BioProject

Objectives: Therapies being safe, effective and not vulnerable to develop resistance are highly desirable to counteract bacterial infections. More...

Objectives: Therapies being safe, effective and not vulnerable to develop resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by the use of host-directed drugs to counteract microbial infections. This study sought to identify cellular genes and pathways differentially expressed during airways epithelial infection by nontypable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). Based on the proposed relationship between NTHi intracellular location and persistence, the antimicrobial potential of a panel of drugs perturbing host pathways used by NTHi to enter epithelial cells was investigated. Methods: We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing A549 cell whole genome expression profiling, and identified a panel of host target candidates which were pharmacologically modulated. Interfering drugs were tested for their bactericidal effect, cytotoxicity, effect on the interplay NTHi-epithelial cell, and effect on NTHi respiratory infection in vivo, by assessing lung bacterial loads in a murine intranasal infection model. Results: The sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi; the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts both intracellularly and in the lungs of infected mice. Conclusions: PDE4 inhibition is currently prescribed in COPD; resveratrol is a geroprotector attractive for COPD treatment by preventing lung aging. This work provides evidence for the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection. Overall design: Haemophilus influenzae clinical strain NTHi375 induced gene expression in A549 human type II pneumocyte cell line was measured at 2 h post-infection. Non infected cells were used as a control. Four independent experiments were performed for each condition. Less...