| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Review |
Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Correspondence
T. J. Mitchell
t.mitchell{at}bio.gla.ac.uk
Introduction
Integral to the survival of a bacterium is the ability to sense and respond to its environment. This can have huge significance in infection processes through the regulation of virulence factors, such as Bacillus anthracis spore germination and virulence gene expression in response to phagocytosis by alveolar macrophages (Guidi-Rontani, 2002).
Two-component systems (TCSs), also referred to as two-component signal transduction systems, are recognized as a key mechanism through which bacteria perceive and respond to their environment. Here we discuss the significant advances that have been made in the understanding of TCSs in Streptococcus pneumoniae (the pneumococcus), in particular with regards to the role of these systems in the virulence of this important human pathogen.
The pneumococcus
With the exception of atypical equine isolates (Whatmore et al., 1999), S. pneumoniae is normally found as a harmless commensal of the human upper respiratory tract. However, depending on host and bacterial factors that are not fully understood, the pneumococcus is also a major cause of diseases such as pneumonia, meningitis, septicaemia, bronchitis and otitis media. An illustration of its significance as a pathogen comes from the estimate that S. pneumoniae causes the death of 1 million young children per year in developing countries (Mulholland, 1997). Its impact, however, is also significant in the developed world; for example, in the USA the pneumococcus is responsible for 50 000 cases of pneumonia, 3000 cases of meningitis and 7 million cases of otitis media annually (Obaro, 2000). Furthermore, inadequate diagnosis, especially in the developing world, is suspected to underestimate the true burden imposed by pneumococcal disease. Current vaccines based on the pneumococcal polysaccharide capsule have significant disadvantages (Bogaert et al., 2004). In the case of purified polysaccharides, these are poorly immunogenic in children under 2 years old, an age group that suffers a high incidence of pneumococcal disease. Conjugate vaccines with purified capsular polysaccharide conjugated to a protein carrier resolve this problem. However, conjugate vaccines are beset by high production costs and limited coverage of pneumococcal serotypes, of which 90 are known. Adding to concerns over pneumococcal disease is the increase and spread of antibiotic resistance (Tan, 2003). Renewed efforts are now being made to understand the pathogenesis of pneumococcal disease with TCSs receiving much attention of late.
Bacterial TCSs
Bacterial adaptation to external stimuli is often mediated by systems known as two-component systems or two-component signal transduction systems (Hoch, 2000; Stock et al., 2000). The basic model TCS (Fig. 1
) is composed of two proteins: a membrane-associated sensor histidine kinase (HK) and a cytoplasmic cognate response regulator (RR). Upon receipt of a specific external stimulus the kinase domain of the HK sensor protein is activated to autophosphorylate a conserved histidine residue. HK proteins tend to be found as homodimers that operate in trans with the kinase domain of one catalysing phosphorylation of the second (Dutta et al., 1999). This phosphate group is then transferred by the HK to a conserved aspartate residue in its cognate RR. In turn, the RR undergoes a conformational change allowing it to regulate gene expression or protein function. In most cases this is through the activity of the RR as a DNA-binding transcriptional regulator. Such histidine-phosphorelay systems are widespread among bacteria and have been shown to modulate a variety of cellular responses including osmoregulation, chemotaxis, sporulation, photosynthesis and pathogenicity (Hoch, 2000; Stock et al., 2000). Some systems are essential for bacterial viability (Fabret & Hoch, 1998; Lange et al., 1999; Martin et al., 1999; Throup et al., 2000) and because TCSs are absent in vertebrates they have received attention as potential targets for antimicrobials (Barrett & Hoch, 1998).
|
These investigations provided the foundation for analysis of these systems in pneumococcal biology. The better-studied pneumococcal TCSs with regards to virulence are discussed here, with Table 1 providing a summary of all known pneumococcal TCSs and their contribution to virulence.
|
Further supporting its role as a pneumococcal virulence factor, rr09 was identified in the signature-tagged mutagenesis (STM) screen of the sequenced strain TIGR4 (Hava & Camilli, 2002). Additional investigation by these workers showed that in TIGR4, rr09 contributed to virulence in pneumonia but not to bacteraemia. This result is similar to that seen with strain 0100993 and again shows that the importance of genes to virulence varies with the site of infection.
RR09 (and presumably TCS09) therefore has the potential to contribute significantly to pneumococcal virulence but this contribution varies between pneumococcal strains and infection sites. The genes regulated by this system and the reason for these strain- and site-specific effects are yet to be characterized. Interestingly, a second pneumococcal RR, RR04, also has strain-specific effects on virulence, the basis of which is beginning to be elucidated (see below).
