Significant immunomodulatory effects of Pseudomonas aeruginosa quorum-sensing signal molecules: possible link in human sepsis.
Pathogenic bacteria use quorum-sensing signal molecules to co-ordinate the expression of virulence genes. Animal-based studies have demonstrated the immunomodulatory effects of quorum-sensing signal molecules. In the present study, 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 the sera of patients. Quorum-sensing signal molecules inhibited normal dendritic cell and T-cell activation and proliferation, and down-regulated the expression of co-stimulatory molecules on dendritic cells; in MLDCRs (mixed lymphocyte dendritic cell reactions), secretion of IL (interleukin)-4 and IL-10 was enhanced, but TNF-alpha (tumour necrosis factor-alpha), IFN-gamma (interferon-gamma) 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(+) Th1/Th2 (T-helper 1/2) cell apoptotic rate, and modified Th1/Th2 cell cytokine profiles in MLDCRs 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.
Boontham
Pisake
P
Division of Surgery, University of Nottingham, Nottingham NG7 2UH, U.K.
Robins
Adrian
A
Chandran
Palanichamy
P
Pritchard
David
D
Cámara
Miguel
M
Williams
Paul
P
Chuthapisith
Suebwong
S
McKechnie
Alasdair
A
Rowlands
Brian J
BJ
Eremin
Oleg
O
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D051940:B7-2 Antigen / Q000097:blood; D001426:Bacterial Proteins / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D006714:Homoserine / Q000031:analogs & derivatives* / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D053038:Quorum Sensing / Q000276:immunology*; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D051940:B7-2 Antigen; D001426:Bacterial Proteins; D016207:Cytokines; C109860:N-(3-oxododecanoyl)homoserine lactone; D006714:Homoserine; D015107:4-Butyrolactone