Early Life Rhinovirus Infection and Childhood Asthma

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Project Summary Birth cohort studies have found significant associations between early-life wheezing-associated respiratory tract infections and the development of asthma in children up to 13 years of age. These studies suggest that early life respiratory tract infections have a direct effect on lung and/or immune cell development and the risk of asthma. To determine possible mechanisms, we established a mouse model of early-life RV infection. Infection of 6 day-old mice, but not mature mice, induces long-lasting mucous metaplasia, eosinophilic inflammation and airways hyperresponsiveness (AHR) which is associated with type 2 innate lymphoid cell (ILC2) expansion and dependent on IL-13, IL-25 and IL-33. For this renewal application, we have developed preliminary data showing that early-life RV infection increases the number of airway IL-25+ DCLK1+ brush cells, providing a mechanism for a persistent ILC2-dependent asthma-like phenotype. In addition, we have found that, in immature mice, activation of the NLRP3 inflammasome and IL-1β maturation inhibits type 2 cytokine expression and mucous metaplasia. In this proposal, we will test the general hypothesis that, following early- life RV infection, development of ILC2-dependent type 2 airway inflammation and mucous metaplasia represents a balance between tuft cell RV-induced IL-25 signaling (promotes the phenotype) and NLRP3- dependent IL-1β signaling (suppresses the phenotype). To test this, we propose the following Aims: Specific Aim 1. Determine the contribution of airway brush (tuft) cells to viral-induced IL-25 production. We hypothesize that: 1) early-life RV infection stimulates a persistent increase in the number of IL-25-producing airway tuft cells; 2) tuft cells are required for RV-induced ILC2 expansion, mucous metaplasia and AHR; 3) RV-induced IL-25 and IL-13 production (by ILC2s and M2 polarized macrophages) constitute a feed-forward mechanism for tuft cell development. Specific Aim 2. Determine the role of IL-1β on the development of RV-induced mucous metaplasia and AHR. We hypothesize that: 1) in immature mice, RV-induced, NLRP3 inflammasome-dependent IL-1β production suppresses the asthma-like phenotype; 2) IL-1β inhibits epithelial cell innate cytokine expression; and 3) LPS and dog-associated house dust each attenuate development of the mucous metaplasia phenotype by stimulating inflammasome priming and activation. Specific Aim 3. Determine the effects of early-life RV-C infection. We hypothesize that: 1) compared to RV-A, RV-C infection of 6 day-old mice induces more type 2 inflammation, mucous metaplasia and AHR; 2) RV-C induces greater expansion of tuft cells; 3) RV-C elicits inflammasome priming but not activation, thereby permitting greater and more long-lasting type 2 cytokine expression and mucous metaplasia. Immature mice and infants with respiratory viral infections will be studied. Completion of the proposed work will provide new insight into the pathogenesis of asthma development, and identify new targets for prevention.