Erik Gerner - The role of sodium salicylate as a virulence inhibitor for soft tissue infections

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This thesis aims to investigate the potential of sodium salicylate as an inhibitor of quorum sensing signaling, a bacterial communication system regulating virulence, in the pathogens Pseudomonas aeruginosa and Staphylococcus aureus. A wide range of different assays are utilized to study quorum sensing and associated virulence factors using well established laboratory strains as well as clinical isolates from chronic wound and periprosthetic joint infections. Furthermore, the effects of treating P.aeruginosa with sodium salicylate on host immune functions are studied in vitro and in an in vivo rodent infection model.

ABSTRACT

Approximately 1-2% of the total population will suffer from chronic wounds during their life-time. These wounds, which can last for years, are associated with considerable patient suffering and large socioeconomic costs. Infection is considered as an important factor for delayed healing. Due to the continued development of antibiotic resistance, novel alternative treatment strategies are urgently needed. Quorum sensing (QS), a signaling system used by important wound pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus, regulates virulence factor production, and is thus an attractive target.

The aim of this thesis is to evaluate the effect of sodium salicylate (NaSa) on P. aeruginosa and S. aureus QS activity and production of virulence factors, and how this influences the host immune response, both in vitro and in vivo. Furthermore, a collection of P. aeruginosa chronic wound isolates is characterized in terms of QS signal and virulence factor production.

The results showed that about 50% of the clinical isolates produced a majority of the investigated virulence factors and QS signals. In P. aeruginosa, NaSa reduced QS activity and the production of virulence factors such as pyocyanin, pyoverdine, proteases and biofilm. P. aeruginosa biofilms formed in presence of NaSa contained fewer large bacterial aggregates, and were easier eradicated with silver. In S. aureus, the effect of NaSa on QS and virulence factor production was concentration dependent, with high levels of NaSa reducing QS and toxin production, while the opposite was observed for lower NaSa concentrations. Biofilm formation was induced by NaSa, but without increasing its tolerance towards silver.

In vitro, immune cells stimulated with supernatant from NaSa-treated P. aeruginosa cultures demonstrated increased migration and phagocytic capacity compared to control supernatants. In vivo, rats stimulated with NaSa-treated supernatants demonstrated increased immune cell infiltration and reduced secretion of proinflammatory cytokines. In conclusion, NaSa influences QS and virulence factor production in P. aeruginosa and S. aureus, resulting in stimulation of important immune functions in vitro and in vivo.
 

MORE INFORMATION

• This research was funded by the Swedish Foundation for Strategic Research (SSF; RMA15-0110 2016) and Mölnlycke Health Care.