Targeting PI3K-p110α suppresses influenza virus infection in chronic obstructive pulmonary disease

Alan Chen Yu Hsu, Malcolm R. Starkey, Irwan Hanish, Kristy Parsons, Tatt Jhong Haw, Linda J. Howland, Ian Barr, James B. Mahony, Paul S. Foster, Darryl A. Knight, Peter A. Wark, Philip M. Hansbro

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Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations. Objectives: To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD and the potential for therapeutic targeting. Methods: We used a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke-induced experimental COPD, and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors. Measurements and Main Results: COPDpBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity, reduced retinoic acid-inducible gene-I, and IFN/cytokine and chemokine responses. Increased PI3K-p110a levels and activity inCOPDpBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110a inhibitors, or exogenous IFN-b restored protective antiviral responses, suppressed infection, and improved lung function. Conclusions: The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which are mediated by increased PI3K-p110a activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and/or treat influenza.

Original languageEnglish
Pages (from-to)1012-1023
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume191
Issue number9
DOIs
Publication statusPublished - 1 May 2015
Externally publishedYes

Keywords

  • Chronic obstructive pulmonary disease
  • Influenza
  • Innate immunity
  • PI3K

Cite this

Hsu, A. C. Y., Starkey, M. R., Hanish, I., Parsons, K., Haw, T. J., Howland, L. J., Barr, I., Mahony, J. B., Foster, P. S., Knight, D. A., Wark, P. A., & Hansbro, P. M. (2015). Targeting PI3K-p110α suppresses influenza virus infection in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine, 191(9), 1012-1023. https://doi.org/10.1164/rccm.201501-0188OC