Early-Life Intranasal Colonization with Nontypeable Haemophilus influenzae Exacerbates Juvenile Airway Disease in Mice

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.A sthma has nearly doubled in incidence in developed nations since 1980 and now affects almost 10% of all children and adults in the United States (1). One reason for this increase in incidence may be that the biological response to early-life antigen exposure is altered by emerging factors in the environment associated with industrialized societies (2, 3).Asthma has traditionally been classified as a type 1 hypersensitivity disease that is characterized by a T H 2 response and the production of interleukin-4 (IL-4), IL-5, and IL-13. These cytokines play pivotal roles in mediating IgE production, mucus secretion, and airway hyperreactivity (AHR). Inflammation also promotes infiltration of regulatory T cells (Treg), which act to dampen IL-5 and IL-13 secretion by CD4 ϩ CD25 Ϫ T H 2 cells in both human and mouse models of asthma (4, 5). Along with infiltration of eosinophils, these responses in the airways have been considered a defining feature of asthma. However, recent studies indicate that eosinophils are prominent in only 50% of asthmatic patients (2, 3, 6).A subtype of noneosinophilic asthma called neutrophilic asthma is now recognized to afflict a significant number of patients and is associated with severe and persistent symptoms that are refractory to treatment with corticosteroids, a mainstay o...

Chronic rhinosinusitis with nasal polyps is characterized by dysbacteriosis of the nasal microbiota

“…This study identifies that the relative abundance of H. influenzae is remarkably higher in CRSwNP cases compared to normal subjects. Combining the experimental data from mice 31 , the epidemiological data from humans 32 , and our observation of an association of H. influenzae with CRSwNP, we hypothesize that H. influenzae can initiate and drive inflammatory responses to develop nasal polyposis and therefore it may be hypothesized that elimination of H. influenzae in an acute phase might reduce incidence of NP cases. It might further be assumed that success or failure of the antibiotic treatment of the acute phase infection might drive an ongoing inflammation into resolution or NP formation, respectively.…”

The Interplay Between Immune Response and Bacterial Infection in COPD: Focus Upon Non-typeable Haemophilus influenzae

“…Cigarette smoke-induced anti-inflammatory activity of Tregs in a COPD model is further suppressed by NTHi infection. The pathogen causes downregulation of Foxp3 (biomarker of Tregs), and thus impairs the anti-inflammatory/pro-inflammatory balance of Tregs ( 273 , 274 ). This may lead to the extensive immunosuppressive activity by Tregs on the proliferation of NTHi P6-specific effector T cells, causing a diminished response of effector T cells to sputum IL-6 and IL-8 induction, and increased levels of IL-10 and TGF-β1 ( 272 , 275 ).…”

The role of NTHi colonization and infection in the pathogenesis of neutrophilic asthma

“…Asthma can be divided into subtypes, which include eosinophilic asthma, neutrophilic asthma, mixed granulocytic asthma and paucigranulocytic asthma, according to the sputum cell count and classification [3]. While eosinophilic inflammation has been considered to be the hallmark of airway inflammation in asthma [2], it is present in only 50% of asthmatic patients [4]. Compared with eosinophilic asthma, neutrophilic asthma is described as persistent, more severe and corticosteroidresistant.…”