; Quality control; RNA sequencing; Sensitivity enhancement; Signatures; TGFB1; Transforming growth factor-b1; Viral infections; United States; Atopic asthma; Bulk RNA-Seq; TGFB1; Network analysis; LPS; Peripheral blood
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/s12931-023-02478-3

Asthma exacerbations in children are associated with respiratory viral infection and atopy, resulting in systemic immune activation and infiltration of immune cells into the airways. The gene networks driving the immune activation and subsequent migration of immune cells into the airways remains incompletely understood. Cellular and molecular profiling of PBMC was employed on paired samples obtained from atopic asthmatic children (n = 19) during acute virus-associated exacerbations and later during convalescence. Systems level analyses were employed to identify coexpression networks and infer the drivers of these networks, and validation was subsequently obtained via independent samples from asthmatic children. During exacerbations, PBMC exhibited significant changes in immune cell abundance and upregulation of complex interlinked networks of coexpressed genes. These were associated with priming of innate immunity, inflammatory and remodelling functions. We identified activation signatures downstream of bacterial LPS, glucocorticoids and TGFB1. We also confirmed that LPS binding protein was upregulated at the protein-level in plasma. Multiple gene networks known to be involved positively or negatively in asthma pathogenesis, are upregulated in circulating PBMC during acute exacerbations, supporting the hypothesis that systemic pre-programming of potentially pathogenic as well as protective functions of circulating immune cells preceeds migration into the airways. Enhanced sensitivity to LPS is likely to modulate the severity of acute asthma exacerbations through exposure to environmental LPS.