Significant immunomodulatory effects of Pseudomonas aeruginosa quorum-sensing signal molecules: possible link in human sepsis
Résumé
Pathogenic bacteria use quorum-sensing signal molecules to coordinate the expression of virulence genes. Animal-based studies have demonstrated the immunomodulatory effects of quorum-sensing signal molecules. We have examined the impact of these molecules on normal human immune function in vitro, and compared this with immune changes in patients with sepsis where quorum-sensing signal molecules were detected in patients' sera. Quorum-sensing signal molecules inhibited normal dentritic cell and T cell activation and proliferation, down-regulated expression of co-stimulatory molecules on dendritic cells; in mixed lymphocyte dendritic cell reactions (MLDCRs), secretion of IL-4 and IL-10 was enhanced, but TNF-α, IFN-γ and IL-6 was reduced. Quorum-sensing signal molecules induced apoptosis in dendritic cells and CD4+ cells, but not CD8+ cells. Dendritic cells from patients with sepsis were depleted and ex vivo showed defective expression of co-stimulatory molecules and dysfunctional stimulation of allogeneic T lymphocytes. Enhanced apoptosis of dendritic cells and differential CD4+ Th 1}/Th 2} apoptotic rate, and modified Th 1}/Th 2} cytokine profiles in mixed lymphocyte dendritic cell reactions were also demonstrated in patients with sepsis. The pattern of immunological changes in patients with sepsis mirrors the effects of quorum-sensing signal molecules on responses of immune cells from normal individuals in vitro, suggesting that quorum-sensing signal molecules should be investigated further as a cause of immune dysfunction in sepsis.
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