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Current Opinion in Microbiology

Volume 63, October 2021, Pages 70-75
Current Opinion in Microbiology

Transcriptional and metabolic regulation of EHEC and Citrobacter rodentium pathogenesis

https://doi.org/10.1016/j.mib.2021.06.002Get rights and content

Highlights

  • •

    Enterohaemorrhagic Escherichia coli and the murine pathogen Citrobacter rodentium regulate their T3SSs in response to diverse host and microbiota derived cues.

  • •

    Signals that regulate virulence range from bacterial and dietary derived metabolites, to hormones and immune modulators.

  • •

    Host cell metabolism is profoundly influenced by pathogen colonisation and virulence factor expression.

Enterohaemorrhagic Escherichia coli (EHEC) is a gastrointestinal pathogen that colonizes the colonic epithelium of humans and ruminants using a Type Three Secretion System (T3SS). This system is indispensable for disease and is regulated in response to a plethora of host and microbiota derived signals. The murine pathogen, Citrobacter rodentium, has become an instrumental tool in studying EHEC infection mechanisms in vivo, given its natural ability to infect mice and reliance on the same colonisation machinery. Here, we provide a review of the most recent advancements in EHEC infection biology, focusing on transcriptional regulation of the T3SS in response to physiologically relevant signals and how colonisation impacts on the metabolic micro-environment of the host niche. We pay particular attention to studies that have employed the C. rodentium model for elucidation of such mechanisms in vivo.

Introduction

Escherichia coli O157:H7 was first recognized as a cause of disease in 1982 during investigations of two outbreaks of haemorrhagic colitis, one in Oregon and one in Michigan, associated with the consumption of hamburgers [1]. As a member of the Enterohaemorrhagic E. coli (EHEC) pathotype, strains within this group invariably carry Shiga-like toxins, as well as a vast array of secreted virulence proteins [2]. The sequencing of EHEC in 2001 opened the door to genome-wide studies of how this complex array of virulence factors is regulated and is now an area of intense research [3, 4, 5, 6]. In vivo studies using the related murine pathogen Citrobacter rodentium act as a surrogate for EHEC infection and allow specific mechanisms underpinning host-pathogen interactions to be addressed in a murine model [7]. For example, studies have elucidated how sensing of metabolites, derived from both the host and microbiota, can influence the infection process [8]. Here, we review the most recent developments in our understanding of transcriptional and metabolic regulation in EHEC, highlighting how experiments using C. rodentium have helped provide a much-needed in vivo context to extensive mechanistic studies.

Section snippets

Nutrient sensing by EHEC/C. rodentium during infection

Enteric pathogens have evolved to sense the dynamic nutrient composition of the gastrointestinal (GI) tract. Pathogens can use this ability to gain a competitive advantage by appropriate regulation of their virulence repertoire (Figure 1) [9••]. Colonic nutrients, mainly defined by microbiota-derived metabolites, are integrated into regulatory networks typically via cognate transcriptional regulators that oversee the spatial-temporal expression of virulence genes [10]. These signals are crucial

Host cell and pathogen metabolic responses triggered during EHEC/C. rodentium infection

In addition to regulating their own behaviour in response to the environment, pathogens can influence the reprogramming of host metabolic pathways to better adapt to changes encountered in the intestine [19•]. Apart from playing a role as a physical barrier against pathogens, intestinal epithelial cells (IEC) detect pathogens through pattern recognition receptors [20] and induce immune responses, for example LDHA, MCT4, ALPKP1 and NLRP3 in C3H/HeN IEC [21]. C. rodentium counteracts this by

The role of the microbiota in virulence regulation

The role of the microbiota in host-pathogen interactions is broad, and not solely defined by their ability to supply nutrients and influence transcriptional regulation. Distinct members such as Bacteroides thetaiotaomicron (Bt) are implicated in the initiation of immune responses [31••], modification of the pathogen’s environment [32•] and control of virulence expression at the post-transcriptional and post-translational level [33]. A number of key studies have recently explored this concept.

Quorum sensing during host-pathogen interaction

Bacteria use quorum sensing (QS) for cell-to-cell communication which enables coordination of group behaviour in response to environmental changes. QseC is a histidine kinase encoded by many proteobacteria and has been thoroughly reviewed elsewhere [37]. As a QS receptor, it plays a fundamental role in detecting both bacteria-derived auto-inducers and host-generated neurotransmitters, epinephrine and norepinephrine. QseC signalling has been shown to be critical for EHEC virulence, as its

Concluding remarks

There is increasing evidence of a fine molecular balance between host physiology, the microbiota and the regulation of pathogen virulence. Infection studies employing C. rodentium as a model for EHEC have revealed significant insight into specific mechanisms of colonisation, such as nutrient regulation of virulence transcription and host responses that influence the metabolic status within the pathogen’s niche. While this model is powerful, it is important to reflect on the distinctive host

Conflict of interest statement

Nothing declared.

Funding

KRW is supported by an Eleanor Emery PhD Scholarship. CC has a scholarship provided by the Barbour foundation. JPRC is supported by a Springboard award from the Academy of Medical Sciences (SBF0051029). AJR receives funding from the BBSRC (BB/R006539/1).

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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    These authors contributed equally.

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