- Paper report
- Open Access
Quorum sensing in Vibrio cholerae?
- Wim D'Haeze
© BioMed Central Ltd 2002
- Received: 1 April 2002
- Published: 24 May 2002
An investigation of the effects of Vibrio cholerae cell density on virulence
- High Cell Density
- Infection Center
- Mutant Bacterium
Vibrio cholerae is a human pathogen that causes cholera, a severe diarrheal disease in humans. Although virulence is due to the production of a cholera enterotoxin (CT) and a toxin-co-regulated pilus (TCP), required for colonization, there are several environmental factors, whose mode of action are not well understood, that are also important in regulating virulence. It has been proposed that the sensor proteins ToxR and TcpPsense environmental factors that activate a signal transduction pathway, leading to the expression of genes required for CT and TCP production. It has also recently been shown that bacteria monitor their cell densities through the exchange of chemical compounds - auto-inducers - in a process called quorum sensing. The marine bacterium V. harveyi, for instance, has a quorum-sensing system and produces two auto-inducers, AI-1 and AI-2. Analysis of the V. cholerae genome sequence shows that it also carries the genes required for the synthesis of AI-2. Zhu et al. now show that V. cholerae has a V. harveyi-like quorum-sensing system, which is involved in virulence. This study provides useful information about how V. cholerae behaves during its initial infection of humans.
The luxCDABE operon of V. harveyi, responsible for the quorum-sensing-dependent bioluminescence phenotype, was introduced into wild-type V. cholerae, and into strains that contain a mutation in the luxO or hapR genes. These encode negative and positive regulators of the operon, respectively. The results showed that a quorum-sensing circuit is present in V. cholerae. In contrast to V. cholerae hapR mutants, luxO mutants were unable to colonize host tissues - no luxO mutant bacteria could be recovered from the small intestines of treated mice - suggesting a requirement for the quorum-sensing circuit for V. cholerae pathogenicity. Furthermore, many genes were found to be either up- or down-regulated in a luxO mutant as compared to the wild-type strain. This latter group of genes includes the entire ToxR regulon, which is involved in the synthesis of CT and TCP. The LuxO-dependent down-regulation of the virulence regulon was mediated through a down-regulation of the TcpP protein, encoded by tcpP, whose expression required LuxO. LuxO does not, however, regulate tcpP directly, but via the HapR protein. The expression of hapR increases significantly in a luxO mutant, and HapR represses tcpP expression, resulting in downregulation of the ToxR regulon. Interestingly, hapR is expressed at low cell densities in luxO mutants but not in wild-type bacteria, suggesting that HapR acts at an early stage of growth to affect virulence. As well as being involved in the repression of the ToxR regulon, HapR is also required for the production of the HA protease (encoded by hapA) at high cell densities; this protein is considered to be a 'detachase' during colonization, thereby promoting the induction of new infection centers. HA protease production by a luxO mutant started earlier during growth and was increased compared to the wild-type strain, but was severely inhibited in a hapA or a hapR mutant. A motility study showed, in addition, that a luxO mutant was less motile than wild-type bacteria, in agreement with there being altered expression of genes involved in chemotaxis in a luxO mutant.
The Institute of Genomic Research website provides links to the V. cholerae genome database.
Zhu et al. demonstrated that a quorum-sensing system of V. cholerae is involved in the negative regulation of virulence, via cessation of the inhibition of HapR. HapR negatively regulates expression of the ToxR regulon, but stimulates the production of a protease at higher cell densities that is involved in the detachment of V. cholerae cells, thereby promoting the induction of new infection centers.
This study contributes significantly to our understanding of the molecular mechanisms that occur during initial infection by V. cholerae. Identification of the auto-inducers, and finding out how they are synthesized and secreted, might be useful in the search for therapeutics that could block the spread of V. cholerae at the beginning of infection.