Department of Medicine, Section of Digestive and Liver Diseases, University of Illinois at Chicago, West Side Department of Veterans Affairs Medical Center, Chicago, Illinois 60612
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ABSTRACT |
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Enteropathogenic Escherichia coli (EPEC) is primarily associated with infantile diarrhea in developing countries. This intriguing pathogen exerts numerous physiological effects on its host target tissue, the intestinal epithelium, all from an extracellular location. Expression of a type III secretory apparatus allows this organism to transfer bacterial effector molecules directly into host cells. As a result of EPEC attachment to and/or translocation of proteins into intestinal epithelial cells, many signaling cascades are activated. Ultimately, host functions are perturbed, including alteration of ion transport, disruption of the tight junction barrier, and activation of the inflammatory response.
enteric pathogens; ion transport; tight junctions; inflammation; intestinal epithelium
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INTRODUCTION |
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IN 1945, BRAY (1) IDENTIFIED a unique strain of Escherichia coli that caused life-threatening diarrhea in infants. What differentiated this particular strain of pathogenic E. coli from others was that its virulence mechanisms could not be attributed to an enterotoxin. Hence, the term enteropathogenic E. coli (EPEC) was coined by Neter (24) to refer to specific serotypes of E. coli found responsible for these outbreaks of infantile diarrhea that occurred in the 1940s and 1950s.
Intriguingly, after more than 50 years, the pathogenic mechanisms of
this important microbe still remain elusive. Unlike prototypic enteric
bacterial pathogens, EPEC is essentially noninvasive and produces no
toxins. It was observed, however, that attachment of EPEC to host
intestinal epithelial cells caused a unique morphological change called
an attaching and effacing (A/E) lesion (Fig.
1). A/E lesions are characterized by
elevation of the host cell membrane up to 10 µM above the cell, a
central invagination wherein the bacterial microcolony is situated in
intimate association with its host, and accumulation of cytoskeletal
proteins beneath the adherent microcolony. These sites of cup and
pedestal formation are accompanied by the degeneration of surrounding
microvilli, hence the description of this lesion as effacing. This
latter finding led to the assumption that the dissolution of surface hydrolases and overall loss of absorptive surface area would result in
malabsorption. Although malabsorption may well contribute to EPEC-associated diarrhea, it cannot fully account for the enhanced fluid and electrolyte loss. This statement is supported by the fact
that diarrhea can manifest as early as 3 h after ingestion of this
pathogen (5).
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Over the past decade, major advances toward defining the pathogenesis of EPEC have been made. These forward strides have resulted from diverse investigative approaches including genetics, cell biology, biochemistry, and host intestinal physiology. Unfortunately, space constraints do not allow an in-depth review here of the large body of literature that now exists concerning EPEC. The reader is therefore referred to recent extensive reviews of this pathogen (13, 34) for additional information. Although this themes article includes a general overview of the pathogen, it is written with a focus on the host intestinal epithelium and its myriad of responses to this most interesting organism.
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EPEC PATHOGENICITY |
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As it became apparent that the mechanisms whereby EPEC induces disease were not readily identifiable, new investigative tactics were used; one tactic was aimed at dissecting the genetic complex pathogenicity, another was aimed at exploring the basis of interaction between pathogen and host, and, last, one tactic was directed at examining the impact of infection on host cell events, signaling as well as function. One of the major advances toward unraveling the pathogenesis of EPEC was the sequencing of the 35-kb pathogenicity island, called the locus of enterocyte effacement (LEE) (21). The LEE houses 41 open reading frames divided into 5 operons. Contained within three of these operons are genes that encode a type III secretory apparatus (see below). Another houses genes involved in the intimate attachment of EPEC to host cells, and the last contains genes that encode proteins secreted by type III secretion, called Esps (E. coli-secreted proteins).
Type III secretion systems, expressed exclusively by gram-negative
pathogens, are compromised of ~20 proteins that collectively form a
bridge between the bacterial pathogen and the host cell. Specifically,
these proteins span the inner membrane, periplasmic space, and outer
membrane of the microbe and, through filaments, composed of EspA for
EPEC, bacterial effectors are delivered directly into host cells (Fig.
