The persistence of Nontypeable Haemophilus influenzae fuels airway inflammation

*Nontypeable Haemophilus influenzae (NTHi) is commonly isolated from airway of cystic fibrosis (CF) patients. However, to what extent NTHi persistence contributes to the lung inflammatory burden during CF chronic airway disease is controversial. Here, we aimed at determining the pathological role of NTHi persistence in a cohort of CF patients and in a newly generated mouse model of NTHi persistence. In our study cohort, we found that CF patients chronically colonized by NTHi had significantly higher levels of IL-8 and CXCL1 than those who were not colonized. To better define the impact of NTHi persistence in fuelling inflammatory response, we developed a new mouse model using both laboratory and CF clinical strains. NTHi persistence was associated with chronic inflammation of the lung, characterized by recruitment of neutrophils and cytokine release (KC, G-CFS, IL-6 and IL-17A) at 2 and 14 days postinfection. An increased burden of T cell mediated response (CD4+ and {gamma}{delta} 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 cytokine were enriched in mice at advanced stage of NTHi chronic infection. Moreover, by immunohistochemistry we found CD3+, B220+ and CXCL-13+ cells localized in bronchus-associated lymphoid tissue-like structures at day 14. Our results demonstrate that NTHi persistence exerts a pro-inflammatory activity in the human and murine lung, and could therefore contribute to the exaggerated burden of lung inflammation in CF patients.