Holt PG, Mok D, Bosco A, Hollams EM
We have established that children most likely to develop persistent asthma are those who experienced repeated/intense lower respiratory tract infections (LRIs) during infancy, especially if they showed early signs of atopy. This suggests that their antimicrobial responses are dysregulated such that they contribute directly to airway tissue damage. Findings in the Childhood Asthma Study (CAS) birth cohort indicate that the most asthmatogenic infant LRIs are those accompanied with fever, a classical marker of acute inflammation and associated with the underlying activation of the inflammasome complex, which mediates production of the fever-inducing cytokine, IL-1. Using cryobanked peripheral blood mononuclear cells (PBMCs) from the CAS, we examined age-associated changes in regulation of inflammasome-associated functions. We performed microcultures from cord blood samples and PBMCs obtained at 4 and 10 years of age, in the presence of innate stimuli. Regulatory and inflammatory cytokine responses, including IL-1 were examined and cultured cells were cryobanked for transcriptomic studies. A subset of cord blood samples, comprising those who did not exhibit fever against those who had multiple fevers during an LRI, was assessed by flow cytometry for caspase-1 activity, a critical component of the inflammasome complex. These data are being utilized in integrative analyses, which aim to identify risk factors for asthma development by ages 5 and 10yrs. During 2017 we will undertake further analyses involving transcriptomic profiling of innate immune responses from groups of children who displayed high versus low susceptibility to severe symptomatic lower respiratory tract infections during infancy, focusing on the function of the inflammasome. These will directly test the hypothesis that dysregulated inflammasome function during infancy is responsible for heightened susceptibility to airways disease in this age group.
Plain language summary: Previous findings from our research group has demonstrated that one of the strongest risk factors for subsequent development of asthma is having chest infections during infancy that are so severe that they trigger symptoms of fever and wheeze. It is not known what predisposes susceptible infants to these severe infections, and this project will attempt to define the mechanisms of susceptibility.
Funder: National Health and Medical Research Council