2). The contribution of specific EPEC
proteins to the composition of the type III secretory machinery has
been defined in part. EspA, mentioned above, is delivered across the EPEC membrane to form filaments through which other translocated proteins are delivered (17). EspB and EspD are believed to
form pores within the host cell membrane, because transmembrane domains are predicted for both of these proteins and their association with
host cell membranes has been reported (35). That EspB may also act as an effector molecule is suggested by its presence in the
cytosol of infected host cells and by the finding that deletion of the
gene espB ablates EPEC-associated activation of host cell
signaling cascades (6). Furthermore, transfection of
espB into HeLa cells alters actin stress fibers and cell
morphology, suggesting a role for this protein in pathogenesis
(33).
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Recently, EspF has been identified as an effector molecule (23). The unique nature of EspF is highlighted by the fact that, unlike the other Esps whose expression is required for the formation of A/E lesions, deletion of the gene espF has no impact on the quantity or character of A/E lesions, actin nucleation, or tyrosine phosphorylation of the translocated intimin receptor (Tir, see below) (22). EspF, which is not a structural component of the type III secretory machinery, is translocated by type III secretion into host cells, as demonstrated by both confocal microscopy and a Bordetella pertussis adenylate cyclase reporter system, making it a candidate effector. Although initial morphological and biochemical studies were unable to identify a given phenotype for the espF mutant strain, the coupling of prokaryotic genetic engineering with host physiological investigations unveiled an important finding. EspF expression is required for the full impact of EPEC on intestinal epithelial tight junctions (TJs). This finding opens the door to new speculations concerning EPEC pathogenesis. The contribution of A/E lesion formation itself to EPEC-associated disease has not been clarified. Now that the espF deletion mutant has been demonstrated to form A/E lesions but not to exert full functional effects on host tissues, it is tempting to view EPEC intimate attachment and pedestal formation as a maneuver to anchor itself to the host cell in the face of increased fluid movement through the intestine, thus ensuring the delivery of effector molecules into those cells. Others have offered the suggestion that this altered host morphology may in some way prevent internalization into host cells and subsequent antigen presentation. In fact, EPEC even escapes phagocytosis by macrophages (12), thus supporting this contention. Nonetheless, the induction of this characteristic morphological change appears to be insufficient, in and of itself, to effect physiological alterations, such as on barrier function (23). Instead, the delivery of key effector molecules, such as EspF and possibly others, is crucial. EspF is an interesting protein in that it contains proline-rich domains that confer the capacity for interacting with host cell proteins (22). The specific mechanism by which EspF exerts effects on the host tissue barrier is not known, but a dose-dependent correlation between EspF expression, disruption of the TJ barrier, and redistribution of the transmembrane TJ protein occludin has been demonstrated (Ref. 23; see below).
Perhaps one of the most intriguing aspects of EPEC infection is that
through type III secretion, this organism inserts its own receptor into
host cell membranes. The Tir is injected into host cells, where it is
then modified by host cell enzymes (4, 16). Specifically,
Tir is phosphorylated on tyrosine, and possibly serine and threonine,
residues and then inserted in the host cell membrane. In this
location, Tir is available to interact with its EPEC outer membrane
ligand, intimin. Interestingly, intimin also possesses a binding site
for 1-integrin (7). Although the
interaction between intimin and
1-integrin appears
unnecessary for the induction of A/E lesion formation, it is possible
that it contributes to EPEC-initiated signaling and physiological
effects. Disruption of intestinal epithelial TJs allows molecules
normally restricted to either the apical or basolateral domain of the
cell to redistribute to the other membrane. Opening of TJs by either calcium chelation or neutrophil transmigration has been shown to allow
the migration of
1-integrin from its normal basolateral location to the apical membrane, where it would be available to interact with luminal organisms. Yersinia has been shown to
exploit
1-integrin in this way (20).
Because EPEC perturbs TJs, it is possible that the same scenario
applies to this pathogen. Within the past few years, exploitation of
host cell integrin molecules seems to have been an emerging paradigm
for microbial pathogenesis.
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EFFECTS ON HOST INTESTINAL EPITHELIAL FUNCTION |
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Ion transport.
