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Zoonotic and Animal Pathogens Research Laboratory, Medical Microbiology, Teviot Place, University of Edinburgh, Edinburgh, EH8 9AG, UK
Correspondence David L. Gally d.gally{at}ed.ac.uk
Escherichia coli is a successful commensal and pathogen. Its pathogenic diversity stems from the acquisition and expression of multiple virulence-associated loci. Many of the key virulence factors are surface structures involved in adherence and motility. These are important antigens and their expression is limited by phase-variable genetic switches that are considered to act randomly. This review considers the possibility that such stochastic expression within a bacterial population belies sequential or co-ordinate control at the level of the individual bacterium. Co-ordinated expression or cross-talk between virulence loci can lead to a programmed set of events within a bacterium analogous to a simple form of electronic memory that is of benefit during infection.
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Introduction |
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 TOP Introduction Organization of fimbrial gene...Phase variationType 1 fimbriaeP fimbriaeCross-talk between adhesin gene...Cross-talk between adhesins and...ConclusionReferences |
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Heterogeneous presentation of surface-associated structures is generated by both antigenic and phase variation. Antigenic variation enables a bacterium to express different forms of a key antigen whereas phase variation allows the antigen to be switched on or off by individual bacteria. Bacterial adhesins are surface-expressed structures required for colonization of the host but in most cases are also antigenic. Therefore, the expression of many adhesins is phase-variable, reflecting a balance between attachment and immune evasion. The sequencing of Gram-negative enteric pathogens such as Salmonella enterica serovar Typhimurium and Escherichia coli has shown them to contain multiple fimbrial and non-fimbrial adhesin gene clusters. When functional, this repertoire means the bacteria can bind to an assortment of receptors that may be present in different sites within the host, within different hosts or on surfaces outside the host. Different pathotypes have different adhesin collections, often built on top of a set of generic adhesins. In some cases evolution towards a single niche or host has been driven by or resulted in the silencing of certain adhesin gene clusters.
Appropriate adhesin regulation is required during an infection to optimize colonization and prevent removal by both the innate and adaptive arms of the immune response. During any infection in which large numbers of bacteria are produced, there is a chance that this regulation will be fine-tuned through natural selection. This has included the evolution of co-ordinated control mechanisms that act between adhesin gene clusters. These prevent co-expression of certain adhesins and allow sequential expression to consolidate colonization.
Regulation of surface components is highly complex and dependent on multiple inputs. This review is limited to cross-regulation between virulence loci and does not cover the much wider aspect of environmental sensing and response in bacteria. Transcriptional regulation is conventionally thought of as either global, where a regulator affects a large number of genes, or local, involving a regulator that only controls expression of a specific set of genes, often in its own operon. However, to achieve co-ordinate control or sequential regulation, the most useful regulators are those that are expressed by the operons themselves but can also act on other loci. For example, in order to prevent co-expression of two surface factors, the simplest strategy is for a regulator to be produced when operon X is expressed which represses the expression of operon Y. When operon X is switched off, operon Y can now be expressed, but only in sequence after operon X. In a single cell, regulators acting positively or negatively in this way could achieve a sequential programme of gene expression events that promote persistence within the host.
The main concept discussed in this review is that of sequential expression of surface antigens, in particular adhesins, through cross-talk. Particular programmes have been selected that consolidate attachment or favour proliferation/survival in the next phase of the infection. The response is therefore not just adaptive but incorporates information ‘stored’ from previous events. Combinations of genetic switches are one way that inputs can be stored and can lead to subsequent changes in output (gene expression). This is analogous to how simple relays and gates work in electrical circuits. In this way bacteria can be considered to have a basic ‘memory’ as the term applies to electronic memory in computers. This review will consider virulence gene expression at the level of the single bacterium, in particular the regulation between specific fimbrial and flagellal operons. To limit the extent of the review it will use examples mainly from E. coli but when necessary also from other members of the Enterobacteriaceae.
