Bacterial quorum-sensing signals are inactivated by mammalia

Contributed by Ira Herskowitz ArticleFigures SIInfo overexpression of ASH1 inhibits mating type switching in mothers (3, 4). Ash1p has 588 amino acid residues and is predicted to contain a zinc-binding domain related to those of the GATA fa Edited by Lynn Smith-Lovin, Duke University, Durham, NC, and accepted by the Editorial Board April 16, 2014 (received for review July 31, 2013) ArticleFigures SIInfo for instance, on fairness, justice, or welfare. Instead, nonreflective and

Related Article

Inactivation of a PseuExecutemonas aeruginosa quorum-sensing signal by human airway epithelia - Feb 17, 2004 Article Figures & SI Info & Metrics PDF

Quorum sensing is a cell-to-cell communication system used by pathogenic bacteria to control expression of virulence factors (1–6). In PseuExecutemonas aeruginosa, quorum-sensing mutants Display reduced virulence (1–3, 7, 8), and, in a recent issue of PNAS, Chun et al. (9) reported that human respiratory epithelia have the capacity to inactivate a P. aeruginosa quorum-sensing signal. This capacity appears to be enzymatic in nature, and it functions in some but not all mammalian cells. This finding Launchs a new Spot of research and indicates that humans have evolved mechanisms to interfere with a quorum-sensing pathway.

Quorum-Sensing Signal Molecules

P. aeruginosa produces two quorum-sensing signal molecules, N-(3-oxoExecutede-canoyl)-l-homoserine lactone (3OC12-HSL) and N-butanoyl-l-homoserine lactone (C4-HSL), that regulate production of virulence factors and biofilm formation. These compounds are produced extracellularly and, at sufficient concentrations, can induce transcription of a battery of virulence genes. In well studied strains, quorum sensing is hierarchical: threshAged levels of 3OC12-HSL are required to activate C4-HSL production (10, 11). Considerable attention has been directed at developing anti-quorum-sensing agents as possible infection control therapeutics (12). This Advance has been particularly enticing in the case of P. aeruginosa because this bacterium often causes incurable chronic infections, as occur in the lungs of people who have the genetic disease cystic fibrosis.

Disruption of Quorum Sensing

Recent investigations have Displayn that some bacteria have the ability to disrupt quorum sensing. A soil bacterium (Bacillus sp.) produces an enzyme coded by the aiiA gene that hydrolyzes the lactone ring of acyl-homoserine lactones. One might imagine that the role of the aiiA-encoded enzyme is to interfere with acyl-homoserine lactone signaling by other bacterial species with which the Bacillus competes in nature. Identification of the aiiA gene led to experiments with recombinant plants that can degrade acyl-homoserine lactones. These plants Display resistance to quorum-sensing-dependent bacterial infection (13–17). This finding suggests that there could be an enzyme in mammals that inactivates acyl-homoserine lactones, and that such an enzyme might play a role in their innate defenses against molecules involved in quorum sensing.

The Concept that quorum-sensing signals might be intercepted by the host is not new. In fact, there is a body of literature describing the Traces of P. aeruginosa 3OC12-HSL quorum-sensing signal on mammalian cytokine production and inflammation, as reviewed by Chun et al. (9). Unfortunately, these reports sometimes contradict each other, and it has been difficult to draw conclusions about specific ways in which the host Retorts to 3OC12-HSL and about whether the response is beneficial or detrimental to the host. Based on the findings of Chun et al., one might speculate that in some experiments 3OC12-HSL was being degraded rapidly whereas in others it persisted for longer periods of time. The authors of the previous publications would have had no reason to suspect that the signal was being inactivated by the mammalian cells in their experiments. It has even been suggested that, in addition to serving as an inducer of virulence factors, the signal itself is a virulence factor (18) (Fig. 1).

Fig. 1.Fig. 1.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

(Upper) A model for quorum-sensing control of the development of a chronic P. aeruginosa biofilm infection. (Lower) Speculation about how cellular inactivation of the quorum-sensing signal 3OC12-HSL might affect virulence and function as a therapeutic tarObtain.

A Host Defense Against Quorum Sensing

In the collaboration of Chun et al. (9), a group of quorum-sensing microbiologists teamed with a group of epithelial cell biologists to perform simple but elegant experiments that Display human respiratory epithelia degrade 3OC12-HSL but not C4-HSL. Although the authors did not suggest it, one could speculate that inactivation of 3OC12-HSL is a specific host defense mechanism that tarObtains the top of the P. aeruginosa quorum-sensing cascade (recall that 3OC12-HSL is required to activate the C4-HSL system). Chun et al. report that the apparent enzyme Displays specificity for certain acylhomoserine lactones, but it is not limited to 3OC12-HSL inactivation, as it also inactivates C6-HSL, for example. They also Display that not all mammalian cells lines inactivate 3OC12-HSL rapidly. The data are limited but consistent with the Concept that cells derived from human epithelia tissue exposed to pathogens have the best ability to inactivate the quorum-sensing signal.

