Inhibition of uric acid or IL‐1β ameliorates respiratory syncytial virus immunopathology and development of asthma

• Published in: Allergy (Copenhagen) Vol. 75; no. 9; pp. 2279 - 2293
• Main Authors: Schuler, Charles F., Malinczak, Carrie‐Anne, Best, Shannon K. K., Morris, Susan B., Rasky, Andrew J., Ptaschinski, Catherine, Lukacs, Nicholas W., Fonseca, Wendy
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.09.2020
• Subjects: Allergens; allopurinol; Animal models; Animals; Asthma; Chronic infection; Immune response; Immunity, Innate; Infants; Infections; interleukin‐1 beta; Lung; Lymphocytes; Mice; Mice, Inbred BALB C; mRNA; Neonates; Respiratory syncytial virus; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Uric Acid; Xanthine oxidase; asthma; interleukin-1 beta; allopurinol; respiratory syncytial virus; uric acid
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.14310

Background Respiratory syncytial virus (RSV) affects most infants early in life and is associated with increased asthma risk. The specific mechanism remains unknown. Objective To investigate the role of uric acid (UA) and IL‐1β in RSV immunopathology and asthma predisposition. Methods Tracheal aspirates from human infants with and without RSV were collected and analyzed for pro‐IL‐1β mRNA and protein to establish a correlation in human disease. Neonatal mouse models of RSV were employed, wherein mice infected at 6‐7 days of life were analyzed at 8 days postinfection, 5 weeks postinfection, or after a chronic cockroach allergen asthma model. A xanthine oxidase inhibitor or IL‐1 receptor antagonist was administered during RSV infection. Results Human tracheal aspirates from RSV‐infected infants showed elevated pro‐IL‐1β mRNA and protein. Inhibition of UA or IL‐1β during neonatal murine RSV infection decreased mucus production, reduced cellular infiltrates to the lung (especially ILC2s), and decreased type 2 immune responses. Inhibition of either UA or IL‐1β during RSV infection led to chronic reductions in pulmonary immune cell composition and reduced type 2 immune responses and reduced similar responses after challenge with cockroach antigen. Conclusions Inhibiting UA and IL‐1β during RSV infection ameliorates RSV immunopathology, reduces the consequences of allergen‐induced asthma, and presents new therapeutic targets to reduce early‐life viral‐induced asthma development. Neonatal RSV infection is associated with increases in pulmonary uric acid and IL‐1β and lung immunopathology. XOI or IL‐1RA administration during neonatal RSV infection leads to reduced RSV immunopathology. XOI or IL‐1RA administration during neonatal RSV infection leads to reduced type 2 immune responses during a subsequent model of asthma. Abbreviations: IL‐1RA, IL‐1 receptor antagonist; RSV: Respiratory syncytial virus; XOI, xanthine oxidase inhibitor.