Rhinovirus (RV) and respiratory syncytial virus (RSV) cause common colds in healthy adults, but can cause wheezing and respiratory distress in infants. This condition known as viral bronchiolitis is the top cause of hospitalization in this age group. Infants hospitalized with RV or RSV bronchiolitis have an exceedingly high risk (30-50%) of developing recurrent wheezing and asthma. Thus, understanding why humans are highly susceptible to RV and RSV during infancy is needed for developing novel preventive and treatment strategies. Importantly, using a model of the human infant airway epithelial cell (AEC) recently developed by our lab, we provide novel evidence that relative to adult AECs, infant AECs produce higher levels of thymic stromal lymphopoietin (TSLP), a cytokine that mediates virus-induced type 2 (T2) airway responses. We also find that infant AECs exhibit: I) enhanced production and responsiveness to IL-1?, the most potent stimulus for TSLP secretion; II) markedly increased IL-1?-induced nuclear translocation of NF-kB, the positive regulator of IL-1? and TSLP transcription; and III) reduced transcriptional induction of I?B?, the inhibitor of NF-kB. These age- related molecular differences suggest a novel mechanism of developmentally enhanced TSLP production in the infant airway epithelium that may increase the risk of recurrent wheezing after RV or RSV bronchiolitis. This is supported by our clinical studies demonstrating that: I) RV and RSV infections are associated with elevated airway TSLP levels and parallel IL-1? secretion; II) airway TSLP levels are higher in infants hospitalized with RV or RSV bronchiolitis who then developed recurrent wheezing than in infants who recovered completely. These preliminary data has led us to propose mechanistic studies in human infant AECs to test the central hypothesis that the human infant airway epithelium has enhanced NF-kB signaling activation that promotes IL-1?-driven TSLP airway secretion and increases the risk for recurrent wheezing after RV or RSV bronchiolitis.
Three Specific Aims are proposed:
Aim 1 : To test the hypothesis that the human infant airway epithelium exhibits enhanced NF-kB nuclear activation due to maturational differences in IkB? synthesis and degradation.
Aim 2 : To test the hypothesis that the human infant airway epithelium has enhanced TSLP responses to RV and RSV infections due to intrinsic maturational differences in the production and responsiveness to IL-1?.
Aim 3 : To test the hypothesis that the development of recurrent wheezing in human infants after the first episode of RV or RSV infection is associated with AEC maturational differences in TSLP and IL-1? production due to enhanced NF-kB signaling activation. This proposal will move forward our understanding of the AEC pathways involved in the pathogenesis of viral-induced wheezing in early life by defining mechanisms underlying the maturational differences in pro-inflammatory responses between human infant and adult AECs. This new knowledge may ultimately lead to novel interventions to reduce the incidence of recurrent wheezing and asthma in millions of infants suffering from RV and RSV infections.
We will use a novel model of the human infant airway epithelium to elucidate the molecular mechanisms by which rhinovirus and RSV induce wheezing illnesses in early life, which is the most common cause of infant hospitalizations.