Resveratrol therapeutics combines both antimicrobial and immunomodulatory properties against respiratory infection by nontypeable Haemophilus influenzae

Abstract

The respiratory pathogen nontypeable Haemophilus influenzae (NTHi) is an important cause of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) that requires efficient treatments. A previous screening for host genes differentially expressed upon NTHi infection identified sirtuin-1, which encodes a NAD-dependent deacetylase protective against emphysema and is activated by resveratrol. This polyphenol concomitantly reduces NTHi viability, therefore highlighting its therapeutic potential against NTHi infection at the COPD airway. In this study, resveratrol antimicrobial effect on NTHi was shown to be bacteriostatic and did not induce resistance development in vitro. Analysis of modulatory properties on the NTHi-host airway epithelial interplay showed that resveratrol modulates bacterial invasion but not subcellular location, reduces inflammation without targeting phosphodiesterase 4B gene expression, and dampens β defensin-2 gene expression in infected cells. Moreover, resveratrol therapeutics against NTHi was evaluated in vivo on mouse respiratory and zebrafish septicemia infection model systems, showing to decrease NTHi viability in a dose-dependent manner and reduce airway inflammation upon infection, and to have a significant bacterial clearing effect without signs of host toxicity, respectively. This study presents resveratrol as a therapeutic of particular translational significance due to the attractiveness of targeting both infection and overactive inflammation at the COPD airway.

Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review

“…Resveratrol has exerted immunomodulating effects in various studies ( Table 2) [46][47][48]. Resveratrol modulates immune response against pathogens like viruses, bacteria, and some toxic materials.…”

“…Additionally, resveratrol maintained the immune function in rotavirus-infected piglets, resulting in attenuated diarrhea and inflammation [51]. Moreover, resveratrol triggered an immune response to protect against non-typeable Haemophilus influenzae (a respiratory bacterium) without developing resistance in vitro [46]. Resveratrol also decreased bacterial viability and reduced infectious airway inflammation without noticeable host toxicity in vivo [46,52].…”

“…Moreover, resveratrol triggered an immune response to protect against non-typeable Haemophilus influenzae (a respiratory bacterium) without developing resistance in vitro [46]. Resveratrol also decreased bacterial viability and reduced infectious airway inflammation without noticeable host toxicity in vivo [46,52]. In addition, resveratrol showed immunomodulatory properties via reducing bacterial and inflammatory biomarkers in lipopolysaccharides (LPS)-challenged primary Atlantic salmon macrophages [52].…”

“…In vitro A549 cells 56.25, 112.5 µg/mL Triggering an immune response to protect against non-typeable Haemophilus influenzae without developing resistance [46] In vitro H1HeLa cells, Human nasal epithelia 0-300 µM Inhibiting human rhinoviruses-16 replication and normalized virus-induced IL-6, IL-8, and RANTES as well as the expression of ICAM-1 [47] In vitro Rhabdosarcoma cells 2.5-100 µg/mL Preventing EV71 replication, reducing the virus-induced elevated IL-6 and TNF-α secretion via suppressing IKK/NF-κB signaling pathway [48] In vivo Chickens 200, 400, 800 mg/kg Reducing immunocyte apoptosis in chickens receiving conventional vaccinations, and improving the growth of young chickens [49] In vivo Piglets 3, 10, 30 mg/kg/d Maintaining the immune function and attenuating diarrhea and inflammation [51] In vitro Atlantic salmon macrophages 10, 30, 50 µM Reducing bacterial and inflammatory biomarkers in LPS-challenged primary Atlantic salmon macrophages [52] In Improving central arterial wall stiffening based on its antioxidative and anti-inflammation [7] In vivo Rabbits 2.5 mg/kg Mitigating atrial fibrillation by upregulating PI3K/AKT/eNOS [8] In vitro Peripheral blood mononuclear cells 3-80 µM Blocking atherosclerotic plaque progression by acting against pro-atherogenic oxysterol signaling in M1 and M2 macrophages [57] In vivo Rats 50 mg/kg/day Preventing the activation of inflammasome via downregulating NF-κB p65 and p38 MAPK expression, and upregulating SIRT1 expression [62] In vivo Mice 20 mg/kg Regulated the FERM-kinase and Nrf2 interaction, decreasing the expression of ICAM-1, and inhibiting monocyte adhesion [63] In vivo Rats 1.24 µg/d Improving the cardiac and vascular autonomic function [65] In vitro Human RBCs 100 µM Protecting the erythrocytes via interacting with hemoglobin and reducing heme-iron oxidation [66] Cancers In vitro LNCaP cells 5, 10, 20, 50 µM Inducing the expression of COX-2, promoting ERK1/2 activation, and facilitating p53-dependent anti-proliferation gene expression [14] In vitro; In vivo tBregs; Mice 12.5 µM; 20, 50, 500 µg/mouse Preventing breast cancer metastasis by promoting antitumor immune responses via blunting STAT3, leading to inhibited generation and function of tBregs as well as decreased production of TGF-β [67] In In vitro A2780, OVCAR-3, SKOV-3 cells 10, 50, 100 µM…”

The persistence of Nontypeable Haemophilus influenzae fuels airway inflammation

“…To date, animal models have been developed to mimic the acute phase of NTHi infection rather than the chronic phase, limiting steps forward in the field. Airway persistence of NTHi is common in CF disease but also in other lung diseases with different aetiology, including COPD or lung cancer [29][30][31]. In this context, Croasdell A. et al exploited an acute infection model in which different amounts of NTHi were inoculated by oropharyngeal aspiration in C57BL/6J mice (up to 10 8 CFU) and 24 hours post-infection they found >90% of bacteria had been cleared, independently from the inoculum dose [32].…”