I.1. BACTERIA: PATHOGENICITY FACTORS – 49
changing environmental conditions. The notion that bacteria can signal each other and
co-ordinate their assault patterns against susceptible hosts is now well established (Miller
and Bassler, 2001). When invading their host, bacteria do not operate in isolation.
Pathogens employ a series of chemical signals and sensing systems that jointly engage
bacterial communities to genetically respond in concert to specific conditions in the host
and promote an advantageous lifestyle within a given environmental niche. A central
component in this process is a sophisticated communication system known as quorum
sensing (QS) (Ng and Bassler, 2009). QS systems regulate microbial pathogenesis
through the following points: 1) helping pathogens’ invasion and colonisation;
2) regulating production of the virulent factor; 3) giving pathogens the ability of
immunity or drug resistance (Wu and Xie, 2009).
QS was first observed in the marine halophilic bioluminescent bacterium Vibrio
fischeri (Nealson et al., 1970), in which the bacterial light-emitting luciferase operon is
activated when the population reaches a threshold concentration. It was later realised that
QS is achieved through the production, release, and subsequent detection of and response
to threshold concentrations of signal molecules called autoinducers, which are
synthesised throughout the growth of the bacterium. When a threshold concentration is
reached, these signals interact with a transcriptional regulator, allowing the expression of
specific genes (Bassler, 2002).
QS systems were shown to regulate a multitude of transcriptional programmes in
bacteria in vitro and probably in vivo, which are relevant for the pathogenic phenotype.
These include biofilm formation, growth potential, antibiotic resistance expression and
genetic determinants of virulence (Kendall and Sperandio, 2007; Yarwood and
Schlievert, 2003; Mack et al., 2007; Kong, Vuong and Otto, 2006; Costerton et al., 2003;
Bjarnsholt et al., 2010). That QS has a fundamental role in bacterial pathogenesis was
confirmed as researchers began to find that many clinically relevant microbial pathogens
displayed auto-inducer systems homologous to the one discovered in V. fischeri. Many
common bacterial pathogens, including Escherichia coli, Pseudomonas aeruginosa,
Bacteroides, Yersinia, Burkholderia and Enterococcus spp., and many clinically
important staphylococcal and streptococcal pathogens were shown to contain QS genes,
which participate in the regulation of multiple bacterial genes, including virulence genes
(Miller and Bassler, 2001; Greenberg, 2003; Cámara, Williams and Hardman, 2002;
Shiner, Rumbaugh and Williams, 2005; Qazi et al., 2006; Parsek and Greenberg, 2000;
Brady et al., 2008; Williams, 2007).
QS circuits can also regulate human transcriptional programmes to the advantage of
the pathogen. Human stress hormones and cytokines can be detected by bacterial quorum
sensing systems. By this mechanism, the pathogen can detect the physiologically stressed
host, providing an opportunity to invade when the patient is most vulnerable. (Li et al.,
2009).
QS systems are broadly grouped into three categories. The quorum sensing systems
identified in many gram-negative bacteria mostly resemble the typical quorum sensing
circuit of the bioluminescent bacterium V. fischeri (Miller and Bassler, 2001; Smith et al.,
2006) in which they consist, at a minimum, of homologues of the two V. fischeri
regulatory proteins called LuxI and LuxR. The LuxI-like proteins (the auto-inducer
synthases) are responsible for the biosynthesis of a specific acylated homoserine lactone
signaling molecule, termed type 1 autoinducers (AI-1). The autoinducer concentration
increases with increasing cell-population density. The LuxR-like proteins (the
transcription factors) bind cognate AI-1 autoinducers that have achieved a critical