Genome expression profiling identifies host-directed antimicrobial drugs against respiratory infection by nontypable Haemophilus influenza.

Abstract

[Introduction and Aim] 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 which is based on perturbing host pathways subverted by pathogens during their life cycle by using host-directed drugs to counteract microbial infections. This study applied this concept to the identification of host-directed target and drug candidates against respiratory infection by nontypable Haemophilus influenzae (NTHi), through the screening of cellular genes and pathways differentially expressed during airways epithelial infection by this pathogen. NTHi is an intracellular facultative opportunistic pathogen, which is an important cause of exacerbation associated to the progression of chronic obstructive pulmonary disease (COPD). Based on the proposed relationship between NTHi intracellular location and persist infection, 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 human type II pneumocyte A549 cells 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 (adhesion, invasion and inflammatory response on respiratory cells), and effect on NTHi respiratory infection in vivo, by assessing lung bacterial loads in a murine intranasal infection model.

[Results] he sirtuin-1 activator resveratrol showed a dose dependent bactericidal effect against NTHi; the non-bactericidal phosphodiesterase 4 (PDE4) inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts intracellularly and in the lungs of infected mice.

[Conclusions] PDE4 inhibition is currently prescribed in COPD; resveratrol is a natural 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.