Breaching the mucosal barrier by stealth: an emerging pathogenic mechanism for enteroadherent bacterial pathogens

Fleckenstein, James M.; Kopecko, Dennis J.

doi:10.1172/jci11792

Cited by 44 publications

(23 citation statements)

References 24 publications

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“…The absence of an inflammatory response noted in our mouse colonization studies could play a role in limiting the development of diarrhea. Indeed, migration of polymorphonuclear leukocytes to the mucosa could itself lead to diarrhea (24,38). Exploration of these and other differences between mouse and human factors which influence the host response to colonization could elucidate additional mechanisms involved in the pathogenesis of diseases caused by these organisms, as recently demonstrated in a mouse model of Shigella infection (60).…”

Section: Discussionmentioning

confidence: 98%

Importance of Heat-Labile Enterotoxin in Colonization of the Adult Mouse Small Intestine by Human EnterotoxigenicEscherichia coliStrains

Allen¹,

Randolph²,

2006

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Enterotoxigenic Escherichia coli (ETEC) infections are a significant cause of diarrheal disease and infant mortality in developing countries. Studies of ETEC pathogenesis relevant to vaccine development have been greatly hampered by the lack of a suitable small-animal model of infection with human ETEC strains. Here, we demonstrate that adult immunocompetent outbred mice can be effectively colonized with the prototypical human ETEC H10407 strain (colonization factor antigen I; heat-labile and heat-stable enterotoxin positive) and that production of heat-labile holotoxin provides a significant advantage in colonization of the small intestine in this model.Enterotoxigenic Escherichia coli (ETEC) infections are a significant cause of diarrheal disease worldwide. Infections caused by this heterogeneous group of pathogens remain major causes of diarrheal morbidity and infant mortality in developing countries (11,33,61), are perennially associated with disease in travelers (4, 7, 43) and in soldiers deployed to developing countries (8, 32), and have recently been associated with large outbreaks in developed countries, including the United States (1, 13).In the presently accepted paradigm for ETEC pathogenesis, fimbrial (or fibrillar) colonization factors (CFs) (10,22,27) mediate colonization of the small intestine, where organisms elaborate heat-labile enterotoxin (LT) and/or heat-stable enterotoxin (ST) (21, 68). Vaccine development has largely focused on the CFs; however, development of a broadly protective ETEC vaccine has been hampered due to the considerable heterogeneity of the known CFs (6,52,58,62).While a number of other surface antigens of ETEC have been described (20,25,51), their utility as potential vaccine candidates has not been effectively explored, largely due to the lack of a suitable animal model for testing. Animal models that have been used in previous studies of ETEC include infant (3, 16-18, 28, 47) and adult (9) mice, rats (34, 35), and rabbits (19,46,51). All of these models have inherent difficulties in utilization or require anesthesia and/or significant surgical manipulation. Some of the models have not been thoroughly evaluated.We sought to develop a murine model of small-intestinal colonization with human ETEC isolates using adult immunocompetent mice. Here, we report our initial use of this model using the prototypical human ETEC H10407 strain. Furthermore, similar to recent studies of porcine ETEC infection of gnotobiotic piglets (2), we demonstrate that elaboration of the heat-labile toxin provides a distinct advantage to the organism in establishing early colonization of the small-intestinal mucosa.

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Section: Discussionmentioning

confidence: 98%

Importance of Heat-Labile Enterotoxin in Colonization of the Adult Mouse Small Intestine by Human EnterotoxigenicEscherichia coliStrains

Allen¹,

Randolph²,

2006

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“…Strategies used by Shigella, Salmonella, and other bacterial pathogens to accomplish these goals include the invasion of the intestinal epithelium (47) and, in some cases, using the mucosa as a portal of entry to spread to distal sites by subsequently infecting professional phagocytes (14). As a result, most studies examining host defenses against these intestinal pathogens have focused on the responses of epithelial cells to bacterial invasion (10,47) as well as on the antimicrobial mechanisms activated within phagocytes (6,63).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Inducible Nitric Oxide Synthase Expression by the Attaching and Effacing Bacterial Pathogen Citrobacter rodentium in Infected Mice

et al. 2002

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Citrobacter rodentium belongs to the attaching and effacing family of enteric bacterial pathogens that includes both enteropathogenic and enterohemorrhagic Escherichia coli. These bacteria infect their hosts by colonizing the intestinal mucosal surface and intimately attaching to underlying epithelial cells. The abilities of these pathogens to exploit the cytoskeleton and signaling pathways of host cells are well documented, but their interactions with the host's antimicrobial defenses, such as inducible nitric oxide synthase (iNOS), are poorly understood. To address this issue, we infected mice with C. rodentium and found that iNOS mRNA expression in the colon significantly increased during infection. Immunostaining identified epithelial cells as the major source for immunoreactive iNOS. Finding that nitric oxide (NO) donors were bacteriostatic for C. rodentium in vitro, we examined whether iNOS expression contributed to host defense by infecting iNOS-deficient mice. Loss of iNOS expression caused a small but significant delay in bacterial clearance without affecting tissue pathology. Finally, immunofluorescence staining was used to determine if iNOS expression was localized to infected cells by staining for the C. rodentium virulence factor, translocated intimin receptor (Tir), as well as iNOS. Interestingly, while more than 85% of uninfected epithelial cells expressed iNOS, fewer than 15% of infected (Tir-positive) cells expressed detectable iNOS. These results demonstrate that both iNOS and intestinal epithelial cells play an active role in host defense during C. rodentium infection. However, the selective expression of iNOS by uninfected but not infected cells suggests that this pathogen has developed mechanisms to locally limit its exposure to host-derived NO.

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“…Even if LPS is a key activator of subepithelial macrophages, a protein called flagellin, a component of bacterial flagella, now appears to play a major role in triggering intestinal mucosal stimulation of an intestinal response, such as IL-8 secretion (14). Recently, Steiner et al generated a novel paradigm of E. coli enteric pathogenesis (42).…”

Section: Discussionmentioning

confidence: 99%

“…This type III system allows the translocation of the intimin receptor (Tir) in EPEC and EHEC infections. Whereas in EPEC infections Tir is implicated in several host cell responses (Ca 2ϩ , inositol triphosphate), in EHEC infections Tir is involved only in structural cellular rearrangements (10,14,26,33,34). In order to understand the mechanism of EHEC infection, identification of secreted proteins required for initiating the signaling events in host cells is currently being investigated in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

EnterohemorrhagicEscherichia coliInfection Induces Interleukin-8 Production via Activation of Mitogen-Activated Protein Kinases and the Transcription Factors NF-κB and AP-1 in T84 Cells

Dahan¹,

Busuttil

Imbert

et al. 2002

Infect Immun

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Breaching the mucosal barrier by stealth: an emerging pathogenic mechanism for enteroadherent bacterial pathogens

Cited by 44 publications

References 24 publications

Importance of Heat-Labile Enterotoxin in Colonization of the Adult Mouse Small Intestine by Human EnterotoxigenicEscherichia coliStrains

Importance of Heat-Labile Enterotoxin in Colonization of the Adult Mouse Small Intestine by Human EnterotoxigenicEscherichia coliStrains

Modulation of Inducible Nitric Oxide Synthase Expression by the Attaching and Effacing Bacterial Pathogen Citrobacter rodentium in Infected Mice

EnterohemorrhagicEscherichia coliInfection Induces Interleukin-8 Production via Activation of Mitogen-Activated Protein Kinases and the Transcription Factors NF-κB and AP-1 in T84 Cells

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