Introduction Cystic Fibrosis (CF) lung disease is characterized by transient airway P. aeruginosa infections and excessive neutrophil-dominated inflammation early in life followed by permanent chronic infection that causes persistent respiratory symptoms and decline in lung functions.As the disease progresses, strain variants can be distinguished from the strain initially acquired.However, the contribution of P. aeruginosa adaptation to lung disease is not completely understood.Comparing sequential strains isolated from a CF patient in multihost pathogenesis system, including non-mammalian and mammalian hosts, our previous works showed that P. aeruginosa early strains were lethal, while late adapted clonal isolates were attenuated in acute virulence but retained their capacity to persist in murine lungs 1,2,3 . Methods To dissect the contribution of P. aeruginosa patho-adaptive strains during the progression of lung disease, we report the host-response in murine models of acute and chronic P. aeruginosa infection.As a model system in studying long term and persistent CF infections, the agar beads mouse model was used in a time course for up to three months in C57Bl/6 mice and Cftrtm1UNCTgN (FABPCFTR) mice.Bacterial count, cytokines profile, assessed by bioplex assay, and lung pathology, assessed by H& E, Masson’s and AB-PAS staining, were evaluated. Results During acute infection, cytokines and chemokines amounts in the whole lungs were lower after infection with late P. aeruginosa patho-adaptive strains compared with early strain, confirming that late strains have evolved the capacity to reduce innate immune system detection.After one month of chronic infection with P. aeruginosa late strains, cytokines/chemokines involved in leukocytes recruitment (IL-1 β , IL-6, KC, MIP-1 α and MIP-2) were lower than after acute infection.Impressively, MCP-1, IL-17A, IFN- γ and TNF- α , correlated to tissue damage control, were maintained during acute and chronic infection, indicating a continuous and elevated triggering of specific pathways.Furthermore, high TGF- β production were found in the whole lung, confirming that late adapted strains may modulate tissue damage control during chronic infection.Preliminary results in CF mice showed similar trends to wt mice.Moreover cytokines mainly correlated with Th17 lymphocytes pathways, like CD40L, IL-17F, IL-23p19, IL-22, MIP-3 α and IL-21, were tested in the lung homogenates by bioplex.Results show that these markers are activated after one month of chronic infection in CF and wt mice, indicating that late adapted strains may modulate tissue damage control through this pathway.Immune cellular phenotype of lymphocytes involved in this chronic model of infection is under investigation.In addition, histopathological examination of lung tissue sections showed that late adapted strains induced mucin-positive goblet cells metaplasia, collagen deposition and apoptosis, typical hallmarks of damage in the airway of CF patients. Conclusion Our findings suggest that during chronic infection, P. aeruginosa patho-adaptive variants attenuate cytokines involved in innate immune system detection, while modulate those mainly linked to tissue damage control, favoring bacterial survival and persistence. Supported by Italian CF Research Foundation (FFC#20_2011)