Jones Aa, Bosco Aa , Strickland DHa, Holt PGa in collaboration with Sly PDb
Division of Cell Biologya, The Kids Research Institute Australia, University of Western Australia, Perth, Australia
bQueensland Children’s Medical Research Institute, Brisbane, Australia.
Severe lower respiratory viral infections (sLRI) cause acute viral bronchiolitis (AVB) in infancy and are a major risk factor for the development of asthma. Current treatments for this age group are suboptimal and new advances in effective treatment options are necessary. To enable the development of new therapies we need to identify and characterise the molecular mechanisms that underpin the pathogenesis of AVB during infancy, which are currently unknown. We are employing cutting-edge systems biology approach to dissect the inflammatory gene networks in local and systemic responses underlying AVB. Further, we aim to investigate the contribution of different cell populations to the inflammatory response in AVB and will identify age-related changes in AVB-associated inflammatory responses. Molecular profiling (RNA-Seq) is being carried out on airway epithelial cells (AECs) and PBMC derived inflammatory cells acquired from hospitalised infants (<18 months of age) and pre-schoolers (>18 months – 5 years of age) with moderate to severe AVB, and at 6-8 weeks convalescence, at Royal Children’s Hospital Brisbane. PBMC-derived RNA samples from a third cohort of school-age children (6-16yrs) recruited in Perth during acute viral-induced asthma exacerbations will be included later, for comparative purposes. The gene expression profiling data will be analysed with network analysis and bioinformatics to elucidate the underlying disease mechanisms. Drug compounds will then be screened in silico, to identify drugs that perturb AVB-associated gene networks. Finally, the identified drug candidates will be validated with in vitro cell culture. The project will be the first study to look at AECs from the upper airway mucosa and their likely contribution to the local inflammation in the airways. It will allow for a direct comparison between local versus systemic signals in AVB.
Lay summary
The drugs currently available for treatment of severe AVB in infants have all been developed based on studies on older children and adults. However it is known that immune and inflammatory functions are immature in infants and it is unclear whether the currently available anti-inflammatory drugs are therefore appropriate for this age group. This project aims to plug this knowledge gap, and to open up new opportunities for development of better treatments targeted specifically at infants.
This project is funded by the National Health and Medical Research Council of Australia.