RT Journal Article
SR Electronic
T1 Aerosolized TLR Agonists Suppress Acute Sendai Virus Lung Infection and Chronic Airway Disease in Mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 668368
DO 10.1101/668368
A1 David L. Goldblatt
A1 Jose R. Flores
A1 Gabriella Valverde Ha
A1 Ana M. Jaramillo
A1 Sofya Tkachman
A1 Carson T. Kirkpatrick
A1 Shradha Wali
A1 Belinda Hernandez
A1 David E. Ost
A1 Brenton L. Scott
A1 Jichao Chen
A1 Scott E. Evans
A1 Michael J. Tuvim
A1 Burton F. Dickey
YR 2019
UL http://biorxiv.org/content/early/2019/06/13/668368.abstract
AB 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. Treatment with 1 µM oligodeoxynucleotide (ODN) M362, an agonist of the TLR9 homodimer, and 4 µM Pam2CSK4 (Pam2), an agonist of the TLR2/6 heterodimer, within a few days before or after Sendai virus challenge, resulted in a ∼75% reduction in lung Sendai virus burden five 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 downregulating Type 2 (allergic) inflammation. 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 progression of asthma.One Sentence Summary Respiratory viral infections can induce chronic airway disease, and we find that stimulating innate immunity within the lungs of mice reduces the severity of acute infection and development of a chronic asthma phenotype.