Elevated hMPV, but not RSV, replication in the nasal epithelium of asthmatic adults is facilitated by an IFN-independent integrated stress response — ASN Events
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  3. Elevated hMPV, but not RSV, replication in the nasal epithelium of asthmatic adults is facilitated by an IFN-independent integrated stress response

Elevated hMPV, but not RSV, replication in the nasal epithelium of asthmatic adults is facilitated by an IFN-independent integrated stress response (#6)

Engin Baturcam 1 2 3 , Tiong Han Yeo 1 2 3 , Johanna Schagen 3 , Emma Thomas 3 , Janine Di-Masi 3 , Simon Phipps 4 5 , Emmanuelle Fantino 3 , Peter Sly 3 4 , Kirsten Spann 1 2 4
  1. SASVRC, Herston, QLD, Australia
  2. CMVC, Herston, QLD, Australia
  3. QCMRI, Herston, QLD, Australia
  4. AIDRC, St Lucia, QLD, Australia
  5. University of Queensland, St Lucia, QLD, Australia

Introduction

Human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) cause acute respiratory tract disease and play an important role in the initiation and exacerbation of asthma. Our recently published data demonstrate that loss of viral control in nasal epithelial cells (NECs) from pre-asthmatic children is viral specific and IFN-independent. However this has not yet been established in asthmatic adults. Virus-induced Endoplasmic Reticulum (ER) stress leads to the activation of the unfolded protein response (UPR), and can contribute to viral replication and pathogenesis. The objectives of this study are to identify if intrinsic innate immune deficiencies exist in asthmatic adult NECs in response to RSV and hMPV, and whether this is associated with the ER stress response.

Methods

NECs were collected from healthy (n=10) and asthmatic (n=10) adults and cultured as submerged monolayers. Cells were infected with RSV-A2 or hMPV-CAN97/83 strains at high (3) multiplicity of infection. IFN-β, ER stress markers, caspase 3/7 activity and viral replication were quantified 24 hours post-infection.

Results

Increased viral replication of hMPV, but not RSV, was observed in asthmatic NECs compared to healthy controls, although the IFN-β response was similar. qPCR analysis revealed an elevated expression of ER chaperone, Grp78 (p<0.05), spliced X-box binding protein 1 (sXBP1) (p<0.01) and CHOP (p<0.05) in hMPV-infected asthmatic NECs compared to healthy NECs or asthmatic NECs infected with RSV. Caspase 3/7 activation by hMPV indicated a 2-fold increase in apoptosis of asthmatic NECs compared to healthy NECs.

Conclusion

Our data indicate that asthmatic NECs are more susceptible to infection by hMPV, but not RSV, despite a normal IFN-β response. Elevated ER stress and apoptosis were associated with elevated hMPV replication in asthmatic NECs. The stress response of NECs was virus-specific and associated with disease status, thus highlighting the importance of the UPR in viral infections in asthmatic individuals.