9 research outputs found
Methylation status of SOCS1 and SOCS3 in BCR-ABL negative and JAK2V617F negative chronic myeloproliferative neoplasms
Genome expression profiling-based identification and administration efficacy of host-directed antimicrobial drugs against respiratory infection by nontypeable Haemophilus influenzae
Therapies that are safe, effective, and not vulnerable to developing resistance are highly desirable to counteract bacterial infections.
Host-directed therapeutics is an antimicrobial approach alternative to conventional antibiotics based on perturbing host
pathways subverted by pathogens during their life cycle by using host-directed drugs. In this study, we identified and evaluated
the efficacy of a panel of host-directed drugs against respiratory infection by nontypeable Haemophilus influenzae (NTHi).
NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease
(COPD). We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing cell
whole-genome expression profiling and identified a repertoire of host target candidates that were pharmacologically modulated.
Based on the proposed relationship between NTHi intracellular location and persistence, we hypothesized that drugs perturbing
host pathways used by NTHi to enter epithelial cells could have antimicrobial potential against NTHi infection. Interfering
drugs were tested for their effects on bacterial and cellular viability, on NTHi-epithelial cell interplay, and on mouse pulmonary
infection. Glucocorticoids and statins lacked in vitro and/or in vivo efficacy. Conversely, the sirtuin-1 activator resveratrol
showed a bactericidal effect against NTHi, and the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375
counts intracellularly and in the lungs of infected mice. PDE4 inhibition is currently prescribed in COPD, and resveratrol is an
attractive geroprotector for COPD treatment. Together, these results expand our knowledge of NTHi-triggered host subversion
and frame the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection
Análisis del estado de metilación de los genes PIAS en neoplasias mieloproliferativas crónicas BCR-ABL1 y V617FJAK2 negativas
Análisis del estado de metilación de los genes PIAS en neoplasias mieloproliferativas crónicas BCR-ABL1 y V617FJAK2 negativas
Preclinical evaluation of the antimicrobial-immunomodulatory dual action of xenohormetic molecules against haemophilus influenzae respiratory infection
Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammation
and impaired airway immunity, providing an opportunistic platform for nontypeable Haemophilus
influenzae (NTHi) infection. In this context, therapies targeting not only overactive inflammation
without significant adverse effects, but also infection are of interest. Increasing evidence suggests that
polyphenols, plant secondary metabolites with anti-inflammatory and antimicrobial properties, may
be protective. Here, a Cistus salviifolius plant extract containing quercetin, myricetin, and punicalagin
was shown to reduce NTHi viability. Analysis of these polyphenols revealed that quercetin has a
bactericidal effect on NTHi, does not display synergies, and that bacteria do not seem to develop
resistance. Moreover, quercetin lowered NTHi airway epithelial invasion through a mechanism
likely involving inhibition of Akt phosphorylation, and reduced the expression of bacterially-induced
proinflammatory markers il-8, cxcl-1, il-6, pde4b, and tnfα. We further tested quercetin’s effect on NTHi
murine pulmonary infection, showing a moderate reduction in bacterial counts and significantly
reduced expression of proinflammatory genes, compared to untreated mice. Quercetin administration
during NTHi infection on a zebrafish septicemia infection model system showed a bacterial clearing
effect without signs of host toxicity. In conclusion, this study highlights the therapeutic potential of
the xenohormetic molecule quercetin against NTHi infection
Methylation status of SOCS1 and SOCS3 in BCR-ABL negative and JAK2V617F negative chronic myeloproliferative neoplasms
Modulation of Haemophilus influenzae interaction with hydrophobic molecules by the VacJ/MlaA lipoprotein impacts strongly on its interplay with the airways
Airway infection by nontypeable Haemophilus influenzae (NTHi) associates to chronic obstructive pulmonary disease (COPD) exacerbation and asthma neutrophilic airway inflammation. Lipids are key inflammatory mediators in these disease conditions and consequently, NTHi may encounter free fatty acids during airway persistence. However, molecular information on the interplay NTHi-free fatty acids is limited, and we lack evidence on the importance of such interaction to infection. Maintenance of the outer membrane lipid asymmetry may play an essential role in NTHi barrier function and interaction with hydrophobic molecules. VacJ/MlaA-MlaBCDEF prevents phospholipid accumulation at the bacterial surface, being the only system involved in maintaining membrane asymmetry identified in NTHi. We assessed the relationship among the NTHi VacJ/MlaA outer membrane lipoprotein, bacterial and exogenous fatty acids, and respiratory infection. The vacJ/mlaA gene inactivation increased NTHi fatty acid and phospholipid global content and fatty acyl specific species, which in turn increased bacterial susceptibility to hydrophobic antimicrobials, decreased NTHi epithelial infection, and increased clearance during pulmonary infection in mice with both normal lung function and emphysema, maybe related to their shared lung fatty acid profiles. Altogether, we provide evidence for VacJ/MlaA as a key bacterial factor modulating NTHi survival at the human airway upon exposure to hydrophobic molecules