Differential Immune Modulatory Activity of Pseudomonas aeruginosa Quorum-Sensing Signal Molecules

Abstract

Pseudomonas aeruginosa releases a spectrum of well-regulated virulence factors, controlled by intercellular communication (quorum sensing) and mediated through the production of small diffusible quorum-sensing signal molecules (QSSM). We hypothesize that QSSM may in fact serve a dual purpose, also allowing bacterial colonization via their intrinsic immune-modulatory capacity. One class of signal molecule, the N-acylhomoserine lactones, has pleiotropic effects on eukaryotic cells, particularly those involved in host immunity. In the present study, we have determined the comparative effects of two chemically distinct and endobronchially detectable QSSM, N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C 12 -HSL) and 2-heptyl-3-hydroxy-4 (1H)-quinolone or the Pseudomonas quinolone signal (PQS), on human leukocytes exposed to a series of stimuli designed to detect differential immunological activity in vitro. 3-Oxo-C 12 -HSL and PQS displayed differential effects on the release of interleukin-2 (IL-2) when human T cells were activated via the T-cell receptor and CD28 (a costimulatory molecule). 3-Oxo-C 12 -HSL inhibited cell proliferation and IL-2 release; PQS inhibited cell proliferation without affecting IL-2 release. Both molecules inhibited cell proliferation and the release of IL-2 following mitogen stimulation. Furthermore, in the presence of Escherichia coli lipopolysaccharide, 3-oxo-C 12 -HSL inhibited tumor necrosis factor alpha release from human monocytes, as reported previously (K. Tateda et al., Infect. Immun. 64:37-43, 1996), whereas PQS did not inhibit in this assay. These data highlight the presence of two differentially active immune modulatory QSSM from P. aeruginosa, which are detectable endobronchially and may be active at the host/pathogen interface during infection with P. aeruginosa, should the bronchial airway lymphoid tissues prove to be accessible to QSSM.

N-(3-Oxo-acyl)homoserine Lactones Signal Cell Activation through a Mechanism distinct from the Canonical Pathogen-associated Molecular Pattern Recognition Receptor Pathways

“…Although further work is needed to characterize the direct effects of C12-containing P. aeruginosa biofilms on macrophages, these results are consistent with the hypothesis that C12 contributes to the establishment and maintenance of chronic infection with P. aeruginosa through its effects on macrophages. Previous findings that C12 accelerates apoptosis (24) and inhibits LPSinduced production of TNF in macrophages and human monocytes (22,48) are in accordance with this suggestion. However, the nature of biochemical mechanisms responsible for C12-mediated effects on mammalian cells has been unclear.…”

Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals

“…40). For example, AHLs can influence inflammatory responses (41)(42)(43), chemotaxis (44), induction of apoptosis (45)(46)(47), and mucus secretion (10). All of these responses are relatively slow and involve changes in gene regulatory networks or secretory mechanisms.…”

Biosensor-based assays for PQS, HHQ and related 2-alkyl-4-quinolone quorum sensing signal molecules

“…Subsequently, AHQs were discovered to inhibit the growth of Gram-positive bacteria, algae and phytoplankton, to modulate host immune defences, chelate iron and act as QS signal molecules [12][13][14][15][16][17][18] . Other pseudomonads, Burkholderia and Alteromonas species also produce AHQs and it is highly likely that other Gram-negative bacteria such as Ralstonia species synthesize these compounds as they possess homologs of the P. aeruginosa and B. pseudomallei AHQ biosynthetic genes 19 .…”