TCS04 TCS04 was first identified as a pneumococcal virulence factor by Throup et al. (2000), where they demonstrated that a 0100993 mutant in rr04 was attenuated during murine pneumonia. This was expanded upon by the work of McCluskey et al. (2004) with the comparison of rr04 mutants in three different strains, TIGR4, D39 and 0100993, using a similar pneumonia model. Only the TIGR4 rr04 mutant was attenuated relative to its parental wild-type in this second study thereby expanding the finding of a strain-specific effect in virulence for rr09 to include rr04 also. Microarray analysis of the transcriptome of these mutants was used to investigate the genes regulated by RR04 and the reason for the strain-specific effects on virulence. The strains showed considerable variation with regard to the genes regulated by RR04. In particular, the psa operon encoding a manganese ABC transporter system was down-regulated in the TIGR4 rr04 mutant but not in D39 and 0100993 mutants. This operon, consisting of psaB, C and A, is known to contribute to pneumococcal virulence and resistance to oxidative stress (McAllister et al., 2004). Based on those data, the down-regulation of this operon in TIGR4 was postulated to contribute, at least in part, to the specific attenuation of this strain. Indeed, in agreement with reduced psaBCA expression the TIGR4 rr04 mutant was hypersensitive to killing by hydrogen peroxide (McCluskey et al., 2004). The reason for these strain-specific differences in rr04-dependent transcription have yet to be elucidated but RR04 itself is highly conserved.
Interestingly, the results of McCluskey et al. (2004) using the 0100993 rr04 mutant differ from the findings of Throup et al. (2000) using the same mutant and parent strain. Whereas the former found no attenuation in a pneumonia model based on survival and blood and lung counts, Throup et al. (2000) showed a significant reduction in lung counts for the mutant compared with wild-type (106-fold reduction). The cause of this discrepancy is not known but may be caused by the use of different infection models, in particular the use of different mouse strains, adding further to the complexity of studying these systems.
Inter-strain variation, TCSs and virulence
The strain-to-strain variation in the role of rr09 and rr04 in virulence is a feature repeated in several pneumococcal virulence factor studies (Blue & Mitchell, 2003; Chapuy-Regaud et al., 2003; McCluskey et al., 2004; Orihuela et al., 2004; Paterson & Mitchell, 2006). Such variation is perhaps to be expected given the diversity of the pneumococcus as a bacterial species. For example, microarray examination of genome content showed that 8–10 % of genes are divergent/absent in any one clinical strain relative to the reference strain TIGR4 with the pool of variable genes making up 
20 % of the TIGR4 genome (Hakenbeck et al., 2001). Actual genomic diversity will likely be much greater, given this analysis would miss test strain-specific genes. Thus conflicting results with different strains likely reflect the diversity in natural pneumococcal populations. The growing data on strain variation and strain-specific effects show clearly the complexity of this bacterium and argue strongly for the analysis of multiple strains in future investigations. Likewise, the data highlight the dangers of extrapolation of results from one strain to another and the over-reliance on any single ‘reference’ or ‘model’ strain.
TCS12 competence and virulence
The pneumococcus is naturally competent, a well-studied phenomenon contributing to its genetic diversity (Claverys & Havarstein, 2002). It is through TCS12 that competence is activated (Fig. 2). TCS12 consists of the HK encoded by comD and the RR encoded by comE, which together respond to competence stimulating peptide, CSP, the product of comC, secreted via the ComA/B ABC transporter. TCS12 mutants were not tested in the pneumonia model of Throup et al. (2000). However, a clear link between competence and virulence was demonstrated with the finding that a comD (hk12) mutant in D39 was attenuated in models of both pneumonia and bacteraemia (Bartilson et al., 2001). This link was further supported by the serotype 3 STM of Lau et al. (2001), where ComB, the ATP-binding protein in the ComAB CSP transporter, was identified as a virulence factor in a bacteraemia model. However, it cannot be ruled out that ComAB transports additional substrates responsible for this effect. Further investigation showed comD (hk12) to contribute to pneumonia and bacteraemia models in competitive infections with wild-type (Lau et al., 2001). Additionally, comD was identified as a virulence factor in pneumonia by the TIGR4 STM screen (Hava & Camilli, 2002). How competence is tied to virulence is not yet fully clear. The most comprehensive analysis of the effect of competence on gene expression comes from the use of microarray expression analysis following exposure to CSP (Dagkessamanskaia et al., 2004; Peterson et al., 2004). Together these groups identified a repertoire of 240 CSP-responsive genes. The power of microarray technology is clearly demonstrated given that prior to these studies only 40 CSP-responsive genes were known. CSP-responsive genes represented 7–8 % of the genome, illustrating the considerable global impact of competence on the cell. Of the responsive genes identified by Peterson et al. (2004), the majority were shown to be dispensable for transformation. Therefore competence has the ability to affect a large number of genes, many of which are apparently unrelated to transformation. With regards to the link between competence and virulence, 18 of the 124 (14·5 %) up-regulated genes seen by Peterson et al. (2004) were identified in the TIGR4 STM screen as virulence factors, thereby providing a mechanistic explanation for the role of competence in virulence (Hava & Camilli, 2002). These up-regulated virulence factors included the autolysin lytA, htrA, a stress response protein and a choline-binding protein gene (cbpD).
|
Adding further to the complexity of competence and pneumococcal TCSs is the involvement of TCS02 and the TCS05, which act to repress competence development (Echenique et al., 2000; Echenique & Trombe, 2001).
