Table of Contents

Volume 3, Issue 2

  March/April 2012

Special Issue on Enteric Pathogens

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EDITOR'S CORNER

Special Edition of Gut Microbes

Beth McCormick and Brett Finlay
http://dx.doi.org/10.4161/gmic.19936
PDF




REVIEWS

Innate immune response to Salmonella typhimurium, a model enteric pathogen

Petr Broz, Maikke Ohlson and Denise Monack
http://dx.doi.org/10.4161/gmic.19141
Abstract | Full Text | PDF

The innate immune system provides the first line of defense against invading microorganisms by inducing a variety of inflammatory and antimicrobial responses. These responses are particularly important in the gastrointestinal tract, where the needs for efficient nutrient uptake and host defense collide. Many pathogens have evolved to specifically colonize the intestine, causing millions of cases of enteric infections a year. A paradigm of an enteric pathogen is Salmonella enterica, a gram-negative bacterium that causes a wide range of gastrointestinal and systemic diseases. Infections with Salmonella enterica serovar Typhimurium (S. typhimurium) lead to an acute intestinal inflammation in human and animal hosts, as a result of the bacterium invading the mucosa. A distinctive feature of Salmonella is that it has not only adapted to survive in a strong inflammatory environment, but it also uses this adaptation as a strategy to gain a growth advantage over the intestinal microbiota. We will use the model organism S. typhimurium to discuss the innate immune mechanisms employed by the mammalian gastrointestinal system and how the pathogen responds and subverts these mechanisms. In particular, we focus on the recognition of extra- and intra-cellular Salmonellae by germline-encoded pattern recognition receptors of the TLR and NLR families, and how Salmonella might profit from the activation of these receptors.

Infection strategies of enteric pathogenic E. coli

Abigail Clements, Joanna Young, Nicholas Constantinou and Gad Frankel
http://dx.doi.org/10.4161/gmic.19182
Abstract | PDF

Enteric Escherichia coli (E. coli) are both natural flora of humans and important pathogens causing significant morbidity and mortality worldwide. Traditionally enteric E. coli have been divided into 6 pathotypes, with further pathotypes often proposed. In this review we suggest expansion of the enteric E. coli into 8 pathotypes to include the emerging pathotypes of adherent invasive E. coli (AIEC) and Shiga-toxin producing enteroaggregative E. coli (STEAEC). The molecular mechanisms that allow enteric E. coli to colonize and cause disease in the human host are examined and for two of the pathotypes that express a type 3 secretion system (T3SS) we discuss the complex interplay between translocated effectors and manipulation of host cell signaling pathways that occurs during infection.

Typhoid fever: "You can't hit what you can't see"

Tamding Wangdi, Sebastian E. Winter and Andreas J. Bäumler
http://dx.doi.org/10.4161/gmic.18602
Abstract | Full Text | PDF

The host restricts dissemination of invasive enteric pathogens, such as non-typhoidal Salmonella serovars, by mounting acute inflammatory responses characterized by the recruitment of neutrophils. However, some enteric pathogens, such as Salmonella enterica serovar Typhi (S. typhi), can bypass these defenses and cause an invasive bloodstream infection known as typhoid fever. Recent studies on virulence mechanisms of S. typhi suggest that tight regulation of virulence gene expression during the transition from the intestinal lumen into the intestinal mucosa enables this pathogen to evade detection by the innate immune system, thereby penetrating defenses that prevent bacterial dissemination. This example illustrates how the outcome of host pathogen interaction at the intestinal mucosal interface can alter the clinical presentation and dictate the disease outcome.

Signature tagged mutagenesis in the functional genetic analysis of gastrointestinal pathogens

Joanne Cummins and Cormac G.M. Gahan
http://dx.doi.org/10.4161/gmic.19578
Abstract | Full Text | PDF

Signature tagged mutagenesis is a genetic approach that was developed to identify novel bacterial virulence factors. It is a negative selection method in which unique identification tags allow analysis of pools of mutants in mixed populations. The approach is particularly well suited to functional genetic analysis of the gastrointestinal phase of infection in foodborne pathogens and has the capacity to guide the development of novel vaccines and therapeutics. In this review we outline the technical principles underpinning signature-tagged mutagenesis as well as novel sequencing-based approaches for transposon mutant identification such as TraDIS (transposon directed insertion-site sequencing). We also provide an analysis of screens that have been performed in gastrointestinal pathogens which are a global health concern (Escherichia coli, Listeria monocytogenes, Helicobacter pylori, Vibrio cholerae and Salmonella enterica). The identification of key virulence loci through the use of signature tagged mutagenesis in mice and relevant larger animal models is discussed.

Shigella: A model of virulence regulation in vivo

Benoit Marteyn, Anastasia Gazi and Philippe Sansonetti
http://dx.doi.org/10.4161/gmic.19325
Abstract | Full Text | PDF

Much is known about the molecular effectors of pathogenicity of gram-negative enteric pathogens, among which Shigella can be considered a model. This is due to its capacity to recapitulate the multiple steps required for a pathogenic microbe to survive close to its mucosal target, colonize and then invade its epithelial surface, cause its inflammatory destruction and simultaneously regulate the extent of the elicited innate response to likely survive the encounter and achieve successful subsequent transmission. These various steps of the infectious process represent an array of successive environmental conditions to which the bacteria need to successfully adapt. These conditions represent the selective pressure that triggered the “arms race” in which Shigella acquired the genetic and molecular effectors of its pathogenic armory, including the regulatory hierarchies that regulate the expression and function of these effectors. They also represent cues through which Shigella achieves the temporo-spatial expression and regulation of its virulence effectors. The role of such environmental cues has recently become obvious in the case of the major virulence effector of Shigella, the type three secretion system (T3SS) and its dedicated secreted virulence effectors. It needs to be better defined for other major virulence components such as the LPS and peptidoglycan which are used as examples here, in addition to the T3SS as models of regulation as it relates to the assembly and functional regulation of complex macromolecular systems of the bacterial surface. This review also stresses the need to better define what the true and relevant environmental conditions can be at the various steps of the progression of infection. The “identity” of the pathogen differs depending whether it is cultivated under in vitro or in vivo conditions. Moreover, this “identity” may quickly change during its progression into the infected tissue. Novel concepts and relevant tools are needed to address this challenge in microbial pathogenesis.

