Oral Presentation 8th Australasian Virology Society Meeting and 11th Annual Meeting of the Australian Centre for Hepatitis & HIV Virology Meeting 2015

Susceptibility of the asthmatic airway epithelium to viral infection is due to both cellular and viral factors (#10)

Engin Baturcam 1 2 3 , Tiong Han Yeo 4 , Natale Snape 1 2 5 , Johanna Schagen 2 3 , Emma Thomas 2 3 , Jayden Logan 2 3 , Sally Galbraith 2 3 , Simon Phipps 6 , Emmanuelle Fantino 2 3 , Peter Sly 2 3 , Kirsten Spann 3 5
  1. School of Medicine, University of Queensland, Brisbane, QLD, Australia
  2. Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia
  3. Queensland Childrens Medical Research Institute, Brisbane, QLD, Australia
  4. School of Chemistry and Molecular Biosciences,, University of Queensland, Brisbane, QLD, Australia
  5. School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
  6. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia

The airway epithelium of asthmatics is more susceptible to viral infection than that of non-asthmatics due to impaired antiviral responses. However, this mechanism is not well known. We have investigated the antiviral response of AEC from the upper respiratory track (nasal epithelial cells; NECs), to the respiratory paramyxoviruses respiratory syncytial virus (RSV) and human metapneumovirus (hMPV). In a previous study we demonstrated elevated susceptibility of primary cultured NECs from wheezy children (2-10 yo) to infection with RSV and hMPV that was independent of the host's ability to produce interferons (IFN).  In the current study we have used NECs from atopic asthmatic and healthy adults to study antiviral responses to RSV and hMPV. NECs from asthmatic and non-asthmatic adults produced similar levels of IFN in response to RSV and hMPV, however hMPV viral load was significantly elevated in NECs from asthmatic adults. Annexin-V staining revealed reduced apoptosis in response to hMPV, but not RSV, in NECs from asthmatics which correlated to reduced activation of caspase-9 and -3/7. However, hMPV induced Endoplasmic Reticulum Stress - specific pro-apoptotic factors (CHOP, PUMA and NOXA) similarly in NECs from asthmatics and non-asthmatics. This suggests that asthmatic NECs activate these upstream effectors of the caspase cascade but fail to undergo apoptosis. We then identified that hMPV significantly upregulated heat shock protein 70 (hsp70), which is a known apoptosis inhibitor, in asthmatic NECs. When hsp70 was functionally blocked by a chemical inhibitor, apoptosis was elevated in hMPV-infected asthmatic NECs and viral load reduced to levels similar to that of healthy NECs. These data demonstrate that susceptibility of NECs to viral infection in association with asthma is not due to impaired IFN responses, but rather defective apoptosis which is exacerbated by specific viral-cellular interactions that can be overcome by targeted chemical inhibition.