TCS02 RR02 is notable as being the only RR essential for pneumococcal viability (Lange et al., 1999; Throup et al., 2000). In agreement with this, TCS02 shows homology to the essential YycFG TCS of Bacillus subtilis and Staphylococcus aureus (Fabret & Hoch, 1998; Martin et al., 1999). A difference of note, however, is that in these latter two systems, both the rr and hk are essential; in the case of the pneumococcus this appears true only for the rr gene. Presumably, the essential function of RR02 is phosphorylation-independent or possibly RR02 may be phosphorylated from an alternative donor in the absence of HK02 (Throup et al., 2000). Recent work shows that TCS02 contributes to the regulation of cell wall and fatty acid biosynthesis as well as expression of the virulence factor pspA (Mohedano et al., 2005; Ng et al., 2003, 2005). The essential status of rr02 can be suppressed by overexpression of the murein-hydrolase-encoding gene pcsB, showing that control of this gene is a key function of TCS02 (Ng et al., 2003, 2004).
Overexpression and deletion of various components of the TCS02 operon, which includes a third ORF of unknown function, caused attenuated virulence in intraperitoneal infections (Wagner et al., 2002). The finding that overexpression mutants had reduced virulence shows that controlled expression of TCS02, and presumably other TCSs, is vital to virulence. Furthermore, hk02 mutants in two different strains showed attenuation in a pneumonia model (Kadioglu et al., 2003). This latter work is in conflict with the findings of Throup et al. (2000), where a hk02 knockout in 0100993 was not attenuated. The reason for this is unclear but may relate to strain and experimental differences.
TCS05/CiaRH TCS05 or the CiaRH system was the first pneumococcal TCS identified (Guenzi et al., 1994). The influences of this TCS on pneumococcal biology are diverse and complex, affecting virulence, competence and antibiotic resistance (Guenzi et al., 1994; Guenzi & Hakenbeck, 1995; Ibrahim et al., 2004a; Throup et al., 2000; Zahner et al., 2002). In addition, analysis of cells undergoing transformation suggests that CiaRH is important in protecting cells from the stress of competence development (Dagkessamanskaia et al., 2004). In the absence of ciaR, cultures showed enhanced autolysis in response to competence induction. A role in virulence through the use of knockout mutants has been demonstrated by several groups (Ibrahim et al., 2004a; Marra et al., 2002; Throup et al., 2000). Investigation of the CiaRH regulon identified the major virulence factor htrA as being down-regulated in ciaRH mutants (Ibrahim et al., 2004a; Mascher et al., 2003; Sebert et al., 2002). Restoration of htrA expression in a ciaRH mutant restores the virulence defect of the TCS mutant, showing that up-regulation of htrA is a key component in the contribution of CiaRH to virulence (Ibrahim et al., 2004a). The exact role of htrA, a stress response serine protease, in virulence is unclear (Hava & Camilli, 2002; Ibrahim et al., 2004b). It should be noted, however, that several other known and putative virulence factors were regulated or potentially regulated by CiaRH and these too may contribute significantly to the role of CiaRH in virulence (Sebert et al., 2002; Mascher et al., 2003). These include the dlt and pit2/pia operons. Evidence suggests that the pneumococcal response to oxygen and calcium ions involves CiaRH (Echenique & Trombe, 2001; Giammarinaro et al., 1999).
TCS13 TCS13 was identified as contributing to pneumococcal virulence in the TCS identification and characterization work of Throup et al. (2000). They found that a rr13 mutant was significantly attenuated in their respiratory tract infection model with bacterial lung counts reduced by about 10 000-fold compared with wild-type 0100993. This system was subsequently named blp TCS for bacteriocin-like peptide when it was found by microarray expression analysis to control a 16-gene quorum-sensing regulon controlling the synthesis and export of bacteriocin-like peptides and immunity proteins (de Saizieu et al., 2000). The system is paralogous to the competence system (TCS12) with the small peptide BlpC signalling via Blp TCS to up-regulate target genes including blpC itself. Further confirmation of a role in virulence for this system came from the TIGR4 STM screen, where blpA, purportedly involved in BlpC export, was identified as a virulence factor (Hava & Camilli, 2002). Interestingly, several strains, including the commonly studied strains TIGR4, R6 and D39, contain a reading frame shift mutation in the blpA gene resulting in premature termination of translation. Not all strains have this feature and its significance is as yet unclear (de Saizieu et al., 2000). Bacteriocins are bacterial products that kill or inhibit the growth of related strains or species, with immunity proteins protecting the producing organism. Although poorly characterized as yet, pneumococcal bacteriocin activity has been described previously and presumably provides a growth advantage in the microbial rich nasopharynx (Mindich, 1966). However, the bacteriocin activity of blp products and a role in colonization remains unstudied. Interestingly, given that the lung is sterile, the function of bacteriocins in virulence at this site presumably does not involve killing competing microbes at this site. Rather, it is proposed that blp bacteriocins may be acting via a cytotoxic affect on host cells (de Saizieu et al., 2000).
