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Title: Quorum sensing control of Type VI secretion factors restricts the proliferation of quorum-sensing mutants}
Article:
Abstract:
Burkholderia thailandensis uses acyl-homoserine lactone-mediated quorum sensing systems to regulate hundreds of genes. Here we show that cell-cell contact-dependent type VI secretion( T6S) toxin-immunity systems are among those activated by quorum sensing in B. thailandensis. We also demonstrate that T6S is required to constrain proliferation of quorum sensing mutants in colony cocultures of a BtaR1 quorum-sensing signal receptor mutant and its parent. However, the BtaR1 mutant is not constrained by and outcompetes its parent in broth coculture, presumably because no cell contact occurs and there is a metabolic cost associated with quorum sensing gene activation. The increased fitness of the wild type over the BtaR1 mutant during agar surface growth is dependent on an intact T6SS-1 apparatus. Thus, quorum sensing activates B. thailandensis T6SS-1 growth inhibition and this control serves to police and constrain quorum-sensing mutants. This work defines a novel role for T6SSs in intraspecies mutant control.
Introduction:
Bacterial quorum sensing( QS) often controls factors that benefit cells in groups; it controls cooperative activities. A well-studied type of QS common to a number of Proteobacteria species is mediated by acyl-homoserine lactone( AHL) signals. AHLs are made by members of the LuxI family of signal synthases. The AHLs can diffuse in and out of cells. At sufficient cell densities, the AHLs accumulate to concentrations needed for expression of specific genes by binding signal receptors of the LuxR family of transcriptional regulators( for reviews of QS see( Fuqua et al., 1996)). In some bacterial species, QS controls just a few genes and in others it controls hundreds of genes. Genes for production of secreted or excreted products are overrepresented in AHL quorum sensing regulons. These extracellular products have at least in some cases been shown to serve as public goods. Any member of a group can benefit from the public good regardless of whether that individual has contributed its share of the good( West et al., 2006). There is a metabolic cost associated with QS and QS-activation of gene expression. QS control of public goods has been studied in some detail in Pseudomonas aeruginosa. Because QS activates production of extracellular proteases, QS signal receptor mutants have a fitness advantage over the wild type when growth is on milk protein as the sole carbon and energy source( Diggle et al., 2007; Sandoz et al., 2007). The receptor mutant fitness advantage presents a conundrum; how is QS-mediated cooperation preserved? QS itself can be considered a cooperative trait, the QS signal is a public good, and QS is susceptible to exploitation by QS mutant social cheats. In P. aeruginosa, three mechanisms of QS cheater restraint have been demonstrated. The first is a direct benefit-based strategy called metabolic constraint( Schuster et al., 2013; Dandekar et al., 2012); Quorum sensing activates genes coding for public goods( such as extracellular proteases), as well as a limited set of privately utilized goods( such as a hydrolase that allows producing cells to utilize adenosine). When cells are supplied with both casein and adenosine, QS signal receptor( LasR) mutant cheats are penalized and constrained( Dandekar et al., 2012). A second mechanism has been called metabolic prudence( Xavier et al., 2011) where the QS-controlled public good is only made when it’s production is not costly. Metabolic prudence minimizes the cost of cooperation. Recently, a mechanism whereby P. aeruginosa cooperators punish or police cheats has been described. QS competent cooperators produce cyanide and are more resistant to cyanide than QS mutant cheats, and thus the cooperators can constrain cheats by slowing their growth with cyanide( Wang et al., 2015). The P. aeruginosa policing is a rare example of this sort of activity in bacteria, and because cyanide production and resistance has some semblance to a toxin-immunity-like mechanism we hypothesis that QS activation of toxin-immunity systems might have some generality as a policing mechanism where QS bacteria can control QS mutants. We recently used RNAseq to identify genes in the Burkholderia thailandensis QS regulon( Majerczyk et al., 2014). B. thailandensis has three AHL QS systems, BtaR1-I1, BtaR2-I2 and BtaR3-I3( Ulrich et al., 2004; Chandler et al., 2009; Duerkop et al., 2009). Together, the QS systems control hundreds of genes. The BtaR1-I1 regulon appears to be the largest as BtaR1 regulates >150 genes( Majerczyk et al., 2014). We queried the transcriptomics data and discovered that expression of several genes shown to encode Type VI secretion system( T6SS) substrates, including characterized toxins and their cognate immunity or antitoxin genes, are activated by QS. Expression of a toxin and its antitoxin results in a toxin-resistant producer cell, which can deliver toxins via the secretion apparatus via cell-cell contact to a sensitive cell thereby inhibiting growth of the sensitive cell( Russell et al., 2014). We show that T6S provides wild-type B. thailandensis with an ability to constrain BtaR1 mutants in a contact-dependent manner. This supports the hypothesis that QS activation of toxin-immunity systems can serve as a policing mechanism to control QS mutants growing among QS competent wild-type cells. Our findings also reveal yet another role for T6S in bacteria. T6S has been shown to provide a competitive interspecies or interstrain advantage, and some T6Ss have been shown to play a role in bacterial virulence( Schwarz et al., 2010; 2014). Here we describe intraspecific control of QS mutants. This provides a rationale for why T6S toxin and immunity genes might be under QS control.
