Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control
Total Page：16
File Type：pdf, Size：1020Kb
Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control Steven T. Rutherford1 and Bonnie L. Bassler1,2 1Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815 Correspondence: [email protected] Quorum sensing is a process of cell–cell communication that allows bacteria to share information about cell density and adjust gene expression accordingly. This process enables bacteria to express energetically expensive processes as a collective only when the impact of those processes on the environment or on a host will be maximized. Among the many traits controlled by quorum sensing is the expression of virulence factors by path- ogenic bacteria. Here we review the quorum-sensing circuits of Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Vibrio cholerae. We outline these canonical quorum-sensing mechanisms and how each uniquely controls virulence factor production. Additionally,we examine recent efforts to inhibit quorum sensing in these pathogens with the goal of designing novel antimicrobial therapeutics. uorum sensing (QS) is a bacterial cell–cell Despite differences in regulatory compo- Qcommunication process that involves the nents and molecular mechanisms, all known production, detection, and response to extra- QS systems depend on three basic principles. cellular signaling molecules called autoinducers First, the members of the community produce (AIs). AIs accumulate in the environment as the AIs, which are the signaling molecules. At low bacterial population density increases, and bac- cell density (LCD), AIs diffuse away, and, there- teria monitor this information to track changes fore, are present at concentrations below the in their cell numbers and collectively alter gene threshold required for detection. At high cell www.perspectivesinmedicine.org expression. QS controls genes that direct ac- density (HCD), the cumulative production of tivities that are beneficial when performed by AIs leads to a local high concentration, enabling groups of bacteria acting in synchrony. Pro- detection and response (Kaplan and Greenberg cesses controlled by QS include biolumines- 1985). Second, AIs are detected by receptors cence, sporulation, competence, antibiotic pro- that exist in the cytoplasm or in the membrane. duction, biofilm formation, and virulence factor Third, in addition to activating expression of secretion (reviewed in Novick and Geisinger genes necessary for cooperative behaviors, de- 2008; Ng and Bassler 2009; Williams and Ca- tection of AIs results in activation of AI produc- mara 2009). tion (Novick et al. 1995; Seed et al. 1995). This Editors: Pascale Cossart and Stanley Maloy Additional Perspectives on Bacterial Pathogenesis available at www.perspectivesinmedicine.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a012427 Cite this article as Cold Spring Harb Perspect Med 2012;2:a012427 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press S.T. Rutherford and B.L. Bassler feed-forward autoinduction loop presumably homoserine lactones (AHLs) or other mole- promotes synchrony in the population. cules whose production depends on S-adeno- Gram-positive and Gram-negative bacteria sylmethionine (SAM) as a substrate (Wei et al. use different types of QS systems (Fig. 1 shows 2011). AIs are produced in the cell and freely the four paradigmatic QS wiring diagrams). diffuse across the inner and outer membranes. Gram-positive bacteria use peptides, called When the concentration of AIs is sufficiently autoinducing peptides (AIPs), as signaling high, which occurs at HCD, they bind cytoplas- molecules. Once produced in the cell, AIPs are mic receptors that are transcription factors. The processed and secreted. When the extracellular AI-bound receptors regulate expression of the concentration of the AIP is high, which occurs at genes in the QS regulon (Fig. 1C). In some cases HCD, it binds to a cognate membrane-bound of Gram-negative bacterial QS, AIs are detected two-component histidine kinase receptor. Usu- by two-component histidine kinase receptors ally, binding activates the receptor’s kinase activ- that function analogously to those described ity, it autophosphorylates, and passes phosphate in the preceding paragraph for Gram-positive to a cognate cytoplasmic response regulator. QS bacteria (Fig. 1D). The phosphorylated response regulator acti- Dozens of clinically-relevant bacteria use vates transcription of the genes in the QS regu- QS to regulate the collective production of vir- lon (Fig. 1A). In some cases of Gram-positive