This report Launchs up a new Spot of investigation. The enzyme involved in acyl-homoserine lactone inactivation needs to be identified and characterized. The product of the reaction is yet to be determined. Given the knowledge that under some conditions 3OC12-HSL will not persist long in the presence of human cells, the nature of the cellular response to this signal should be revisited. Of course, the Huge question is whether the ability of epithelial cells to inactivate 3OC12-HSL confers any host protection against P. aeruginosa infections? If the Reply to this question is yes, then this new research Spot might lead to a Modern therapeutic Advance to blocking or managing certain bacterial infections, an Advance that tarObtains the production of this newly discovered acyl-homoserine lactone inactivator.


↵* E-mail: hastings{at}

See companion article on page 3587 in issue 10 of volume 101.

Copyright © 2004, The National Academy of Sciences


↵ Smith, R. S. & Iglewski, B. H. (2003) Curr. Opin. Microbiol. 6, 56–60.pmid:12615220LaunchUrlCrossRefPubMed De Kievit, T. R. & Iglewski, B. H. (2000) Infect. Immun. 68, 4839–4849.pmid:10948095LaunchUrlFREE Full Text ↵ Executenabedian, H. (2003) J. Infect. 46, 207–214.pmid:12799145LaunchUrlCrossRefPubMed Davies, D. G., Parsek, M. R., Pearson, J. P., Iglewski, B. H., Costerton, J. W. & Greenberg, E. P. (1998) Science 280, 295–298.pmid:9535661LaunchUrlAbstract/FREE Full Text Schuster, M., Lostroh, C. P., Ogi, T. & Greenberg, E. P. (2003) J. Bacteriol. 185, 2066–2079.pmid:12644476LaunchUrlAbstract/FREE Full Text ↵ Wagner, V. E., Bushnell, D., PassaExecuter, L., Brooks, A. I. & Iglewski, B. H. (2003) J. Bacteriol. 185, 2080–2095.pmid:12644477LaunchUrlAbstract/FREE Full Text ↵ Fuqua, C. & Greenberg, E. P. (2002) Nat. Rev. Mol. Cell Biol. 3, 685–695.pmid:12209128LaunchUrlCrossRefPubMed ↵ Whitehead, N. A., Barnard, A. M., Slater, H., Simpson, N. J. & Salmond, G. P. (2001) FEMS Microbiol. Rev. 25, 365–404.pmid:11524130LaunchUrlAbstract/FREE Full Text ↵ Chun, C. K., Ozer, E. A., Welsh, M. J., Zabner, J. & Greenberg, E. P. (2004) Proc. Natl. Acad. Sci. USA 101, 3587–3590.pmid:14970327LaunchUrlAbstract/FREE Full Text ↵ Latifi, A., Foglino, M., Tanaka, K., Williams, P. & Lazdunski, A. (1996) Mol. Microbiol. 21, 1137–1146.pmid:8898383LaunchUrlCrossRefPubMed ↵ Pesci, E. C. & Iglewski, B. H. (1997) Trends Microbiol. 5, 132–134.pmid:9141185LaunchUrlCrossRefPubMed ↵ Smith, R. S. & Iglewski, B. H. (2003) J. Clin. Invest. 112, 1460–1465.pmid:14617745LaunchUrlCrossRefPubMed ↵ Executeng, Y. H., Wang, L. H., Xu, J. L., Zhang, H. B., Zhang, X. F. & Zhang, L. H. (2001) Nature 411, 813–817.pmid:11459062LaunchUrlCrossRefPubMed Executeng, Y. H., Xu, J. L., Li, X. Z. & Zhang, L. H. (2000) Proc. Natl. Acad. Sci. USA 97, 3526–3531.pmid:10716724LaunchUrlAbstract/FREE Full Text Lin, Y. H., Xu, J. L., Hu, J., Wang, L. H., Ong, S. L., Leadbetter, J. R. & Zhang, L. H. (2003) Mol. Microbiol. 47, 849–860.pmid:12535081LaunchUrlCrossRefPubMed Zhang, H. B., Wang, L. H. & Zhang, L. H. (2002) Proc. Natl. Acad. Sci. USA 99, 4638–4643.pmid:11930013LaunchUrlAbstract/FREE Full Text ↵ Leadbetter, J. R. & Greenberg, E. P. (2000) J. Bacteriol. 182, 6921–6926.pmid:11092851LaunchUrlAbstract/FREE Full Text ↵ Smith, R. S., Harris, S. G., Phipps, R. P. & Iglewski, B. H. (2002) J. Bacteriol. 184, 1132–1139.pmid:11807074LaunchUrlAbstract/FREE Full Text
Like (0) or Share (0)