Discussion:
We present evidence that QS control of T6SS-1-mediated toxicity and immunity genes allows QS competent members of B. thailandensis colonies to police against BtaR1- QS mutants. During planktonic growth in broth where T6SS-1 does not function due to limited cell contact, BtaR1- mutants have a substantial fitness advantage over wild-type cells, presumably because of the cost associated with BtaR1-dependent activities. Policing of social deviants in Myxococcus xanthus and Pseudomonas aeruginosa has been reported previously( Manhes and Velicer, 2011; Sandoz et al., 2007). Here we describe a novel mechanism, for limiting quorum sensing mutant growth in bacterial groups. Several functions have been ascribed to T6S. B. thailandensis T6S-mediated killing is active against Proteobacteria species other than B. thailandensis and is thought to be important for interspecies competition( Schwarz et al., 2010). T6Ss occur in many species of Proteobacteria where they can provide an advantage over competing species( see Russell et al., 2014 for review). We note that in other organisms including, Pectobacterium atrosepticum( Liu et al., 2008), P. aeruginosa( Lesic et al., 2009), Aeromonas hydrophila( Khajanchi et al., 2009), Yersinia pseudotuberculosis( Zhang et al., 2011), Chromobacterium violaceum( Stauff and Bassler, 2011), Vibrio cholerae( Zheng et al., 2010), Vibrio alginolyticus,( Sheng et al., 2012), and Vibrio parahaemolyticus( Wang et al., 2013), QS regulates genes for the T6S apparatus( not the effector and immunity factors as we describe for B. thailandensis). We suspect QS regulation of the T6S apparatus might play a role in policing QS mutants during polymicrobial competitions or in other scenarios where T6S might benefit the producing cell. Furthermore, we note that other types of toxin-antitoxin systems have been reported to be under control of other non-AHL-mediated quorum sensing systems, for example the E. coli mazEF encoded toxin-antitoxin genes are controlled by a linear pentapeptide quorum sensing signal( Kolodkin-Gal et al., 2007). Under the conditions of our experiments the BtaR1-BtaI1 QS system carries with it a metabolic cost, which is evident in broth culture competition experiments and to a lesser extent in pure broth culture grow curves. The BtaR2-BtaI2 and BtaR3-BtaI3 QS systems do not appear to carry this large cost. We describe a mechanism by which wild-type populations can mitigate the cost of BtaR1-BtaI1 gene regulation by hindering the growth of QS mutants via regulation of cell-contact-dependent toxin and immunity proteins. This is a form of microbial policing; QS-proficient bacteria are outcompeted in populations of signal blind non-cooperators in the absence of the T6S cell-contact growth inhibition system. It is interesting that BtaR1 also promotes aggregation of cells under some conditions( Chandler et al., 2009). One can imagine that this system brings cells into close proximity where they can resist infiltration by other strains and species while at the same time protect themselves against social deviant BtaR1 mutant bacteria( Figure 4). 10. 7554/eLife. 14712. 008Figure 4. A policing model where QS control of T6S contact-dependent killing( effector and immunity proteins) enforces cooperation.( A) The bacterium on the left depicts a situation where QS co-regulates a public good with the T6SS-1 effector and immunity factors. Under these conditions, QS-proficient bacteria( cooperators, shown as white cells) limit the proliferation of a QS mutant( potential cheater, black cell) in a population.( B) In this situation, QS no longer co-regulates public good production with the T6SS-1 killing mechanism. Without co-regulation of the killing mechanism, QS mutants( potential cheaters, black cells) outcompete the wild type cooperators( white cells). DOI: http://dx. doi. org/10. 7554/eLife. 14712. 008
Bacterial cells communicate with each other by using chemical signals . The signals allow cells living in a group to coordinate their behaviors . This cooperation can help all the cells in the group , yet scientists are puzzled about how it could evolve and persist in a population . This is because individual bacteria that essentially cheat and benefit from the cooperation of the rest of the group without contributing their fair share would have a fitness advantage . Now , Majerczyk et al . show that a bacterium called Burkholderia thailandensis , which is commonly found in soil , poisons neighboring freeloaders to prevent such cheating . In the experiments , bacteria with mutations that allow them to ignore the chemical signals that trigger cooperation have an advantage over cooperative bacteria when the two types of bacteria are grown together in a liquid . However , the uncooperative mutants lose their advantage when they are grown on a surface where the cooperative bacteria touch them . To understand why , Majerczyk et al . examined which genes were active in both types of cells in these situations . These experiments showed that chemical signals released by the cooperative bacteria cause them to produce both toxins and proteins that protect against these toxins . This allows the cooperative cells to poison cheaters that they come in contact with , while suffering no ill effects themselves . This allows the cooperative bacteria , via the signaling chemicals , to police cheats and reward only other cooperative bacteria . The next step will be to determine if other types of bacteria also use this policing strategy and to identify more pairs of genes that contribute to protecting the benefits of cooperation .