Inducible epithelial resistance against acute Sendai virus infection prevents chronic asthma‐like lung disease in mice

Goldblatt, David L.; Flores, Jose R.; Valverde Ha, Gabriella; Jaramillo, Ana M.; Tkachman, Sofya; Kirkpatrick, Carson T.; Wali, Shradha; Hernandez, Belinda; Ost, David E.; Scott, Brenton L.; Chen, Jichao; Evans, Scott E.; Tuvim, Michael J.; Dickey, Burton F.

doi:10.1111/bph.14977

Title: Inducible epithelial resistance against acute Sendai virus infection prevents chronic asthma‐like lung disease in mice

Journal Article · Wed Feb 12 00:00:00 EST 2020 · British Journal of Pharmacology

DOI:https://doi.org/10.1111/bph.14977· OSTI ID:1599236

^[1]; Flores, Jose R. ^[1]; Valverde Ha, Gabriella ^[1];

^[1]; Tkachman, Sofya ^[1]; Kirkpatrick, Carson T. ^[1];

^[1]; Hernandez, Belinda ^[1]; Ost, David E. ^[1]; Scott, Brenton L. ^[2]; Chen, Jichao ^[1];

^[1];

^[1]

Department of Pulmonary Medicine The University of Texas MD Anderson Cancer Center Houston TX USA
Pulmotect, Inc. Houston TX USA

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‐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. 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.

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Sponsoring Organization:: USDOE

OSTI ID:: 1599236

Journal Information:: British Journal of Pharmacology, Journal Name: British Journal of Pharmacology Vol. 177 Journal Issue: 10; ISSN 0007-1188

Publisher:: Wiley-BlackwellCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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Cited by: 8 works

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