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Organization of fimbrial gene clusters |
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TOPIntroductionOrganization of fimbrial gene...Phase variationType 1 fimbriaeP fimbriaeCross-talk between adhesin gene...Cross-talk between adhesins and...ConclusionReferences |
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-D-mannose-, diagalactoside- and sialyl-containing receptors, respectively. Generally, the structural subunits are co-transcribed from a single promoter located either directly upstream of the main structural subunit, as for type 1 fimbriae, or upstream of a regulator, for example for P fimbriae. For further detail on the structure and assembly of fimbrial gene clusters the reader is referred to Blomfield (2001); Hultgren et al. (1996); Krogfelt (1991); Low et al. (1996). |
Phase variation |
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TOPIntroductionOrganization of fimbrial gene...Phase variationType 1 fimbriaeP fimbriaeCross-talk between adhesin gene...Cross-talk between adhesins and...ConclusionReferences |
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Two examples of cross-talk will now be described in detail, one negative and one positive, involving type 1, P and S fimbriae in E. coli. For these to be considered, a brief overview of their regulation will be given, although the reader is referred to an excellent recent review for more details (Blomfield, 2001).
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Type 1 fimbriae |
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TOPIntroductionOrganization of fimbrial gene...Phase variationType 1 fimbriaeP fimbriaeCross-talk between adhesin gene...Cross-talk between adhesins and...ConclusionReferences |
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P fimbriae |
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TOPIntroductionOrganization of fimbrial gene...Phase variationType 1 fimbriaeP fimbriaeCross-talk between adhesin gene...Cross-talk between adhesins and...ConclusionReferences |
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Cross-talk between adhesin gene clusters |
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TOPIntroductionOrganization of fimbrial gene...Phase variationType 1 fimbriaeP fimbriaeCross-talk between adhesin gene...Cross-talk between adhesins and...ConclusionReferences |
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Our own unpublished data support the idea that the PapI family of proteins are able to act positively on related gene clusters. As described above, this may result in relatively subtle changes in total fimbriation levels, as measured by total population techniques, but the likelihood of co- or subsequent expression at the single cell level is increased substantially as a result of this control. The situation therefore becomes highly complex if four or five related clusters are present in the genome. One tangible outcome of this would be that clinical isolates containing multiple fimbrial gene clusters would show much higher frequencies of P and S fimbrial gene expression in comparison to clusters that have been cloned and studied in isolation in laboratory strains. This appears to be the case, shown in the fimbrial kinetics studies of neonatal meningitis-associated E. coli (NMEC) and uropathogenic E. coli (UPEC) (Nowicki et al., 1984, 1985). The autoregulatory role of PapB and homologues is likely to be important in tempering this positive cross-talk (Forsman et al., 1989). Our ongoing work is examining the capacity of these highly related regulators to stimulate or repress expression from other fimbrial operons. Preliminary data indicate that very subtle changes in regulators can prevent their ability to cross-talk and that within a pool of homologous regulators only certain ones may have the ability to act away from their own cluster. This raises the possibility of a hierarchy in expression.