As a single layer of cells, the intestinal epithelium has three major
physiological functions: the vectorial transport of ions and solutes,
barrier function as provided by intercellular TJs, and surveillance of
and response to the contents of the intestinal lumen. Although the
pathogenesis of EPEC still remains undefined, infection by this microbe
perturbs each of the basic intestinal epithelial functions. Most
confusing, however, is the effect of EPEC on intestinal transport.
Collington et al. (3) reported that infection of cultured
human intestinal epithelial Caco-2 cells stimulated a rapid and
transient increase in short-circuit current
(Isc), which represents net ion transport
activity. A portion of this response, but not all, was shown to be
attributable to Cl secretion. On the other hand,
infection of a different cultured human intestinal epithelial cell
line, T84, widely used to study the regulation of apical
Cl
secretion, failed to demonstrate a similar response.
In fact, no alteration in basal Isc, which is
quite small, was seen. Instead, stimulation of EPEC-infected monolayers
with the classic Ca2+- and cAMP-mediated
secretagogues carbachol and forskolin yielded an attenuated
response for which altered Cl
secretion was not
responsible (14). Further investigation suggested that
perturbation of bicarbonate-dependent transport processes accounted for
this paradoxical response (14). The use of different cell
lines, which clearly have varying ion transport properties, and
different models of infection potentially explains these discrepant results.
Tight junction effects. One of the most exciting areas of investigation concerning EPEC has been its effects on TJs. Several groups have demonstrated that infection of monolayers of intestinal epithelial cells, both Caco-2 and T84, increases the permeability of these tissues, determined as a decrease in transepithelial electrical resistance (TER) (2, 30). Flux studies using the paracellular marker mannitol defined the permeability defect to be at the level of the TJ (30). It appears that EPEC may perturb TJs by various mechanisms. Contraction of the perijunctional cytoskeletal ring is one way in which the TJ barrier can be disrupted. The biochemical event regulating this process is phosphorylation of the 20-kDa light chain of myosin (MLC20). Years ago, Manjarrez-Hernandez et al. (19) reported that EPEC infection of eukaryotic cells stimulated the phosphorylation of a number of host proteins of which MLC20 was the most prominent. We found (36) that the functional consequence of this biochemical alteration was increased TJ permeability. The steps that lead to MLC20 phosphorylation are an initial increase in intracellular calcium and the formation of calcium-calmodulin complexes that then activate myosin light chain kinase (MLCK). Both sequestration of intracellular calcium and inhibition of MLCK diminished the EPEC-associated increase in TJ permeability (36).
Most recently, however, the structural basis of TJs has been identified. Tsukita and colleagues identified two TJ-associated transmembrane proteins, occludin (9) and a family of claudins (8), which consists of numerous isoforms. Both occludin and claudins possess four transmembrane domains that form two extracellular loops that project into the intercellular space and participate in formation of the barrier, likely by laterally polymerizing. The effect of EPEC, and other enteric pathogens, on TJ structure is just beginning to be explored. Studies from our laboratory (29) have demonstrated that EPEC infection of intestinal epithelial monolayers progressively perturbs the phosphorylation state and distribution of occludin. In other model systems, the importance of occludin phosphorylation in its localization to TJs has been shown. We found (29) that after infection with EPEC, occludin first assumed a beaded appearance in contrast to its normal uniform distribution at the TJ level of the membrane. These early morphological changes were not associated with functional perturbations. By 3 h after infection, however, a significant portion of occludin had dissociated from the TJ and redistributed to the cytoplasm (Fig. 3). Associated with this more dramatic morphological alteration was a significant drop in TER. Functional type III secretory machinery was found to be required for both the morphological and functional changes. In fact, progressively increased expression of EspF via infection with an isopropyl
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Epithelial inflammatory response. One global response of the intestinal epithelium to infection by bacterial pathogens is initiation of the inflammatory response. Initially, it was demonstrated that invasive bacterial pathogens such as Salmonella stimulated this response. Using EPEC as a prototypic noninvasive pathogen, we found (26) that invasion is not necessary to trigger the cascade of signals that ultimately lead to inflammation, in this case defined as transepithelial migration of neutrophils. In fact, McCormick and co-workers have now demonstrated that Salmonella need not invade to stimulate neutrophil transmigration. Their recent report (18) shows that a secreted extracellular Salmonella product, SipA, is sufficient to stimulate a protein kinase C (PKC)-dependent signaling cascade that ultimately leads to neutrophil transmigration. Although a similar effector molecule of EPEC has not been identified, the future demonstration of a similar paradigm as defined for SipA of Salmonella would not be surprising. It should be mentioned, however, that a unique bacterial flagellin from select EPEC, enterohemorrhagic E. coli, and enteroadherent E. coli strains stimulates the secretion of interleukin (IL)-8 by host target intestinal epithelial cells (31). Interestingly, the basal, but not apical, exposure of intestinal epithelial monolayers to flagellin purified from Salmonella typhimurium activates the mucosal inflammatory response (10). The underlying pathways by which these unique bacterial proteins induce this common host response deserve more intense investigation in the future.
