Prostaglandin D2 (PGD2) antagonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.
Queensland-led research has shown that respiratory syncytial virus (RSV) infection up-regulates hematopoietic prostaglandin D synthase expression resulting in PGD2 release by airway epithelial cells. They also found PGD2 production was elevated in nasopharyngeal samples from infants hospitalised with RSV bronchiolitis compared to healthy infants.
In an experimental model of severe viral bronchiolitis, they also found DP2 antagonism decreased viral load, immunopathology and morbidity and ablated the predisposition for subsequent asthma onset in later life.
A/Prof Simon Phipps
The limbic asked Associate Professor Simon Phipps, group leader in Respiratory Immunology at the QIMR Berghofer Medical Research Institute, about the research.
We know that RSV infections are a risk factor for the development of asthma in children. What aspect of this research excites you the most?
This is a great example of a preclinical model that faithfully simulates the clinical scenario. After identifying a novel pathogenic role for PGD2 in the mouse model we validated our findings by sampling nasopharyngeal samples of hospitalized infants, and also through the use of in vitro cultured human airway epithelial cells infected with RSV. This work was supported by our collaborators, Prof Mark Everard (UWA) and A/Prof Kirsten Spann (QUT).
You also found that the beneficial effect of DP2 antagonism is mediated through interferon-λ rather than any effect on type 2 inflammation. What is the significance of this?
It’s known that PGD2 can promote type 2 inflammation, and that the type 2 cytokines (IL-4, IL-13) can suppress the production of antiviral cytokines. However, we found that PGD2 acts directly on epithelial cells to regulate IFN-lambda production and that this directly affects their ability to counter a virus infection. This suggests that DP2 antagonists may offer relief to indications that do not involve type 2 inflammation.
What’s your next step in this line of research?
As well as identifying that PGD2/DP2 signaling suppresses antiviral immunity, we found that PGD2/DP1 signaling elicits the opposite effect, and boosts IFN-lambda production. We are seeking to understand the mechanism by which this occurs as this may lead to the development of a novel antiviral.
You’d have to be happy if this work led to a treatment for severe bronchiolitis AND could also help prevent childhood asthma. How long before we might see an impact on patient care?
The exciting aspect is that DP2 antagonists are already in development and showing promise in trials in patients with severe asthma, so these drugs may be available in the not too distant future. Our data suggest that these compounds will not only attenuate type 2 inflammation as intentioned, but will also help counter the respiratory virus, and so should reduce susceptibility to virally-triggered exacerbations.