Positive cross-talk between adhesin gene clusters may be of benefit for several reasons. (i) As stated, multiple P and S (and other) operons may exist in E. coli pathogens to cope with the receptor diversity in and between hosts. If adhesin expression is controlled by homologous regulators from related clusters then, once one adhesin is expressed, the chances of the others being expressed is increased, thereby increasing the probability of bacterial attachment. This cross-talk would also mean that ‘master’ adhesin operons may exist that are controlled appropriately by environmental cues, and these in turn stimulate expression of other adhesin operons lower in the regulatory hierarchy. (ii) Another possibility is that the concentration of regulator required to stimulate self as opposed to related operons is different. In this case the positive cross-talk could act to bring about sequential fimbrial expression. This means that a cell could run through its repertoire of related adhesins, with the successful being ‘selected’ through their capacity to adhere (Fig. 1). Sequential expression would have advantages over combined expression as it would limit physical interference between structures. (iii) Many fimbrial clusters identified from whole genome sequencing projects contain mutations in particular components such as chaperones and ushers leading to the conclusion that the fimbriae will not be expressed. Co-expression of related clusters through such positive cross-talk could allow complementation to occur and lead to expression of an increased adhesin repertoire. (iv) Finally, there is some evidence that E. coli can detect the fact it is attached to a surface, possibly through changes in membrane stresses (Otto & Silhavy, 2002; Otto & Hermansson, 2004; Zhang & Normark, 1996). Evidence to date supports sensing by the CpxRA two-component pathway, as deletion of cpxR results in impaired adhesion of E. coli (Otto & Silhavy, 2002). It is possible that this sort of attachment signal could either interfere or complement adhesin cross-talk and ensure that a ‘successful’ adhesin is kept in an ‘on’ state.
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(ii) Negative cross-talk
The first evidence that expression of one fimbrial type may repress another was provided by work on S and type 1 fimbriae in a clinical isolate from a case of neonatal sepsis (Nowicki et al., 1985). After 35 h incubation, 33 % of cells were S fimbriate, 52 % type 1 fimbriate, 12 % were afimbriate and 3 % had both S and type 1 fimbriae. If the expression of one had no effect on the other, the percentage co-expressing S and type 1 fimbriae should have been 16 % (52 % of the 33 % S fimbriate population). This was shown very clearly by starting from a fully S fimbriate population. After the bacteria were grown statically in LB broth for 29 h, 80 % of the population still expressed S fimbriae and type 1 fimbriate bacteria represented 9.4 % of the total population. Bacteria that expressed both fimbrial types after 29 h represented only 0.5 % of the total population, rather than 8 % (80 % of 9.4 %).
It has subsequently been shown that both SfaB and PapB are able to inhibit the activity of the FimB recombinase on the fim switch (Holden et al., 2001; Xia et al., 2000). This means that while P or S fimbriae are in the phase-on state the expression of PapB/SfaB should prevent type 1 fimbriae from being switched on. In addition, PapB was shown to increase the expression of FimE, which turns off the expression of type 1 fimbriae (Xia et al., 2000). Therefore, even if type 1 fimbriae are being expressed in a bacterium in which P fimbrial expression is switched on, it is likely that type 1 fimbrial expression will then be switched off (Fig. 1). At present, it is unclear whether type 1 fimbrial expression can alter P or S fimbrial expression.
The importance of the above negative cross-regulation during infection is unknown, although recent work does point to a transition from type 1 fimbrial expression to P fimbrial expression in UPEC during experimental urinary tract infection in mice (Gunther et al., 2001). This transition could result from the PapB inhibition described above. Differences in type 1 fimbrial expression in the mouse model were observed between bacteria associated either with cystitis or pyelonephritis. For cystitis-associated strains, a mean of 81 % of the bacteria attached to bladder epithelium had the fim switch in the on orientation after 24 h compared with 2 % for pyelonephritis isolates at the same time-point. Classically pyelonephritis strains are more likely to express and contain P and S fimbrial gene clusters and therefore down-regulate type 1 fimbriae expression. What is still unknown is how important the cross-talk between P and type 1 fimbriae is to the expression levels during infection.
