Early-Life Intranasal Colonization with Nontypeable Haemophilus influenzae Exacerbates Juvenile Airway Disease in Mice.
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.
Duke University School of Medicine, Department of Pediatrics, Durham, North Carolina, USA jessica.mccann@duke.edu.
Jessica R
JR
McCann
Duke University School of Medicine, Department of Pediatrics, Durham, North Carolina, USA.
Stanley N
SN
Mason
Duke University School of Medicine, Department of Pediatrics, Durham, North Carolina, USA.
Richard L
RL
Auten
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Joseph W
JW
St Geme
Duke University School of Medicine, Department of Pediatrics, Durham, North Carolina, USA.|Duke University School of Medicine, Department of Molecular Genetics and Microbiology, Durham, North Carolina, USA.
Patrick C
PC
Seed
D000818:Animals; D058491:Bacterial Load; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006192:Haemophilus Infections / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D006193:Haemophilus influenzae / Q000276:immunology*; D006967:Hypersensitivity / Q000276:immunology / Q000382:microbiology; D051379:Mice; D055271:Mucin 5AC / Q000096:biosynthesis / Q000235:genetics; D009093:Mucus; D009297:Nasal Mucosa / Q000382:microbiology*; D060737:Reproductive Tract Infections / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology
D016207:Cytokines; D055271:Mucin 5AC