Haemophilus influenzae infection drives IL-17-mediated neutrophilic allergic airways disease

PLoS Pathog. 2011 Oct;7(10):e1002244. doi: 10.1371/journal.ppat.1002244. Epub 2011 Oct 6.

Abstract

A subset of patients with stable asthma has prominent neutrophilic and reduced eosinophilic inflammation, which is associated with attenuated airways hyper-responsiveness (AHR). Haemophilus influenzae has been isolated from the airways of neutrophilic asthmatics; however, the nature of the association between infection and the development of neutrophilic asthma is not understood. Our aim was to investigate the effects of H. influenzae respiratory infection on the development of hallmark features of asthma in a mouse model of allergic airways disease (AAD). BALB/c mice were intraperitoneally sensitized to ovalbumin (OVA) and intranasally challenged with OVA 12-15 days later to induce AAD. Mice were infected with non-typeable H. influenzae during or 10 days after sensitization, and the effects of infection on the development of key features of AAD were assessed on day 16. T-helper 17 cells were enumerated by fluorescent-activated cell sorting and depleted with anti-IL-17 neutralizing antibody. We show that infection in AAD significantly reduced eosinophilic inflammation, OVA-induced IL-5, IL-13 and IFN-γ responses and AHR; however, infection increased airway neutrophil influx in response to OVA challenge. Augmented neutrophilic inflammation correlated with increased IL-17 responses and IL-17 expressing macrophages and neutrophils (early, innate) and T lymphocytes (late, adaptive) in the lung. Significantly, depletion of IL-17 completely abrogated infection-induced neutrophilic inflammation during AAD. In conclusion, H. influenzae infection synergizes with AAD to induce Th17 immune responses that drive the development of neutrophilic and suppress eosinophilic inflammation during AAD. This results in a phenotype that is similar to neutrophilic asthma. Infection-induced neutrophilic inflammation in AAD is mediated by IL-17 responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / immunology*
  • Asthma / microbiology
  • Asthma / pathology
  • Disease Models, Animal
  • Eosinophils / immunology
  • Female
  • Haemophilus Infections / immunology*
  • Haemophilus Infections / microbiology
  • Haemophilus Infections / pathology
  • Haemophilus influenzae / pathogenicity*
  • Immunity, Cellular
  • Inflammation / pathology
  • Interferon-gamma / immunology
  • Interleukin-13 / immunology
  • Interleukin-17 / immunology*
  • Interleukin-17 / metabolism
  • Interleukin-5 / immunology
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils / immunology*
  • Ovalbumin / adverse effects
  • Ovalbumin / immunology
  • Phenotype
  • T-Lymphocytes, Regulatory / immunology
  • Th17 Cells / cytology
  • Th17 Cells / immunology

Substances

  • Interleukin-13
  • Interleukin-17
  • Interleukin-5
  • Interferon-gamma
  • Ovalbumin