Our work has shown a range of phase-variation frequencies for P and type 1 fimbriae [Leathart & Gally (1998) and unpublished] and the cross-talk between these clusters will have a direct effect on the level of fimbriation. Expression of particular fimbriae is pro-inflammatory (Wullt et al., 2001), so there is likely to be a relationship between the level of expression and the severity of infection. For example, fimbrial expression is more likely to be repressed in asymptomatic infections (Graham et al., 2001; Hull et al., 1998, 1999; Stenqvist et al., 1987). A recent human trial used an E. coli strain isolated from an asymptomatic patient to investigate the expression of P fimbriae during infection. The strain was transformed with P fimbriae and the in vivo expression status of P fimbriae was shown to decrease rapidly following inoculation of human volunteers. Although this asymptomatic strain does possess the chromosomal genes for expression of type 1 fimbriae, P and F1C, these have been shown not to be expressed in vitro or in vivo. This strain apparently uses another unknown mechanism to persist in the bladder and potentially succeeds by failing to stimulate a pro-inflammatory response. Conversely, the proportion of bacteria expressing fimbriae during symptomatic infections may be high, stimulating a strong response, but leading to a short-lived infection. Host factors (receptors and immune response) in combination with bacterial phase-transition frequencies will govern the degree of fimbriation.
Another example of apparent mutual exclusivity between adhesins is the expression of type 1 fimbriae and the phase-variable auto-aggregation factor antigen 43 (Ag43). Ag43 interactions are responsible for the auto-aggregation phenotype and the extent of auto-aggregation is dependent on the proportion of Ag43-positive bacteria in a population. Ag43 belongs to a class of bacterial auto-transporters, so has a distinct mechanism of export compared to the chaperone usher family. Dam methylase function is required for Ag43 phase-variable expression (Henderson & Owen, 1999). The Ag43-positive phenotype was originally denoted flu+ and it was observed that flu and type 1 fimbrial expression were mutually exclusive at the colony level (Hasman et al., 1999). Introduction of the fim cluster, on a plasmid, or fimB on a plasmid to stimulate type 1 fimbriae expression abolished the auto-aggregation phenotype of a strain which is locked on for Ag43 expression. Therefore, initial studies suggested that prevention of Ag43 autoaggregation by the presence of long fimbrial structures is a physical phenomenon and not at the level of co-ordinated regulation. However, it has since been demonstrated that the flu mRNA level increased 20-fold in the absence of fim. Moreover flu transcription was decreased when type 1 fimbriae were overexpressed (Schembri & Klemm, 2001). A proposed mechanism for this was the reducing state of the cell, in which the biosynthesis of a large number of disulphide-containing surface structures constitutes a signal that alters the cellular thiol-disulphide status, which drives OxyR to the reduced state and, in turn, down-regulates Ag43. OxyR is able to monitor the reducing conditions in the cell and an OxyR recognition sequence covers all three GATC sites within the flu promoter. OxyR binding can effect the access of Dam, as is the case for Lrp in P phase variation, but the importance of the reduced or oxidized form of OxyR for the regulation is not clear. In the absence of oxidative stress, OxyR is almost all, if not all, in the reduced state, since the cytoplasm is a reducing environment. Gel-shift assays showed that a variant of OxyR that is in the oxidative form can bind to agn43 DNA, albeit with approximately fivefold lower affinity than wild-type OxyR (Wallecha et al., 2003). So, while the expression of these adhesins is mutually exclusive, the molecular basis to the regulation is still far from clear.
A key role for negative cross-talk would be to ensure that different adhesin types are not co-expressed by the same bacterial cell, as this may increase the chances of generating an immune response but also that one may functionally inhibit the other, for example if a fimbrial adhesin is expressed at the same time as a (shorter) non-fimbrial adhesin, such as Ag43 and type 1 fimbriae. Moreover, cross-talk may prevent complications occurring with the export of heterogeneous fimbrial components, which could be detrimental to the survival of the cell. As described, such regulation could also set up sequential expression which, for example, could ensure that an afimbrial adhesin (producing more intimate bacterial–host cell contact) is in position to take advantage of initial binding by a fimbrial adhesin.
