Targeting Pseudomonas aeruginosa quorum sensing with sodium salicylate modulates immune responses in vitro and in vivo

Front Cell Infect Microbiol. 2023 Aug 8:13:1183959. doi: 10.3389/fcimb.2023.1183959. eCollection 2023.

Abstract

Introduction: Chronic infections are a major clinical challenge in hard-to-heal wounds and implanted devices. Pseudomonas aeruginosa is a common causative pathogen that produces numerous virulence factors. Due to the increasing problem of antibiotic resistance, new alternative treatment strategies are needed. Quorum sensing (QS) is a bacterial communication system that regulates virulence and dampens inflammation, promoting bacterial survival. QS inhibition is a potent strategy to reduce bacterial virulence and alleviate the negative impact on host immune response.

Aim: This study investigates how secreted factors from P. aeruginosa PAO1, cultured in the presence or absence of the QS inhibitor sodium salicylate (NaSa), influence host immune response.

Material and methods: In vitro, THP-1 macrophages and neutrophil-like HL-60 cells were used. In vivo, discs of titanium were implanted in a subcutaneous rat model with local administration of P. aeruginosa culture supernatants. The host immune response to virulence factors contained in culture supernatants (+/-NaSa) was characterized through cell viability, migration, phagocytosis, gene expression, cytokine secretion, and histology.

Results: In vitro, P. aeruginosa supernatants from NaSa-containing cultures significantly increased THP-1 phagocytosis and HL-60 cell migration compared with untreated supernatants (-NaSa). Stimulation with NaSa-treated supernatants in vivo resulted in: (i) significantly increased immune cell infiltration and cell attachment to titanium discs; (ii) increased gene expression of IL-8, IL-10, ARG1, and iNOS, and (iii) increased GRO-α protein secretion and decreased IL-1β, IL-6, and IL-1α secretion, as compared with untreated supernatants.

Conclusion: In conclusion, treating P. aeruginosa with NaSa reduces the production of virulence factors and modulates major immune events, such as promoting phagocytosis and cell migration, and decreasing the secretion of several pro-inflammatory cytokines.

Keywords: Pseudomonas aeruginosa; biomaterial-associated infection (BAI); immune response; inflammation; phagocytosis; quorum sensing; sodium salicylate; wound infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Pseudomonas aeruginosa*
  • Quorum Sensing*
  • Rats
  • Sodium Salicylate / pharmacology
  • Titanium

Substances

  • Sodium Salicylate
  • Titanium

Grants and funding

This research was funded by the Swedish Foundation for Strategic Research (SSF; RMA15-0110 2016); Mölnlycke Health Care AB (Sweden); the European Commission within the H2020-MSCA grant agreement No. 861046 (BIOREMIA-ETN); the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 754412 [MoRE2020 - Region Västra Götaland]; Centre for Antibiotic Resistance Research in Gothenburg (CARe); Swedish Research Council (2018–02891, 2020-04715, 2022-00853); the Swedish state under the agreement between the Swedish government and the county councils; the ALF agreement (ALFGBG-725641, ALFGBG-978896); the IngaBritt and Arne Lundberg Foundation (LU2021-0048); the Sylvan Foundation, the Hjalmar Svensson Foundation; the Doctor Felix Neuberghs Foundation; the Adlerbertska Foundation; and the Area of Advance Materials of Chalmers/GU Biomaterials within the Strategic Research Area initiative launched by the Swedish government.