PGD2-mediated DP1 and DP2 receptor activation regulate the severity of viral bronchiolitis by controlling the production of IFN-lambda — ASN Events
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PGD2-mediated DP1 and DP2 receptor activation regulate the severity of viral bronchiolitis by controlling the production of IFN-lambda (#87)

Rhiannon B Werder 1 2 , Jason P Lynch 1 2 , Jennifer Simpson 2 , Vivian Zhang 2 , Nick Hodge 1 , Elizabeth Forbes-Blom 3 , Mark Smythe 4 , John Upham 5 6 , Kirsten Spann 5 7 , Mark Everard 8 , Simon Phipps 1 2 5
  1. University of Queensland, St Lucia, QLD, Australia
  2. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  3. Malaghan Institute, Wellington, New Zealand
  4. Institute for Molecular Bioscience, Brisbane, QLD, Australia
  5. Australian Infectious Diseases Research Centre, Brisbane, QLD, Australia
  6. Lung and Allergy Research Centre, School of Medicine, University of Queensland, Brisbane, QLD, Australia
  7. School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
  8. School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia

Prostaglandin D2 (PGD2) signals through two receptors: DP1 or DP2 (CRTH2), the latter of which is expressed on type-2 effector cells and promotes asthma pathogenesis. However, to date, little is known about the role of PGD2 during RSV bronchiolitis, a major risk factor for asthma development. Using cultured human primary airway epithelial cells (AECs), we found that RSV infection up-regulated haematopoietic prostaglandin D synthase (h-PGDS) expression and increased PGD2 production. Moreover, PGD2 levels were significantly elevated in nasopharyngeal samples from young infants hospitalised with RSV bronchiolitis compared to healthy controls. To interrogate this further, we used a neonatal mouse model of bronchiolitis whereby BALB/c mice were inoculated with pneumonia virus of mouse (PVM; 1 pfu) and exposed to low dose (1 µg) cockroach allergen. In this model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology and morbidity, and ablated the predisposition for subsequent asthma onset in later-life. The beneficial effects of DP2 blockade were abolished upon dual DP1/DP2 antagonism, replicated with a specific DP1 agonist, and underpinned by altered IFN-lambda expression. In the RSV-infected AEC cultures, DP1 activation enhanced the production of IFN-lambda, which in turn, upregulated IFN-stimulated gene expression and accelerated viral clearance. Thus, we demonstrate that the respective activation of DP1 or DP2 promotes or suppresses antiviral immunity. Our findings suggest that DP2 antagonists or DP1 agonists may prove useful for the treatment of viral bronchiolitis and as a primary preventative for asthma.

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