Regarding EPEC-induced inflammation, the first studies confirmed that the interactions between EPEC and host intestinal epithelial cells were sufficient to recruit neutrophils across this layer and that IL-8 was in part responsible (27). Because IL-8 expression, like that of most inflammatory response genes, is in large part regulated by the transcription factor NF-
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PERSPECTIVES |
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Remarkable progress has been made in just the past decade toward understanding the pathogenesis of EPEC. One clear conclusion that has emerged from a multitude of studies is that neither one unifying mechanism of pathogenesis nor a single effector molecule is responsible for the symptoms that accompany EPEC infection. Instead, several EPEC virulence factors perturb many facets of host physiology that together culminate in diarrhea. Perturbations in intestinal ion transport, by both direct interactions between microbe and host and indirect effects that result from mediators released by other cell populations in response to infection, clearly contribute to the symptomatology. The maintenance of the intercellular TJ barrier is essential for the physiological functioning of the intestinal epithelium; hence, its disruption by EPEC infection has the potential to perturb many processes including transport, cell polarity, and protection of the underlying compartments from noxious contents of the intestinal lumen.
Seminal investigations into the genetics underlying EPEC pathogenesis have heralded a new approach to the study of EPEC. With the identification and sequencing of the pathogenicity island or LEE of EPEC, the union of genetic manipulation (single gene mutations) of the pathogen with the exploration of the impact on host function will serve to identify key effector proteins. It is this very approach that led to the finding that the secreted, but nonstructural, EPEC protein EspF is intimately involved in the disruption of TJ structure and barrier. The challenge now is to identify the host proteins that interact with EspF and other translocated EPEC effectors. The elucidation of the translocated EPEC receptor, Tir, affords the opportunity to determine the host proteins with which it interacts and the signaling pathways that are ultimately stimulated as a result.
Ultimately, the goal is to use in vitro models to identify candidate genes that deserve study in vivo. Several EPEC genes have been confirmed as virulence factors using this approach. The role of the outer membrane protein intimin, encoded by the gene eae, was highlighted in this way (5). Similarly, the importance of EspB in human infection was demonstrated (32). As functional assays are routinely used to screen newly created EPEC mutant strains, new insights into pathogenesis will be gained. This approach, which integrates genetics, both host and pathogen, cell biology, intestinal physiology, and immune response, will improve our understanding of this pathogen. With enhanced understanding comes opportunity for the development of targeted preventative and therapeutic strategies.
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ACKNOWLEDGEMENTS |
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The author thanks her collaborators, Drs. James Kaper and Michael Donnenberg at the University of Maryland, Baltimore, MD, who have generously supplied her laboratory with many mutated strains of enteropathogenic E. coli for functional studies.
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FOOTNOTES |
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The author's research is supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-50694 and DK-58964 and by the Department of Veterans Affairs through a Merit Review and Research Enhancement Awards Program.
Address for reprint requests and other correspondence: G. Hecht, Dept. of Medicine, Section of Digestive and Liver Diseases, Univ. of Illinois at Chicago, 840 S. Wood, (M/C 787), 920 CSB, Chicago, IL 60612 (E-mail: gahecht{at}uic.edu).
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