Project description:Background: A subset of infants are hyper-susceptible to severe/acute viral bronchiolitis (AVB), for reasons unknown. Purpose: To characterise the cellular/molecular mechanisms underlying infant AVB in circulating cells/local airways tissues. Methods: PBMC and nasal mucosal scrapings (NMS) were obtained from Infants (<18mths) and children (1.5-5yrs) during AVB and post-convalescence. Immune response patterns were profiled by multiplex analysis of plasma cytokines, flow cytometry, and transcriptomics (RNA-Seq). Molecular profiling of group-level data utilised a combination of upstream regulator and coexpression network analysis, followed by individual subject-level data analysis employing personalised N-of-1-pathways methodology. Results: Group-level analyses demonstrated that infant PBMC responses were dominated by monocyte-associated hyper-upregulated type I interferon signalling/pro-inflammatory pathways (drivers: TNF, IL6, TREM1, IL1B), versus a combination of inflammation (PTGER2, IL6) plus growth/repair/remodelling pathways (ERBB2, TGFB1, AREG, HGF) coupled with Th2 and NK-cell signalling in children. Age-related differences were not attributable to differential steroid usage or variations in underlying viral pathogens. Nasal mucosal responses were comparable qualitatively in infants/children, dominated by interferon types I-III, but the magnitude of upregulation was higher in infants (range 6-48-fold) than children (5-17-fold). N-of-1-pathways analysis confirmed differential upregulation of innate immunity in infants and NK cell networks in children, and additionally demonstrated covert AVB response sub-phenotypes that were independent of chronological age. Conclusions: Dysregulated expression of interferon-dependent pathways following respiratory viral infections is a defining immunophenotypic feature of AVB-susceptible infants and a subset of children. Susceptible subjects appear to represent a discrete subgroup who cluster based on (slow) kinetics of postnatal maturation of innate immune competence.

Project description:Pneumonia is a serious problem worldwide. We recently demonstrated that innate defense mechanisms of the lung are highly inducible against pneumococcal pneumonia. To determine the breadth of protection conferred by stimulation of lung mucosal innate immunity, and to identify cells and signaling pathways activated by this treatment, mice were treated with an aerosolized bacterial lysate, then challenged with lethal doses of bacterial and fungal pathogens. Mice were highly protected against a broad array of Gram-positive, Gram-negative, and Class A bioterror bacterial pathogens, and Aspergillus fumigatus. Protection was associated with rapid pathogen killing within the lungs, and this effect was recapitulated in vitro using a respiratory epithelial cell line. Gene expression analysis of lung tissue showed marked activation of NF-kappaB, Type I and II interferon, and antifungal Card9-Bcl10-Malt1 pathways. Cytokines were the most strongly induced genes, but the inflammatory cytokines TNF and IL-6 were not required for protection. Lung-expressed antimicrobial peptides were also highly upregulated. Taken together, stimulated innate resistance (StIR) appears to occur through the activation of multiple host defense signaling pathways in lung epithelial cells, inducing rapid pathogen killing, and conferring broad protection against virulent bacterial and fungal pathogens. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value for protection of patients with neutropenia or impaired adaptive immunity against opportunistic pneumonia, and for defense of immunocompetent subjects against a bioterror threat or epidemic respiratory infection. Keywords: differential gene expression; time course; innate immunity; pneumonia; immunocompromised host; lung epithelium Gene expression patterns in mouse lung homogenates were analyzed 2h after exposure to aerosolized PBS (Sham treatment), 2h after exposure to aerosolized NTHi lysate or 4h after exposure to aerosolized NTHi lysate. Each group consisted of six mice.

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Compartmentalization of human B cell responses in early life through induction of bronchus-associated lymphoid tissue

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