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Sci Transl Med. 2018 May 9;10(440). pii: eaao0052. doi: 10.1126/scitranslmed.aao0052.

PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN-λ production.

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School of Biomedical Sciences, University of Queensland, Queensland 4072, Australia.
Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston 4006, Australia.
School of Paediatrics and Child Health, University of Western Australia, Western Australia 6840, Australia.
Malaghan Institute of Medical Research, Wellington 6242, New Zealand.
Institute for Molecular Bioscience, University of Queensland, Queensland 4072, Australia.
Diamantina Institute, University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Queensland 4102, Australia.
Australian Infectious Diseases Research Centre, University of Queensland, Queensland 4067, Australia.
School of Biomedical Sciences, Queensland University of Technology, Queensland 4001, Australia.
Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston 4006, Australia.


Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon-λ (IFN-λ) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN-λ production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.

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