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Cross-talk between adhesins and flagella expression |
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TOPIntroductionOrganization of fimbrial gene...Phase variationType 1 fimbriaeP fimbriaeCross-talk between adhesin gene...Cross-talk between adhesins and...ConclusionReferences |
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Proteus mirabilis contains a fimbrial adhesin MR/P (mannose-resistant, Proteus-like) that is phase-variable and controlled by an invertible genetic element. The mrp operon contains two divergent transcripts, mrpABCDEFGHJ, with >29 % identity to E. coli papAHCDJKEFG, and mrpI, which is 50 % identical to the fimB gene product at the amino acid level (Bahrani & Mobley, 1994; Li et al., 1999). The main fimbrial promoter is contained within a 251 bp invertible element flanked by two 21 bp inverted repeats (Zhao et al., 1997). MrpI is the sole recombinase that regulates phase variation of MR/P fimbriae in P. mirabilis (Li et al., 2002). Another regulator is encoded by the final gene of the cluster, mrpJ (Li et al., 2001). Its amino acid sequence contains a putative helix–turn–helix domain and also shares homology with the Cro/C1 family of regulators. P. mirabilis transformed with a plasmid encoding mrpJ displayed impaired motility in swimming and swarming, compared to vector only or mrp
. Moreover, an eightfold reduction in flagella synthesis, shown by Western blots with FlaA antisera, occurred when MprJ was overexpressed. Western blot analysis also showed that a deletion of mrpJ resulted in a decrease in the level of MrpA (main structural subunit) and FlaA, to about the same extent. Mutation of mrpJ results in an attenuated phenotype in the murine model of ascending urinary tract infection, when mice are co-challenged with a wild-type strain and mrpJ mutant strain. Taken together, these studies show that MrpJ is able to repress flagella production when MR/P fimbriae are expressed. Furthermore, the repression occurs at the level of transcription of the flagella master operon, since transcription from a flaDC
lacZ fusion strain was repressed with elevated levels of MrpJ. As yet, there is no evidence for direct interactions of MrpJ on fla DNA, implying that this activity is indirect.
Related MrpJ regulators are present at the end of the P- (papX) and S- (sfaX) fimbrial gene clusters in E. coli (Dobrindt et al., 2001; Marklund et al., 1992). Alignment of PapX with MrpJ shows homologous domains with different levels of conservation. Overexpression of PapX in P. mirabilis resulted in decreased motility and FlaA production, compared to the vector control, suggesting that PapX is a functional homologue of MrpJ in P. mirabilis (Li et al., 2001). However, this role has yet to be demonstrated in E. coli. Earlier work where PapX was mutated showed that it did not affect the degree of Prs piliation or the adhesin characteristics of the strain (Marklund et al., 1992).
Recently it has been demonstrated that deletion of fliC, which encodes flagellin, results in a decrease in type 1 fimbrial expression in an invasive E. coli strain isolated from a patient with Crohn's disease (Barnich et al., 2003). Previous work had shown that type 1 pili-mediated adherence plays an essential part in the invasive ability of this strain (Boudeau et al., 2001). Even deletion of motB, which is normally required for flagellar rotation, results in a failure to express type 1 fimbriae in the mutant. The molecular basis of this regulation is unknown but does appear to act at the level of the fim switch or on recombinase expression. Interestingly, the fliC mutation appeared to be affecting expression of another unknown determinant required for invasion. This type of data supports the presence of local regulatory networks essential for co-ordinate control of virulence determinants.