RR489/RitR, the orphan response regulator Unlike the other pneumococcal TCSs, rr489 is not located in the genome next to a cognate hk. It appears, however, to have a key role in virulence given that a knockout mutant showed a >104 reduction in pulmonary bacterial counts compared with wild-type in a murine pneumonia model (Throup et al., 2000). This contribution to virulence was confirmed by Ulijasz et al. (2004) and furthermore found to be tissue-specific whereby a mutant was attenuated for growth in the lung but not in the thigh following infection of these organs. The mechanism for this appears to be due, at least in part, to repression by RitR of the piu iron uptake system (Ulijasz et al., 2004); hence the renaming of rr489 as ritR (regulator of iron transport). This repression appeared to be a direct effect of RitR given it was shown to bind the piu promoter. While iron is essential for the growth of most bacteria it can also be deleterious through the Fenton reaction, where it catalyses the synthesis of reactive oxygen intermediates from hydrogen peroxide. It is therefore essential to regulate its levels. RitR appears to be one such system for the regulation of iron in the pneumococcus. In line with increased iron uptake in the absence of ritR, a ritR mutant was more sensitive to iron-dependent killing by streptonigrin. Resistance to oxidative stress was also altered, with the mutant showing increased susceptibility to hydrogen peroxide killing and this likely contributes to decreased virulence. While increased iron overload may itself contribute to this sensitivity, the ritR mutant also showed reduced expression of various genes implicated in resistance to oxidative stress. Presumably the importance of ritR varies with different sites of infection based on the levels of iron and/or oxidative stress. How RitR operates in the absence of a cognate HK remains unclear. Indeed the mechanism(s) by which the pneumococcus senses iron is unknown. Interestingly, even although RitA contains the conserved aspartate residue which is phosphorylated in other RRs, various phosphate donors did not alter RitR binding to the piu promoter, hinting at a possible phosphorylation-independent regulation (Ulijasz et al., 2004).
Other pneumococcal TCSs and virulence
The remaining TCSs are relatively poorly characterized although most have been shown to contribute to virulence (Table 1
). TCS10 has been implicated in tolerance to the antibiotic vancomycin, a finding now considered controversial (Haas et al., 2004; Robertson et al., 2002), while TCS06 has recently been shown to regulate the important virulence factor cbpA (Standish et al., 2005).
As yet only TCS03, 10 and 11 have not been associated with virulence in at least one study. In the pneumonia model of Throup et al. (2000) where most systems were examined, no attenuation was seen with mutants in tsc03 and rr11 while a rr10 mutant showed only a trend towards mild attenuation that was not significant. However, Hava & Camilli (2002) speculate that the attenuation of STM strain STM237 may be due to polar effects on adjacent tcs11. TCS03 and 11 have recently been implicated in the pneumococcal stress response to antibiotic treatment (Haas et al., 2005).
Pneumococcal TCSs as antimicrobial targets
The role of TCSs in the viability and virulence of a number of pathogenic bacteria, coupled with their absence in mammals, make them potential targets for novel antimicrobial drugs (Barrett & Hoch, 1998). In particular, pneumococcal RR02 being essential for viability makes it a potentially attractive target. Its biochemical characterization in vitro and structural studies may pave the way for rational drug design against this target (Bent et al., 2003, 2004; Clausen et al., 2003; Echenique & Trombe, 2001; Riboldi-Tunnicliffe et al., 2004; Wagner et al., 2002). However, a TCS need not be essential for viability to be a useful target. Inhibition of those with a major role in virulence may also prove beneficial. However, strain- and infection-type-specific roles in virulence as described for rr04 and rr09 may limit the value of specific targeting of such systems in the pneumococcus.
Gene regulation in vivo
An important challenge in understanding genetic regulation by TCSs is to characterize and understand this in the context of in vivo infection. Knowledge of gene regulation in vivo offers insight into bacterial adaptation to the host environment, greatly enhancing basic understanding of the infection process, and is something that cannot be fully gained by in vitro studies alone. This significant advantage is, however, beset by the technical difficulties of recovering sufficient quantities of bacterial RNA of adequate quality from infected tissues. Several studies have shown that the expression of key pneumococcal virulence factors is up-regulated in vivo (Ogunniyi et al., 2002; Orihuela et al., 2000, 2001). For example, pspC mRNA has recently been shown to be up-regulated a massive 870-fold in vivo compared to growth in vitro (Quin et al., 2005). However, such studies are limited by focusing on only a small subset of genes.
