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The interaction of N-acylhomoserine lactone quorum sensing signaling molecules with biological membranes: implications for inter-kingdom signaling.

Davis BM, Jensen R, Williams P, O'Shea P - PLoS ONE (2010)

Bottom Line: The long chain N-acylhomoserine lactone (AHL) quorum sensing signal molecules released by Pseudomonas aeruginosa have long been known to elicit immunomodulatory effects through a process termed inter-kingdom signaling.Our observations support previous findings that increasing AHL lipophilicity increases the immunomodulatory activity of these quorum compounds, while providing evidence to suggest membrane interaction plays an important role in quorum sensing and implies a role for membrane microdomains in this process.Finally, our results suggest the existence of a eukaryotic membrane-located system that acts as an AHL receptor.

View Article: PubMed Central - PubMed

Affiliation: Cell Biophysics Group, Institute of Biophysics, Imaging and Optical Science, University of Nottingham, Nottingham, United Kingdom.

ABSTRACT

Background: The long chain N-acylhomoserine lactone (AHL) quorum sensing signal molecules released by Pseudomonas aeruginosa have long been known to elicit immunomodulatory effects through a process termed inter-kingdom signaling. However, to date very little is known regarding the exact mechanism of action of these compounds on their eukaryotic targets.

Methodology/principal findings: The use of the membrane dipole fluorescent sensor di-8-ANEPPS to characterise the interactions of AHL quorum sensing signal molecules, N-(3-oxotetradecanoyl)-L-homoserine lactone (3-oxo-C14-HSL), N-(3-oxododecanoyl)homoserine-L-lactone (3-oxo-C12-HSL) and N-(3-oxodecanoyl) homoserine-L-lactone (3-oxo-C10 HSL) produced by Pseudomonas aeruginosa with model and cellular membranes is reported. The interactions of these AHLs with artificial membranes reveal that each of the compounds is capable of membrane interaction in the micromolar concentration range causing significant modulation of the membrane dipole potential. These interactions fit simple hyperbolic binding models with membrane affinity increasing with acyl chain length. Similar results were obtained with T-lymphocytes providing the evidence that AHLs are capable of direct interaction with the plasma membrane. 3-oxo-C12-HSL interacts with lymphocytes via a cooperative binding model therefore implying the existence of an AHL membrane receptor. The role of cholesterol in the interactions of AHLs with membranes, the significance of modulating cellular dipole potential for receptor conformation and the implications for immune modulation are discussed.

Conclusions/ significance: Our observations support previous findings that increasing AHL lipophilicity increases the immunomodulatory activity of these quorum compounds, while providing evidence to suggest membrane interaction plays an important role in quorum sensing and implies a role for membrane microdomains in this process. Finally, our results suggest the existence of a eukaryotic membrane-located system that acts as an AHL receptor.

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A strong negative correlation is observed between peripheral mononuclear cell proliferation and AHL lipophilicity.The IC50 for human peripheral mononuclear cell proliferation (PBMCs) isolated from three donors (* denotes n = 2) in the presence of AHLs of chain lengths between 8 and 14 carbons (values obtained from [18]) exhibit a strong negative correlation (Pearsons r = −0.895, p = 0.016) against the predicted octanol/water partition coefficient (LogP) for each compound (calculated using ACD/i-Lab LogP algorithm 12.0). n = 3, ±SEM. Projected LogP are given in Table 1.
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pone-0013522-g002: A strong negative correlation is observed between peripheral mononuclear cell proliferation and AHL lipophilicity.The IC50 for human peripheral mononuclear cell proliferation (PBMCs) isolated from three donors (* denotes n = 2) in the presence of AHLs of chain lengths between 8 and 14 carbons (values obtained from [18]) exhibit a strong negative correlation (Pearsons r = −0.895, p = 0.016) against the predicted octanol/water partition coefficient (LogP) for each compound (calculated using ACD/i-Lab LogP algorithm 12.0). n = 3, ±SEM. Projected LogP are given in Table 1.

Mentions: The concentrations of AHLs required to inhibit 50% proliferation (IC50) of human peripheral blood mononuclear cells (PBMCs) was obtained from Chhabra et al 2003 [18]. These data are plotted against a calculated LogP value in Table 1, (calculated using the ACD/I-Lab Web service (ACD/LogP 12.0)) based on molecular structure. LogP is a measure of molecular lipophilicity and is frequently used in the pharmaceutical industry as an indicator of the likely bioavailability of a drug molecule. Figure 2 indicates that a strong negative correlation (Pearsons r = −0.895, p = 0.016) exists between membrane affinity and immunosuppressive activity.


