Chronic infection by Nontypeable Haemophilus influenzae fuels airway inflammation

Abstract

Nontypeable Haemophilus influenzae (NTHi) is commonly isolated from airways patients suffering from chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). However, to what extent NTHi long-term infection contributes to the lung inflammatory burden during chronic airway disease is still controversial.

Here, we exploited human respiratory samples from a small cohort of CF patients and found that patients chronically infected by NTHi had significantly higher levels of IL-8 and CXCL1 than those who were not infected. To better define the impact of chronic NTHi infection in fuelling inflammatory response in chronic lung diseases, we developed a new mouse model using both laboratory and clinical strains. Chronic NTHi infection was associated with chronic inflammation of the lung, characterised by recruitment of neutrophils and cytokine release (KC, MIP-2, G-CFS, IL-6, IL-17A and IL-17F) at 2 and 14 days post-infection. An increased burden of T cell mediated response (CD4⁺ and γδ cells) and higher levels of matrix metalloproteinase 9, known to be associated with tissue remodelling, were observed at 14 days post-infection. Of note we found that both CD4⁺IL-17⁺ cells and levels of IL-17 cytokines were enriched in mice at advanced stage of NTHi chronic infection. Moreover, by immunohistochemistry we found CD3⁺, B220⁺ and CXCL-13⁺ cells localised in bronchus-associated lymphoid tissue-like structures at day 14.

Our results demonstrate that chronic NTHi infection exerts a pro-inflammatory activity in the human and murine lung, and could therefore contribute to the exaggerated burden of lung inflammation in patients at risk.