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Nontypeable Haemophilus influenzae (NTHi) is commonly isolated from airways of patients suffering from chronic respiratory diseases, such as 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 with NTHi had significantly higher levels of interleukin (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 keratinocyte-derived chemokine (KC), macrophage inflammatory protein 2 (MIP-2), granulocyte colony-stimulating factor (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 pro-matrix metalloproteinase 9 (pro-MMP9), 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 stages 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., The pathological impact of long-term infection by nontypeable Haemophilus influenzae (NTHi) is still debated. Chronic NTHi infection fuels lung inflammation in human samples and in a new mouse model of bacterial long-term persistence. https://bit.ly/3lvyvge

Host genotype is an important determinant of susceptibility to infections. Among opportunistic pathogens, Pseudomonas aeruginosa is a major cause of respiratory infections with markedly variable clinical outcomes in individuals at risk. Comparing susceptibility to P. aeruginosa acute infection in nine inbred mouse strains, we recently found that the host genetic makeup is responsible for diverse cell-mediated immunity and bacterial replication. Most recently we adopted a P. aeruginosa chronic infection model to identify cellular events correlating with infection outcome, i.e. resistance or susceptibility. C3H/HeOuJ and A/J mice were infected with P. aeruginosa embedded in agar beads to mimic chronic infection. We report that by day 2 of infection, resistant C3H/HeOuJ mice show similar neutrophils and macrophages recruitment and phagocytic capacity compared to susceptible A/J mice. However, resistant mice had lower markers of acute inflammation (IL-6, GCSF, IL12, MCP-1, MIP1a and MIP1b) and significantly higher ratio IL17/IFN-gamma-producing CD4 + T cells when compared to susceptible ones; this correlated with lower bacterial counts and faster body weight recovery. By day 14, the frequency of IL-17-producing cells had declined in resistant mice, which resolved the infection, while cells had accumulated in susceptible ones, which showed marked signs of lung pathology. We suggest that the host genetic background might shape the kinetic of Th17-dependent responses, and by that determine susceptibility or resistance to P. aeruginosa airway infection.