The interaction of N-acylhomoserine lactone quorum sensing signaling molecules with biological membranes: implications for inter-kingdom signaling.

Davis BM, Jensen R, Williams P, O'Shea P - PLoS ONE (2010)

A strong negative correlation is observed between peripheral mononuclear cell proliferation and AHL lipophilicity.The IC50 for human peripheral mononuclear cell proliferation (PBMCs) isolated from three donors (* denotes n = 2) in the presence of AHLs of chain lengths between 8 and 14 carbons (values obtained from [18]) exhibit a strong negative correlation (Pearsons r = −0.895, p = 0.016) against the predicted octanol/water partition coefficient (LogP) for each compound (calculated using ACD/i-Lab LogP algorithm 12.0). n = 3, ±SEM. Projected LogP are given in Table 1.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2958149&req=5

pone-0013522-g002: A strong negative correlation is observed between peripheral mononuclear cell proliferation and AHL lipophilicity.The IC50 for human peripheral mononuclear cell proliferation (PBMCs) isolated from three donors (* denotes n = 2) in the presence of AHLs of chain lengths between 8 and 14 carbons (values obtained from [18]) exhibit a strong negative correlation (Pearsons r = −0.895, p = 0.016) against the predicted octanol/water partition coefficient (LogP) for each compound (calculated using ACD/i-Lab LogP algorithm 12.0). n = 3, ±SEM. Projected LogP are given in Table 1.
Mentions: The concentrations of AHLs required to inhibit 50% proliferation (IC50) of human peripheral blood mononuclear cells (PBMCs) was obtained from Chhabra et al 2003 [18]. These data are plotted against a calculated LogP value in Table 1, (calculated using the ACD/I-Lab Web service (ACD/LogP 12.0)) based on molecular structure. LogP is a measure of molecular lipophilicity and is frequently used in the pharmaceutical industry as an indicator of the likely bioavailability of a drug molecule. Figure 2 indicates that a strong negative correlation (Pearsons r = −0.895, p = 0.016) exists between membrane affinity and immunosuppressive activity.

Bottom Line: The long chain N-acylhomoserine lactone (AHL) quorum sensing signal molecules released by Pseudomonas aeruginosa have long been known to elicit immunomodulatory effects through a process termed inter-kingdom signaling.Our observations support previous findings that increasing AHL lipophilicity increases the immunomodulatory activity of these quorum compounds, while providing evidence to suggest membrane interaction plays an important role in quorum sensing and implies a role for membrane microdomains in this process.Finally, our results suggest the existence of a eukaryotic membrane-located system that acts as an AHL receptor.

View Article: PubMed Central - PubMed

Affiliation: Cell Biophysics Group, Institute of Biophysics, Imaging and Optical Science, University of Nottingham, Nottingham, United Kingdom.

ABSTRACT

Background: The long chain N-acylhomoserine lactone (AHL) quorum sensing signal molecules released by Pseudomonas aeruginosa have long been known to elicit immunomodulatory effects through a process termed inter-kingdom signaling. However, to date very little is known regarding the exact mechanism of action of these compounds on their eukaryotic targets.

Methodology/principal findings: The use of the membrane dipole fluorescent sensor di-8-ANEPPS to characterise the interactions of AHL quorum sensing signal molecules, N-(3-oxotetradecanoyl)-L-homoserine lactone (3-oxo-C14-HSL), N-(3-oxododecanoyl)homoserine-L-lactone (3-oxo-C12-HSL) and N-(3-oxodecanoyl) homoserine-L-lactone (3-oxo-C10 HSL) produced by Pseudomonas aeruginosa with model and cellular membranes is reported. The interactions of these AHLs with artificial membranes reveal that each of the compounds is capable of membrane interaction in the micromolar concentration range causing significant modulation of the membrane dipole potential. These interactions fit simple hyperbolic binding models with membrane affinity increasing with acyl chain length. Similar results were obtained with T-lymphocytes providing the evidence that AHLs are capable of direct interaction with the plasma membrane. 3-oxo-C12-HSL interacts with lymphocytes via a cooperative binding model therefore implying the existence of an AHL membrane receptor. The role of cholesterol in the interactions of AHLs with membranes, the significance of modulating cellular dipole potential for receptor conformation and the implications for immune modulation are discussed.

Conclusions/ significance: Our observations support previous findings that increasing AHL lipophilicity increases the immunomodulatory activity of these quorum compounds, while providing evidence to suggest membrane interaction plays an important role in quorum sensing and implies a role for membrane microdomains in this process. Finally, our results suggest the existence of a eukaryotic membrane-located system that acts as an AHL receptor.

Show MeSH
Related in: MedlinePlus