ulence factors. Here, we highlight the QS sys- bacterial QS, AIPs are transported back into the tems of four human pathogens that exemplify cell cytoplasm where they interact with tran- the diversityof QS systems. First, we outline how scription factors to modulate the transcription Staphylococcus aureus uses the paradigmatic Agr factor’s activity and, in turn, modulate gene ex- system to regulate adhesion and production of pression changes (Fig. 1B). virulence factors. Wealso discussthe PlcR/PapR Gram-negative bacteria communicate using system that controls virulence factor production small molecules as AIs. These are either acyl- in the Gram-positive bacterium Bacillus cereus. A AIP B Pro-AIP AIP Process Transport Histidine Out Out Secretion Transport /process kinase In In Pro-AIP Pro-AIP AIP www.perspectivesinmedicine.org AI Response QS AI Receptor- QS ~P synthase regulator regulon synthase AIP regulon C D AI AHL Out Out Periplasm Histidine Periplasm In kinase In AI Receptor- QS AI Response QS ~P synthase AHL regulon synthase regulator regulon Figure 1. Canonical bacterial quorum-sensing (QS) circuits. Autoinducing peptide (AIP) QS in Gram-positive bacteria by (A) two-component signaling, or (B) an AIP-binding transcription factor. Small molecule QS in Gram-negative bacteria by (C) a LuxI/LuxR-type system, or (D) two-component signaling. 2 Cite this article as Cold Spring Harb Perspect Med 2012;2:a012427 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Quorum Sensing and Virulence Next, we describe the canonical Gram-negative dines when bound by the AIP. The phosphoryl LuxI/LuxR QS circuit and how Pseudomonas group is passed from the histidine to a con- aeruginosa exploits two such circuits arranged served aspartate on a cognate cytoplasmic re- in tandem to control virulence factor produc- sponse-regulator protein, and the phosphory- tion and biofilm formation. Finally, we discuss lated response regulator controls expression of QS in Vibrio cholerae, a Gram-negative bacte- QS-target genes. In these Gram-positive QS cir- rium that uses two parallel two-component QS cuits, the pro-AIP, transporter, histidine kinase systems to control virulence factor production receptor, and response regulator are typically and biofilm formation. Importantly, in all of encoded in an operon (Ji et al. 1995; Peterson these cases, the QS circuits are tailored to pro- et al. 2000). Expression of this operon is acti- mote the specific disease. P. aeruginosa and S. vated by the phosphorylated response regulator, aureus cause persistent diseases while V.cholerae resulting in an autoinducing feed-forward loop and B. cereus cause acute infections. We also that synchronizes the QS response. outline efforts to develop inhibitors of these Some examples of Gram-positive QS behav- QS systems to be deployed as novel antimi- iors are competence in Streptococcus pneumonia crobials. and Bacillus subtilis and sporulation in B. sub- tilis (Kleerebezem et al. 1997). QS controls vir- ulence factor production in Gram-positive hu- QS CONTROL OF VIRULENCE FACTORS man pathogens including S. aureus, Listeria IN GRAM-POSITIVE BACTERIA monocytogenes, Enterococcus faecalis, and Clos- tridium perfringens (Autret et al. 2003; Podbiel- Two-Component QS in Gram-Positive ski and Kreikemeyer 2004; Ohtani et al. 2009; Bacteria Riedel et al. 2009; Thoendel et al. 2011). The QS in Gram-positive bacteria relies on princi- most well-studied system in this group of path- ples common to all QS circuits: production, de- ogens is the S. aureus Agr system (reviewed ex- tection, and response to AIs. In many Gram- tensively in Thoendel et al. 2011). positive bacteria, the AIs are oligopeptide AIPs that are detected by membrane-bound two- S. aureus Quorum Sensing component signal transduction systems (Fig. 1A) (Havarstein et al. 1995; Ji et al. 1995; Solo- S. aureus is found among the normal human mon et al. 1996). skin flora. If the epithelial barrier is compro- The AIPs are encoded as precursors (pro- mised, S. aureus can cause minor skin infec- AIPs) and are diverse in sequence and structure tions. These infections can lead to pneumonia, www.perspectivesinmedicine.org (Havarstein et al. 1995; Otto et al. 1998; Lazaz- bacteremia, and sepsis (Lowy 1998; Massey et al. zera 2001; Nakayama et al. 2001; Kalkum et al. 2006). S. aureus is the leading cause of hospital- 2003; Okada et al. 2005; Thoendel et al. 2011). related infections in the United States. Its ability Because the cell membrane is impermeable to to cause disease depends on expression of an peptides, specialized transporters are required array