Abstract
Cytotoxic and neuroinflammatory effects of TiO2 nanoparticles (TiO2‐NP) in human airways are mediated by nerve growth factor (NGF), which is also implicated in the pathophysiology of respiratory syncytial virus (RSV) infection. We tested the hypothesis that exposure to TiO2‐NP results in increased susceptibility to RSV infection and exacerbation of airway inflammation via NGF‐mediated induction of autophagy in lower respiratory tract cells. Human primary bronchial epithelial cells were exposed to TiO2‐NP for 24 h prior to infection with recombinant red RSV (rrRSV). Expression of NGF and its TrkA and p75NTR receptors was measured by real‐time PCR and fluorescence‐activated cell sorting (FACS). Autophagy was assessed by beclin‐1 expression analysis. Cell death was studied by FACS after annexin V/propidium iodide staining. rrRSV infection efficiency more than doubled in human bronchial cells pre‐exposed to TiO2‐NP compared to controls. NGF and its TrkA receptor were upregulated in RSV‐infected bronchial cells pre‐exposed to TiO2‐NP compared to controls exposed to either rrRSV or TiO2‐NP alone. Silencing NGF gene expression with siRNA significantly inhibited rrRSV infection. rrRSV‐infected cells pre‐exposed to TiO2‐NP also showed increase in necrotic cell death and reduction in apoptosis, together with 4.3‐fold increase in expression of the early autophagosomal gene beclin‐1. Pharmacological inhibition of beclin‐1 by wortmannin resulted in increased apoptotic rate along with lower viral load. This study shows that TiO2‐NP exposure enhances the infectivity of RSV in human bronchial epithelial cells by upregulating the NGF/TrkA axis. The mechanism of this interaction involves induction of autophagy promoting viral replication and necrotic cell death.
Highlights
A recent report of the World Health Organization revealed that exposure to pollution is associated with more than one in four deaths among children younger than 5, and 570,000 children in this age range die every year from respiratory infections attributable to pollution
To determine whether Respiratory syncytial virus (RSV) infection induces autophagy in nanoparticle pretreated bronchial cells, we measured expression of beclin-1, a key component of PI3K/beclin1 complex that plays an important role in the initial stage of autophagy
Treated cells were immunostained on coverslips as described above, and the changes in recombinant red RSV (rrRSV) infection efficiency were further confirmed by confocal microscopy
Summary
A recent report of the World Health Organization revealed that exposure to pollution is associated with more than one in four deaths among children younger than 5, and 570,000 children in this age range die every year from respiratory infections attributable to pollution. Respirable particulate matter – especially nanosized particles with aerodynamic diameter ≤0.1 lm – has been linked to inception and exacerbations of asthma and chronic obstructive pulmonary disease (Thurston and Ozkaynak 1992; Bascom 1996) Owing to their smaller size and higher surface area, inhaled virus-sized particles exhibit high deposition in the lower respiratory tract and frequently act as carriers for copollutants of industrial and biological origin (e.g., gases, chemicals, bacteria, viruses) (Oberdorster 2001). RSV adversely affects the elderly and immunocompromised individuals, causing severe lower respiratory tract infection and pneumonia (Falsey 2007) This virus first replicates in epithelial cells of the upper respiratory tract and migrates throughout the lungs, where it induces pulmonary inflammation, epithelial cell necrosis, and mucus plugging leading to airway obstruction and lung hyperinflation (Simoes 2008; Wright and Piedimonte 2011)
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