Inducible epithelial resistance against acute Sendai virus infection prevents chronic asthma-like lung disease in mice.
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Goldblatt DL, Flores JR, Valverde Ha G, Jaramillo AM, Tkachman S, Kirkpatrick CT, Wali S, Hernandez B, Ost DE, Scott BL, Chen J, Evans SE, Tuvim MJ, Dickey BF
Inducible epithelial resistance against acute Sendai virus infection prevents chronic asthma-like lung disease in mice.
Br J Pharmacol. 2020 May;177(10):2256-2273. doi: 10.1111/bph.14977. Epub 2020 Feb 12.
- PubMed ID
- 31968123 [ View in PubMed]
- Abstract
BACKGROUND AND PURPOSE: Respiratory viral infections play central roles in the initiation, exacerbation and progression of asthma in humans. An acute paramyxoviral infection in mice can cause a chronic lung disease that resembles human asthma. We sought to determine whether reduction of Sendai virus lung burden in mice by stimulating innate immunity with aerosolized Toll-like receptor (TLR) agonists could attenuate the severity of chronic asthma-like lung disease. EXPERIMENTAL APPROACH: Mice were treated by aerosol with 1-muM oligodeoxynucleotide (ODN) M362, an agonist of the TLR9 homodimer, and 4-muM Pam2CSK4 (Pam2), an agonist of the TLR2/6 heterodimer, within a few days before or after Sendai virus challenge. KEY RESULTS: Treatment with ODN/Pam2 caused ~75% reduction in lung Sendai virus burden 5 days after challenge. The reduction in acute lung virus burden was associated with marked reductions 49 days after viral challenge in eosinophilic and lymphocytic lung inflammation, airway mucous metaplasia, lumenal mucus occlusion and hyperresponsiveness to methacholine. Mechanistically, ODN/Pam2 treatment attenuated the chronic asthma phenotype by suppressing IL-33 production by type 2 pneumocytes, both by reducing the severity of acute infection and by down-regulating Type 2 (allergic) inflammation. CONCLUSION AND IMPLICATIONS: These data suggest that treatment of susceptible human hosts with aerosolized ODN and Pam2 at the time of a respiratory viral infection might attenuate the severity of the acute infection and reduce initiation, exacerbation and progression of asthma.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions ODN M362 Toll-like receptor 9 Protein Humans UnknownAgonistDetails Pam2csk4 Toll-like receptor 2 Protein Humans UnknownAgonistDetails Pam2csk4 Toll-like receptor 6 Protein Humans UnknownAgonistDetails