A more comprehensive investigation of the pneumococcus response to growth in vivo came following the development of differential fluorescence induction (DFI). First employed on Salmonella typhimurium, DFI allows the identification of promoters activated in response to a particular environment (Valdivia & Falkow, 1996). It works through the cloning of random genome fragments upstream of promoterless green fluorescence protein and screening and sorting by flow cytometry to identify and isolate clones with up-regulated promoter activity following exposure to a specific environment, for example in vivo. The cloned DNA is then sequenced to identify the responsive promoter and ORF. DFI has the advantages of circumventing the requirement for recovering bacterial RNA and makes it easier to simultaneously examine many promoters. Using three infection models and five in vitro cultures mimicking various in vivo conditions a total of 73 in vivo responsive promoters were identified in strain D39 (Marra et al., 2002). However, the fullest examination of pneumococcal transcription in the host has come through the use of microarrays, comparing the transcriptional profile of bacteria recovered from mouse blood, rabbit cerebral spinal fluid or after adherence to human epithelia cells in vitro with that of control cultures (Orihuela et al., 2004). A distinct profile was seen for each ‘infection’ type showing a site-specific transcriptional response. Expression differences between the different infections show that the pneumococcus is responding not just to being in the host but also to specific in vivo environments. This is relevant to human infections with the pneumococcus able to cause infections at different sites such as during pneumonia, otitis media, meningitis and bacteraemia. Presumably these expression differences correspond to exposure to different conditions and stresses and reflect different adaptive strategies to survive in these conditions. While this study is not without important limitations it provides insight into the gene expression changes occurring in vivo and provides a foundation to understand how the pneumococcus responds to the host environment. The challenges ahead include identification of the stimuli, the pathways involved and understanding the biological significance of these transcriptional changes.
Conclusion/summary
Pneumococcal TCSs are important virulence factors of this significant human pathogen. Interestingly, their contribution to virulence can vary depending on pneumococcal strain and infection site. The reasons for this are largely unclear as yet. Microarray analysis is allowing insights into the genes regulated by these systems but important challenges remaining include understanding gene regulation in vivo, understanding of how TCSs interact with each other and investigation of their potential as novel antimicrobial targets.
ACKNOWLEDGEMENTS
Work in the T. J. M. laboratory is supported by The Wellcome Trust, MRC, BBRSC, the Egyptian government and the European Union. Sincere apologies to authors whose work could not be discussed or covered in full detail due to limitations on space.
REFERENCES
Barrett, J. F. & Hoch, J. A. (1998). Two-component signal transduction as a target for microbial anti-infective therapy. Antimicrob Agents Chemother 42, 1529–1536.
Bartilson, M., Marra, A., Christine, J., Asundi, J. S., Schneider, W. P. & Hromockyj, A. E. (2001). Differential fluorescence induction reveals Streptococcus pneumoniae loci regulated by competence stimulatory peptide. Mol Microbiol 39, 126–135.[CrossRef][Medline]
Bent, C. J., Isaacs, N. W., Mitchell, T. J. & Riboldi-Tunnicliffe, A. (2003). Cloning, overexpression, purification, crystallization and preliminary diffraction analysis of the receiver domain of MicA. Acta Crystallogr D Biol Crystallogr 59, 758–760.[CrossRef][Medline]
Bent, C. J., Isaacs, N. W., Mitchell, T. J. & Riboldi-Tunnicliffe, A. (2004). Crystal structure of the response regulator 02 receiver domain, the essential YycF two-component system of Streptococcus pneumoniae in both complexed and native states. J Bacteriol 186, 2872–2879.
Blue, C. E. & Mitchell, T. J. (2003). Contribution of a response regulator to the virulence of Streptococcus pneumoniae is strain dependent. Infect Immun 71, 4405–4413.
Bogaert, D., Hermans, P. W., Adrian, P. V., Rumke, H. C. & de Groot, R. (2004). Pneumococcal vaccines: an update on current strategies. Vaccine 22, 2209–2220.[CrossRef][Medline]
Chapuy-Regaud, S., Ogunniyi, A. D., Diallo, N., Huet, Y., Desnottes, J. F., Paton, J. C., Escaich, S. & Trombe, M. C. (2003). RegR, a global LacI/GalR family regulator, modulates virulence and competence in Streptococcus pneumoniae. Infect Immun 71, 2615–2625.
Clausen, V. A., Bae, W., Throup, J., Burnham, M. K., Rosenberg, M. & Wallis, N. G. (2003). Biochemical characterization of the first essential two-component signal transduction system from Staphylococcus aureus and Streptococcus pneumoniae. J Mol Microbiol Biotechnol 5, 252–260.[CrossRef][Medline]
Claverys, J. P. & Havarstein, L. S. (2002). Extracellular-peptide control of competence for genetic transformation in Streptococcus pneumoniae. Front Biosci 7, d1798–1814.[Medline]
Dagkessamanskaia, A., Moscoso, M., Henard, V., Guiral, S., Overweg, K., Reuter, M., Martin, B., Wells, J. & Claverys, J. P. (2004). Interconnection of competence, stress and CiaR regulons in Streptococcus pneumoniae: competence triggers stationary phase autolysis of ciaR mutant cells. Mol Microbiol 51, 1071–1086.[CrossRef][Medline]
de Saizieu, A., Gardes, C., Flint, N., Wagner, C., Kamber, M., Mitchell, T. J., Keck, W., Amrein, K. E. & Lange, R. (2000). Microarray-based identification of a novel Streptococcus pneumoniae regulon controlled by an autoinduced peptide. J Bacteriol 182, 4696–4703.
Dutta, R., Qin, L. & Inouye, M. (1999). Histidine kinases: diversity of domain organization. Mol Microbiol 34, 633–640.[CrossRef][Medline]
Echenique, J. R. & Trombe, M. C. (2001). Competence repression under oxygen limitation through the two-component MicAB signal-transducing system in Streptococcus pneumoniae and involvement of the PAS domain of MicB. J Bacteriol 183, 4599–4608.
