Abstract
Accumulating evidence suggests a connection between asthma development and colonization with nontypeable Haemophilus influenzae (NTHi). Specifically, nasopharyngeal colonization of human infants with NTHi within 4 weeks of birth is associated with an increased risk of asthma development later in childhood. Monocytes derived from these infants have aberrant inflammatory responses to common upper respiratory bacterial antigens compared to those of cells derived from infants who were not colonized and do not go on to develop asthma symptoms in childhood. In this study, we hypothesized that early-life colonization with NTHi promotes immune system reprogramming and the development of atypical inflammatory responses. To address this hypothesis in a highly controlled model, we tested whether colonization of mice with NTHi on day of life 3 induced or exacerbated juvenile airway disease using an ovalbumin (OVA) allergy model of asthma. We found that animals that were colonized on day of life 3 and subjected to induction of allergy had exacerbated airway disease as juveniles, in which exacerbated airway disease was defined as increased cellular infiltration into the lung, increased amounts of inflammatory cytokines interleukin-5 (IL-5) and IL-13 in lung lavage fluid, decreased regulatory T cell-associated FOXP3 gene expression, and increased mucus production. We also found that colonization with NTHi amplified airway resistance in response to increasing doses of a bronchoconstrictor following OVA immunization and challenge. Together, the murine model provides evidence for early-life immune programming that precedes the development of juvenile airway disease and corroborates observations that have been made in human children.
Original language | English (US) |
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Pages (from-to) | 2022-2030 |
Number of pages | 9 |
Journal | Infection and immunity |
Volume | 84 |
Issue number | 7 |
DOIs | |
State | Published - 2016 |
Funding
J.R.M., J.W.S.G., and P.C.S. designed the experiments, J.R.M., S.N.M., and R.L.A. performed the experiments, J.R.M., J.W.S.G., and P.C.S. wrote the paper, and all authors provided critical feedback on the manuscript. This project was supported fully or in part by a Children's Miracle Network grant (to J.R.M.), NIH grant GM108494 (to P.C.S.), NIH grant AI121742 (to P.C.S.), and NIH grant DC02873 (to J.W.S.G.). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We thank Barbara Theriot, Julie Sproule, and Félix Araujo-Perez for help with sample preparation and data collection. This work, including the efforts of Jessica R. McCann, was funded by Children's Miracle Network. This work, including the efforts of Patrick C. Seed, was funded by HHS | National Institutes of Health (NIH) (GM108494). This work, including the efforts of Joseph W. St. Geme III, was funded by HHS | National Institutes of Health (NIH) (DC02873).
ASJC Scopus subject areas
- Infectious Diseases
- Parasitology
- Microbiology
- Immunology