The molecular basis of gastrointestinal tract infection by enteropathogenic E. coli (EPEC) has been investigated in detail, and current evidence supports a series of steps that lead to epithelial binding (Frankel et al., 1998; Nataro & Kaper, 1998). The initial attachment could be driven by a number of adhesins including flagella (Giron et al., 2002) and bundle-forming pili (Bfp) (Giron et al., 1991; Tobe & Sasakawa, 2001). The role of Bfp is controversial, as these type IV pili are also important for interbacterial interactions and micro-colony formation (Knutton et al., 1999; Tobe & Sasakawa, 2001). Following initial attachment, further interaction with the host cell is mediated by the translocon components of a type III secretion system (McDaniel et al., 1995), in particular EspA filaments. These structures allow the injection of bacterial proteins into the host cell (Knutton et al., 1998). One of the proteins injected is the translocated intimin receptor (Tir), which inserts into the host cell membrane and binds to the bacterial outer-membrane protein intimin (Kenny et al., 1997). This interaction induces cytoskeletal rearrangements in the host cell and the formation of attaching and effacing lesions (Knutton et al., 1989). Variations on this scheme may prevent phagocytosis or M-cell uptake or actually promote invasion in the case of Salmonella serotypes (Celli et al., 2001; Knodler et al., 2002). While such factors are not necessarily controlled by phase-variable switches, the requirement for different surface factors one after the other will have led to an evolved programme of cross-talk between the different virulence loci, resulting in sequential or co-ordinated expression (Elliott et al., 2000; Giron et al., 2002; Knodler et al., 2002; Roe et al., 2003b). Recent research on H6 flagellar expression EPEC has demonstrated co-ordinated expression with type III secretion components and Bfp (Giron et al., 2002). Moreover, this expression appears linked to host-released factors such as epinephrine (Giron et al., 2002; Sperandio et al., 2003).
In enterohaemorrhagic E. coli O157 : H7, the expression of the type III EspA translocon filaments, Tir and intimin is heterogeneous and co-ordinated [Roe et al. (2003b) and unpublished]. In the majority of 60 E. coli O157 : H7 strains examined to date the proportions of bacteria expressing these factors in liquid media are very low (1–5 %) (unpublished). While the locus of enterocyte effacement-encoded regulator (Ler) ensures co-expression of most type III apparatus components and effectors (Elliott et al., 2000), it is clear that a further checkpoint in translocon expression and secretion exists that results in the observed heterogeneity. Initial evidence points to this control being post-transcriptional (Roe et al., 2003a). Again, this variable regulation is likely to have evolved both to limit immune exposure of these key antigens and to allow programmed expression of other surface factors during colonization of the primary bovine host. As with EPEC, these factors are likely to be flagella, fimbriae and outer-membrane proteins that are important in the interaction with host cell receptors.
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Conclusion |
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TOPIntroductionOrganization of fimbrial gene...Phase variationType 1 fimbriaeP fimbriaeCross-talk between adhesin gene...Cross-talk between adhesins and...ConclusionReferences |
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Computing memory is based on simple binary switches, and there is no reason why bacteria using epigenetic methylation and invertible element switches could not execute a programmed series of events that would be dependent on the initial triggering stimulus. As such, bacterial memory, i.e. a programmed response based on previous recent experience, is entirely possible (Fig. 1). At present there are only a few examples of such logical input-related behaviour, but such pathways are very difficult to demonstrate without techniques for imaging gene expression in single cells. As our capacity to do this increases, we predict that more examples of such memory and programming will be uncovered. An important consequence of this type of regulation is that whole-population expression studies can be misleading. Research on microbial pathogens is increasingly making use of DNA microarrays to dissect complex regulatory pathways, but a serious drawback is that heterogeneous expression is virtually impossible to study by this methodology. This limitation will be particularly true for complex in vivo-derived samples. Future research must concentrate on regulation demonstrated at the single cell level in addition to that of the whole population.
In summary, within any niche during infection, environmental monitoring by bacteria generates a certain heterogeneous population. Heterogeneity pre-empts the next stage of infection and allows it to be progressed by a successful bacterial subpopulation. The heterogeneity is required to cope with the unpredictability of different hosts and niches. However, within a single bacterium, its changing surface phenotype could reflect a particular sequential regulatory pathway. Understanding the pathways that control cross-talk between surface-expressed organelles will provide further insights into bacterial pathogenesis.
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References |
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TOPIntroductionOrganization of fimbrial gene...Phase variationType 1 fimbriaeP fimbriaeCross-talk between adhesin gene...Cross-talk between adhesins and...ConclusionReferences |
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