Echenique, J. R., Chapuy-Regaud, S. & Trombe, M. C. (2000). Competence regulation by oxygen in Streptococcus pneumoniae: involvement of ciaRH and comCDE. Mol Microbiol 36, 688–696.[CrossRef][Medline]
Fabret, C. & Hoch, J. A. (1998). A two-component signal transduction system essential for growth of Bacillus subtilis: implications for anti-infective therapy. J Bacteriol 180, 6375–6383.
Giammarinaro, P., Sicard, M. & Gasc, A. M. (1999). Genetic and physiological studies of the CiaH-CiaR two-component signal-transducing system involved in cefotaxime resistance and competence of Streptococcus pneumoniae. Microbiology 145, 1859–1869.[Abstract]
Guenzi, E. & Hakenbeck, R. (1995). Genetic competence and susceptibility to beta-lactam antibiotics in Streptococcus pneumoniae R6 are linked via a two-component signal-transducing system cia. Dev Biol Stand 85, 125–128.[Medline]
Guenzi, E., Gasc, A. M., Sicard, M. A. & Hakenbeck, R. (1994). A two-component signal-transducing system is involved in competence and penicillin susceptibility in laboratory mutants of Streptococcus pneumoniae. Mol Microbiol 12, 505–515.[Medline]
Guidi-Rontani, C. (2002). The alveolar macrophage: the Trojan horse of Bacillus anthracis. Trends Microbiol 10, 405–409.[CrossRef][Medline]
Haas, W., Sublett, J., Kaushal, D. & Tuomanen, E. I. (2004). Revising the role of the pneumococcal vex-vncRS locus in vancomycin tolerance. J Bacteriol 186, 8463–8471.
Haas, W., Kaushal, D., Sublett, J., Obert, C. & Tuomanen, E. I. (2005). Vancomycin stress response in a sensitive and a tolerant strain of Streptococcus pneumoniae. J Bacteriol 187, 8205–8210.
Hakenbeck, R., Balmelle, N., Weber, B., Gardes, C., Keck, W. & de Saizieu, A. (2001). Mosaic genes and mosaic chromosomes: intra- and interspecies genomic variation of Streptococcus pneumoniae. Infect Immun 69, 2477–2486.
Hava, D. L. & Camilli, A. (2002). Large-scale identification of serotype 4 Streptococcus pneumoniae virulence factors. Mol Microbiol 45, 1389–1406.[Medline]
Hoch, J. A. (2000). Two-component and phosphorelay signal transduction. Curr Opin Microbiol 3, 165–170.[CrossRef][Medline]
Ibrahim, Y. M., Kerr, A. R., McCluskey, J. & Mitchell, T. J. (2004a). Control of virulence by the two-component system CiaR/H is mediated via HtrA, a major virulence factor of Streptococcus pneumoniae. J Bacteriol 186, 5258–5266.
Ibrahim, Y. M., Kerr, A. R., McCluskey, J. & Mitchell, T. J. (2004b). Role of HtrA in the virulence and competence of Streptococcus pneumoniae. Infect Immun 72, 3584–3591.
Kadioglu, A., Echenique, J., Manco, S., Trombe, M.-C. & Andrew, P. W. (2003). The MicAB two-component signaling system is involved in virulence of Streptococcus pneumoniae. Infect Immun 71, 6676–6679.
Lange, R., Wagner, C., de Saizieu, A. & 7 other authors (1999). Domain organization and molecular characterization of 13 two-component systems identified by genome sequencing of Streptococcus pneumoniae. Gene 237, 223–234.[CrossRef][Medline]
Lau, G. W., Haataja, S., Lonetto, M., Kensit, S. E., Marra, A., Bryant, A. P., McDevitt, D., Morrison, D. A. & Holden, D. W. (2001). A functional genomic analysis of type 3 Streptococcus pneumoniae virulence. Mol Microbiol 40, 555–571.[CrossRef][Medline]
Luo, P. & Morrison, D. A. (2003). Transient association of an alternative sigma factor, ComX, with RNA polymerase during the period of competence for genetic transformation in Streptococcus pneumoniae. J Bacteriol 185, 349–358.
Luo, P., Li, H. & Morrison, D. A. (2003). ComX is a unique link between multiple quorum sensing outputs and competence in Streptococcus pneumoniae. Mol Microbiol 50, 623–633.[CrossRef][Medline]
Luo, P., Li, H. & Morrison, D. A. (2004). Identification of ComW as a new component in the regulation of genetic transformation in Streptococcus pneumoniae. Mol Microbiol 54, 172–183.[CrossRef][Medline]
Marra, A., Asundi, J., Bartilson, M. & 7 other authors (2002). Differential fluorescence induction analysis of Streptococcus pneumoniae identifies genes involved in pathogenesis. Infect Immun 70, 1422–1433.
Martin, P. K., Li, T., Sun, D., Biek, D. P. & Schmid, M. B. (1999). Role in cell permeability of an essential two-component system in Staphylococcus aureus. J Bacteriol 181, 3666–3673.
