The persistence of Nontypeable Haemophilus Influenzae fuels type 17 immunity in the lung

Abstract

Nontypeable Haemophilus influenzae (NTHi) is commonly isolated from airways patients suffering from chronic respiratory diseases, such as chronic obstructive pulmonary disease 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 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 NTHi persistence in fuelling the airway inflammation, we developed a novel mouse model using both laboratory and CF clinical strains. In mice, NTHi persistence was associated with a sustained inflammation of the lung, including neutrophils and related pro-inflammatory cytokines (KC, Mip-2, G-CSF, IL-6) at 2 and 14 days post-infection. Moreover, an increased burden of T cell mediated response (CD4+ and γδ T cells) was observed in the lungs at 14 days post-infection. We also found that both CD4+ IL-17+ cells and levels of IL-17A cytokine (IL-17A and IL-17F) were enriched in mice at advanced stage of NTHi chronic infection, in association with higher levels a marker of tissue remodelling (Pro-MMP9). In addition, we were able to demonstrate by immunohistochemistry that that CD3, B220 and CXCL-13 expressing cells colocalized in bronchus-associated lymphoid tissues(BALT)-like structure in infected lungs at day 14 post-infection. In conclusion, NTHi persistence exerts a pro-inflammatory activity and could thereforecontribute to the exaggerated burden of lung inflammation in patients with chronic respiratory diseases.