Targeting PI3K-p110α Suppresses Influenza Virus Infection in Chronic Obstructive Pulmonary Disease.
BACKGROUND
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.


OBJECTIVE
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.


RESULTS
COPD pBECs 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-p110α levels and activity in COPD pBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110α inhibitors, or exogenous IFN-β 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-p110α activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and/or treat influenza.
1 Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia.
Alan Chen-Yu
AC
Hsu
Malcolm R
MR
Starkey
Irwan
I
Hanish
Kristy
K
Parsons
Tatt Jhong
TJ
Haw
Linda J
LJ
Howland
Ian
I
Barr
James B
JB
Mahony
Paul S
PS
Foster
Darryl A
DA
Knight
Peter A
PA
Wark
Philip M
PM
Hansbro
D000328:Adult; D000368:Aged; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001980:Bronchi / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000821:virology*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases
PI3K; chronic obstructive pulmonary disease; influenza; innate immunity