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.
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 humaninfants 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 miceinfected 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 RSVinfection. RESULTS:Human tracheal aspirates from RSV-infectedinfants showed elevated pro-IL-1β mRNA and protein. Inhibition of UA or IL-1β during neonatal murineRSVinfection 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 RSVinfection 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 RSVinfection ameliorates RSV immunopathology, reduces the consequences of allergen-induced asthma, and presents new therapeutic targets to reduce early-life viral-induced asthma development.
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