Mascher, T., Zahner, D., Merai, M., Balmelle, N., de Saizieu, A. B. & Hakenbeck, R. (2003). The Streptococcus pneumoniae cia regulon: CiaR target sites and transcription profile analysis. J Bacteriol 185, 60–70.
McAllister, L. J., Tseng, H. J., Ogunniyi, A. D., Jennings, M. P., McEwan, A. G. & Paton, J. C. (2004). Molecular analysis of the psa permease complex of Streptococcus pneumoniae. Mol Microbiol 53, 889–901.[CrossRef][Medline]
McCluskey, J., Hinds, J., Husain, S., Witney, A. & Mitchell, T. J. (2004). A two-component system that controls the expression of pneumococcal surface antigen A (PsaA) and regulates virulence and resistance to oxidative stress in Streptococcus pneumoniae. Mol Microbiol 51, 1661–1675.[CrossRef][Medline]
Mindich, L. (1966). Bacteriocins of Diplococcus pneumoniae. I. Antagonistic relationships and genetic transformations. J Bacteriol 92, 1090–1098.
Mohedano, M. L., Overweg, K., de la Fuente, A., Reuter, M., Altabe, S., Mulholland, F., de Mendoza, D., Lopez, P. & Wells, J. M. (2005). Evidence that the essential response regulator YycF in Streptococcus pneumoniae modulates expression of fatty acid biosynthesis genes and alters membrane composition. J Bacteriol 187, 2357–2367.
Mulholland, K. A. (1997). A Report Prepared for the Scientific Advisory Group of Experts, Global Programme for Vaccines and Immunization, World Health Organization, 1997.
Ng, W. L., Robertson, G. T., Kazmierczak, K. M., Zhao, J., Gilmour, R. & Winkler, M. E. (2003). Constitutive expression of PcsB suppresses the requirement for the essential VicR (YycF) response regulator in Streptococcus pneumoniae R6. Mol Microbiol 50, 1647–1663.[CrossRef][Medline]
Ng, W. L., Kazmierczak, K. M. & Winkler, M. E. (2004). Defective cell wall synthesis in Streptococcus pneumoniae R6 depleted for the essential PcsB putative murein hydrolase or the VicR (YycF) response regulator. Mol Microbiol 53, 1161–1175.[CrossRef][Medline]
Ng, W. L., Tsui, H. C. & Winkler, M. E. (2005). Regulation of the pspA virulence factor and essential pcsB murein biosynthetic genes by the phosphorylated VicR (YycF) response regulator in Streptococcus pneumoniae. J Bacteriol 187, 7444–7459.
Novak, R., Cauwels, A., Charpentier, E. & Tuomanen, E. (1999a). Identification of a Streptococcus pneumoniae gene locus encoding proteins of an ABC phosphate transporter and a two-component regulatory system. J Bacteriol 181, 1126–1133.
Novak, R., Henriques, B., Charpentier, E., Normark, S. & Tuomanen, E. (1999b). Emergence of vancomycin tolerance in Streptococcus pneumoniae. Nature 399, 590–593.[CrossRef][Medline]
Obaro, S. K. (2000). Confronting the pneumococcus: a target shift or bullet change? Vaccine 19, 1211–1217.[CrossRef][Medline]
Ogunniyi, A. D., Giammarinaro, P. & Paton, J. C. (2002). The genes encoding virulence-associated proteins and the capsule of Streptococcus pneumoniae are upregulated and differentially expressed in vivo. Microbiology 148, 2045–2053.
Orihuela, C. J., Janssen, R., Robb, C. W., Watson, D. A. & Niesel, D. W. (2000). Peritoneal culture alters Streptococcus pneumoniae protein profiles and virulence properties. Infect Immun 68, 6082–6086.
Orihuela, C. J., Mills, J., Robb, C. W., Wilson, C. J., Watson, D. A. & Niesel, D. W. (2001). Streptococcus pneumoniae PstS production is phosphate responsive and enhanced during growth in the murine peritoneal cavity. Infect Immun 69, 7565–7571.
Orihuela, C. J., Radin, J. N., Sublett, J. E., Gao, G., Kaushal, D. & Tuomanen, E. I. (2004). Microarray analysis of pneumococcal gene expression during invasive disease. Infect Immun 72, 5582–5596.