Clostridium difficile infection: Toxins and non-toxin virulence factors, and their contributions to disease establishment and host response

Gayatri Vedantam, Andrew Clark, Michele Chu, Rebecca McQuade, Michael Mallozzi and V.K. Viswanathan
http://dx.doi.org/10.4161/gmic.19399
Abstract | PDF

Clostridium difficile infection is the leading cause of antibiotic- and healthcare-associated diarrhea, and its containment and treatment imposes a significant financial burden, estimated to be over $3 billion in the USA alone. Since the year 2000, CDI epidemics/outbreaks have occurred in North America, Europe and Asia. These outbreaks have been variously associated with, or attributed to, the emergence of Clostridium difficile strains with increased virulence, an increase in resistance to commonly used antimicrobials such as the fluoroquinolones, or host susceptibilities, including the use of gastric acid suppressants, to name a few. Efforts to elucidate C. difficile pathogenic mechanisms have been hampered by a lack of molecular tools, manipulatable animal models, and genetic intractability of clinical C. difficile isolates. However, in the past 5 y, painstaking efforts have resulted in the unraveling of multiple C. difficile virulence-associated pathways and mechanisms. We have recently reviewed the disease, its associated risk factors, transmission and interventions (Viswanathan, Gut Microbes 2010). This article summarizes genetics, non-toxin virulence factors, and host-cell biology associated with C. difficile pathogenesis as of 2011, and highlights those findings/factors that may be of interest as future intervention targets.

How a sugary bug gets through the day: Recent developments in understanding fundamental processes impacting Campylobacter jejuni pathogenesis

Christine M. Szymanski and Erin Gaynor
http://dx.doi.org/10.4161/gmic.19488
Abstract | PDF

Campylobacter jejuni is a highly prevalent yet fastidious bacterial pathogen that poses a significant health burden worldwide. Lacking many hallmark virulence factors, it is becoming increasingly clear that C. jejuni pathogenesis involves different strategies compared with other well-characterized enteric organisms. This includes the involvement of basic biological processes and cell envelope glycans in a number of aspects related to pathogenesis. The past few years have seen significant progress in the understanding of these pathways and how they relate to C. jejuni fundamental biology, stress survival, colonization, and virulence attributes. This review focuses on recent studies in three general areas where “pathogenesis” and “basic biology” overlap: physiology, stress responses, and glycobiology.

Models for the study of Clostridium difficile infection

Emma Best, Jane Freeman and Mark Wilcox
http://dx.doi.org/10.4161/gmic.19526
Abstract | PDF

Models of Clostridium difficile infection (C. difficile) have been used extensively for Clostridium difficile (C. difficile) research. The hamster model of C. difficile infection has been most extensively employed for the study of C. difficile and this has been used in many different areas of research, including the induction of C. difficile, the testing of new treatments, population dynamics and characterization of virulence. Investigations using in vitro models for C. difficile introduced the concept of colonization resistance, evaluated the role of antibiotics in C. difficile development, explored population dynamics and have been useful in the evaluation of C. difficile treatments. Experiments using models have major advantages over clinical studies and have been indispensible in furthering C. difficile research. It is important for future study programs to carefully consider the approach to use and therefore be better placed to inform the design and interpretation of clinical studies.




ARTICLE ADDENDUM

Helicobacter pylori DNA's anti-inflammatory effect on experimental colitis

Stephanie Owyang, Jay Luther, Christopher Owyang, Min Zhang and John Y. Kao
http://dx.doi.org/10.4161/gmic.19181
Abstract | PDF

Our laboratory has demonstrated a clinical inverse association between H. pylori infection and inflammatory bowel disease (IBD). In our most recent work we described a possible mechanism by which H. pylori can reduce the risk for developing IBD. Specifically, we were able to demonstrate the immuno-regulatory properties of the H. pylori genome and its ability to downregulate inflammatory responses through interaction with mucosal dendritic cells both in an in-vitro and in-vivo model. Furthermore, we were able to demonstrate the ability of H. pylori DNA to downregulate dendritic cell production of IL-12 and type I interferon, two pro-inflammatory cytokines. In the present work, we conducted further studies to examine the unique properties of the H. pylori genome and the exact mechanism in which it interacts with dendritic cells. Our data highlight a specific immuno-regulatory sequence (IRS), TTTAGGG, which occurs significantly more frequently as compared with other IRS sequences and is unique to the H. pylori genome. Additionally, we illustrate that H. pylori DNA has no effect on modulating the TLR-4 dependent LPS-induction of dendritic cell IL-12 production. This indicates that the inhibitory effect of H. pylori genomic DNA is restricted to the TLR-9 signaling pathway that senses bacterial DNA. In conclusion, the findings of this addendum strengthen the unique properties of H. pylori genome and revealed the importance of TLR-9 mediated mechanism in the pathogenesis of IBD.