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