Mechanisms of respiratory viral infections in hospitalized children

Birth cohort studies have found associations between early-life wheezing-associated respiratory tract infections and the development of asthma in children. 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, the project team established a mouse model of early-life rhinovirus (RV) infection. Infection of six-day-old mice, but not mature mice, induces long-lasting mucous metaplasia, eosinophilic inflammation and airways hyperresponsiveness. For this application, the project team examined changes in the nasal transcriptome of children hospitalized for respiratory viral infections. Twenty-six had bronchiolitis and 32 had asthma. Nasal swab RNA transcripts were measured by bulk RNASeq and differences were calculated in gene expression using DESeq2. Compared to uninfected controls, RV infection significantly increased 2312 transcripts, including those regulating cysteinyl leukotriene (CysLT) metabolism, epithelial mesenchymal transition (EMT) and mast cell proteases. Computational deconvolution of RNA-seq profiles showed increased mast cells and natural killer (NK) cells. However, expression of the NK cell activating receptor KLRK1 (NKG2D) was decreased. On this basis, the team hypothesizes that analysis of the nasal transcriptome in children with respiratory viral infection, combined with mechanistic studies employing mouse models of asthma, can identify novel and impactful pathways underlying asthma development and exacerbation. The following Specific Aims are proposed. 1. Determine the contribution of tuft cell-derived CysLTs in viral-induced asthma development. It is hypothesized that: (i) CysLTs are required and sufficient for the RV-induced asthma phenotype; (ii) airway tuft cells produce CysLTs; and (iii) tuft cell expansion occurs through a process of EMT. 2. Determine the role of dysfunctional natural killer cells in viral-induced asthma development. It is proposed that dysfunctional natural killer cells fail to produce interferon-gamma (IFN-γ) in response to viral infection, permitting type 2 inflammation. In addition, it is hypothesized that: (i) nasal aspirates from children with asthma hold dysfunctional NK cells with reduced IFN-γ production; (ii) in immature mice, lung NK cells fail to produce IFN-γ in response to RV infection; (iii) NK cell activation is required and sufficient to attenuate virus- induced type 2 inflammation in mature mice. 3. Determine the role of mast cells in viral-induced respiratory exacerbations. It is hypothesized that (i) nasal aspirates from children with RV-induced respiratory exacerbations show increased mast cells; and (ii) mast cells are required for RV-induced inflammation and AHR in immature mice. Immature mice and human infants with respiratory viral infections will be studied (flow cytometry, single cell RNASeq and TotalSeq of nasal aspirates). Completion of the proposed work will provide new insight into the pathogenesis of asthma development and identify new targets for prevention. Project Number: 1R01AI195753-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Marc Hershenson | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $598,906 | Activity Code: R01 | Study Section: Lung Immunology and Infection Study Section[LII] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19575301