Paterson, G. K. & Mitchell, T. J. (2006). The role of Streptococcus pneumoniae sortase A in colonisation and pathogenesis. Microbes Infect 8, 145–153.[CrossRef][Medline]
Pestova, E. V., Havarstein, L. S. & Morrison, D. A. (1996). Regulation of competence for genetic transformation in Streptococcus pneumoniae by an auto-induced peptide pheromone and a two-component regulatory system. Mol Microbiol 21, 853–862.[CrossRef][Medline]
Peterson, S. N., Sung, C. K., Cline, R. & 13 other authors (2004). Identification of competence pheromone responsive genes in Streptococcus pneumoniae by use of DNA microarrays. Mol Microbiol 51, 1051–1070.[CrossRef][Medline]
Quin, L. R., Carmicle, S., Dave, S., Pangburn, M. K., Evenhuis, J. P. & McDaniel, L. S. (2005). In vivo binding of complement regulator factor H by Streptococcus pneumoniae. J Infect Dis 192, 1996–2003.[CrossRef][Medline]
Riboldi-Tunnicliffe, A., Trombe, M. C., Bent, C. J., Isaacs, N. W. & Mitchell, T. J. (2004). Crystallization and preliminary crystallographic studies of the D59A mutant of MicA, a YycF response-regulator homologue from Streptococcus pneumoniae. Acta Crystallogr D Biol Crystallogr 60, 950–951.[CrossRef][Medline]
Robertson, G. T., Zhao, J., Desai, B. V., Coleman, W. H., Nicas, T. I., Gilmour, R., Grinius, L., Morrison, D. A. & Winkler, M. E. (2002). Vancomycin tolerance induced by erythromycin but not by loss of vncRS, vex3, or pep27 function in Streptococcus pneumoniae. J Bacteriol 184, 6987–7000.
Sebert, M. E., Palmer, L. M., Rosenberg, M. & Weiser, J. N. (2002). Microarray-based identification of htrA, a Streptococcus pneumoniae gene that is regulated by the CiaRH two-component system and contributes to nasopharyngeal colonization. Infect Immun 70, 4059–4067.
Standish, A. J., Stroeher, U. H. & Paton, J. C. (2005). The two-component signal transduction system RR06/HK06 regulates expression of cbpA in Streptococcus pneumoniae. Proc Natl Acad Sci U S A 102, 7701–7706.
Stock, A. M., Robinson, V. L. & Goudreau, P. N. (2000). Two-component signal transduction. Annu Rev Biochem 69, 183–215.[CrossRef][Medline]
Sung, C. K. & Morrison, D. A. (2005). Two distinct functions of ComW in stabilization and activation of the alternative sigma factor ComX in Streptococcus pneumoniae. J Bacteriol 187, 3052–3061.
Tan, T. Q. (2003). Antibiotic resistant infections due to Streptococcus pneumoniae: impact on therapeutic options and clinical outcome. Curr Opin Infect Dis 16, 271–277.[Medline]
Throup, J. P., Koretke, K. K., Bryant, A. P. & 9 other authors (2000). A genomic analysis of two-component signal transduction in Streptococcus pneumoniae. Mol Microbiol 35, 566–576.[CrossRef][Medline]
Ulijasz, A. T., Andes, D. R., Glasner, J. D. & Weisblum, B. (2004). Regulation of iron transport in Streptococcus pneumoniae by RitR, an orphan response regulator. J Bacteriol 186, 8123–8136.
Valdivia, R. H. & Falkow, S. (1996). Bacterial genetics by flow cytometry: rapid isolation of Salmonella typhimurium acid-inducible promoters by differential fluorescence induction. Mol Microbiol 22, 367–378.[CrossRef][Medline]
Wagner, C., Saizieu Ad, A., Schonfeld, H. J., Kamber, M., Lange, R., Thompson, C. J. & Page, M. G. (2002). Genetic analysis and functional characterization of the Streptococcus pneumoniae vic operon. Infect Immun 70, 6121–6128.
Whatmore, A. M., King, S. J., Doherty, N. C., Sturgeon, D., Chanter, N. & Dowson, C. G. (1999). Molecular characterization of equine isolates of Streptococcus pneumoniae: natural disruption of genes encoding the virulence factors pneumolysin and autolysin. Infect Immun 67, 2776–2782.
Zahner, D., Kaminski, K., van der Linden, M., Mascher, T., Meral, M. & Hakenbeck, R. (2002). The ciaR/ciaH regulatory network of Streptococcus pneumoniae. J Mol Microbiol Biotechnol 4, 211–216.[Medline]
This article has been cited by other articles:
|
|
 |
|
  J. R. Frederick, E. A. Rogers, and R. T. Marconi Analysis of a Growth-Phase-Regulated Two-Component Regulatory System in the Periodontal Pathogen Treponema denticola J. Bacteriol., September 15, 2008; 190(18): 6162 - 6169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Rosch, B. Mann, J. Thornton, J. Sublett, and E. Tuomanen Convergence of Regulatory Networks on the Pilus Locus of Streptococcus pneumoniae Infect. Immun., July 1, 2008; 76(7): 3187 - 3196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Ma and J.-R. Zhang RR06 Activates Transcription of spr1996 and cbpA in Streptococcus pneumoniae J. Bacteriol., March 15, 2007; 189(6): 2497 - 2509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. T. Hendriksen, N. Silva, H. J. Bootsma, C. E. Blue, G. K. Paterson, A. R. Kerr, A. de Jong, O. P. Kuipers, P. W. M. Hermans, and T. J. Mitchell Regulation of Gene Expression in Streptococcus pneumoniae by Response Regulator 09 Is Strain Dependent J. Bacteriol., February 15, 2007; 189(4): 1382 - 1389. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| INT J SYST EVOL MICROBIOL | J MED MICROBIOL | MICROBIOLOGY | J GEN VIROL | ALL SGM JOURNALS |
