Bacterial Toxins: Genetics, Cellular Biology and Practical Applications | Book
Caister Academic Press
Thomas Proft Department of Molecular Medicine and Pathology, School of Medical Sciences, Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand
viii + 234
August 2013Buy hardback
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Toxins are virulence determinants that play an important role in microbial pathogenicity and/or evasion of the host immune response. This makes them ideal targets for the development of novel antimicrobial strategies. The potential applications of toxin research extend beyond simply combating microbial pathogens and include use as novel anti-cancer drugs and other front-line medicines and as tools in neurobiology. In the field of cellular biology, toxins have become invaluable as tools for the manipulation and investigation of fundamental cellular and physiological processes. Research in this area is thriving and at a very exciting stage.
This timely volume serves as an update on the most important recent advances in the genetics, cellular biology and practical applications of the most important bacterial toxins. Written by internationally respected scientists from eight different countries, topics reviewed include: the molecular basis and risk factors for verotoxin pathogenesis; molecular mechanisms of Helicobacter pylori CagA translocation and function; structure and mechanisms of action of pore-forming toxins; bacterial enterotoxins as immunomodulators and vaccine adjuvants; mobile genetic elements as carriers for bacterial virulence genes; the novel family of staphylococcal superantigen-like toxins (SSLs); new insights into the use of botulinum neurotoxins as therapeutics; microbial toxins as tools in cell biology; the role of the large clostridial cytotoxins in C. difficile disease.
Essential reading for everyone with an interest in bacterial toxins and recommended book for researchers interested in microbial genomics and microbial pathogenesis.
Receptor Related Risk Factors for Verotoxin Pathogenesis
The family of E. coli derived verotoxins (Shiga toxins) has been extensively studied over the last 25 years due to its primary role in the infectious etiology of Hemolytic Uremic Syndrome (HUS). This acute pediatric renal disease, defined by the triad of thrombocytopenia, glomerular endothelial damage and hemolytic anemia is mediated by toxin B subunit pentamer binding to its receptor glycosphingolipid, globotriaosyl ceramide (Gb3) within lipid rafts in the glomerular endothelial cell plasma membrane and the subsequent endothelial pathology. HUS is preceded by a self-limiting hemorrhagic colitis prodrome which develops into a systemic pathology in ~10% of patients, after a several days of apparent recovery. Symptoms remain fatal in ~10% of HUS cases and no specific effective interventive therapy has yet been devised. Understanding of the molecular basis and risk factors for HUS following gastrointestinal infection with VT producing E coli, although incomplete and still a matter of controversy, has suffered a severe setback with the most recent highly virulent O104:H4 outbreak which showed more frequent incidence of HUS and death and preferentially targeted the adult female as opposed to the pediatric/elderly population. Since the toxin involved, VT2, was the same as involved in other more typical HUS cases, new concepts to explain this variation in VT-induced pathology are required.
The Helicobacter pylori CagA Protein: A Multifunctional Bacterial Toxin Delivered by Type IV Secretion
Wolfgang Fischer and Benjamin Busch
To deliver proteins with host cell-modulating activities, pathogenic bacteria either secrete protein toxins that are able to enter target cells autonomously, or use specialized secretion systems (type III, type IV or type VI secretion systems) to inject effector proteins directly into the host cell cytosol. The human gastric pathogen Helicobacter pylori secretes one major virulence determinant, the vacuolating cytotoxin VacA, to the extracellular environment, and translocates another, the cytotoxin-associated antigen CagA, by contact-dependent injection using the Cag type IV secretion system. Transfer of CagA into host cells is considered as a major risk factor for development of gastric cancer, and ectopically expressed CagA is sufficient to cause neoplastic transformations. Once injected, CagA becomes phosphorylated by cellular tyrosine kinases, and the subsequent interaction with a large number of host cell proteins results in cytoskeleton rearrangements and in deregulation of several signal transduction pathways that may lead to precancerous changes. Moreover, CagA binds to several interaction partners independently of tyrosine phosphorylation, and these interactions lead to a loss of cell polarity and to increased cell motility. This review summarizes the current knowledge of the molecular mechanisms of the CagA translocation process and of the diverse functions of CagA in target cells.
Juliane Bubeck Wardenburg, James Whisstock and Rodney K. Tweten
Bacterial pore forming protein toxins are widespread among bacterial pathogens and opportunistic pathogens. Their roles in disease progression are varied and complex. In this review the cholesterol dependent cytolysins (CDCs) and the related membrane attack complex/perforin (MACPF) protein families, as well as Staphylococcus aureus α-hemolysin will be discussed. These pore forming proteins exhibit prominent structural and mechanistic features that are paradigms for other pore-forming proteins. In this review we will focus on their structure and mechanisms of action and how they relate to their contribution(s) to pathogenesis.
Bacterial Enterotoxins as Immunomodulators andVaccine Adjuvants
Johan Mattsson and Nils Lycke
The bacterial enterotoxins , cholera toxin (CT) and the closely related E.coli heat-labile toxin (LT) have been found to be the most potent mucosal immunoenhancers (adjuvants) we know of today. Hence, much research is focused on understanding the mechanism behind their potent augmenting function following mucosal immunizations and oral immunizations, in particular. These holotoxins consist of an AB5 structure, where the A1-subunit hosts ADP-ribosylating activity and the B-subunit is the receptor binding element, which exists as a pentamer and specifically binds to GM1 ganglioside on the membrane of most mammalian cells. The A1 and B-subunit pentamer are attached through the linker A2. Because of severe toxicity of the holotoxins following either oral or nasal administration clinical use of the holotoxins is precluded. Therefore, attempts to mutate the A-subunit so as to reduce enzymatic activity with retained augmenting effect have been successful. However, we have developed the CTA1-DD molecule which has retained the full enzymatic activity of CT, but without the toxic side effects of the holotoxin. In the present review we describe the mechanism of action for ADP-ribosylating holotoxins and we discuss the mechanistic benefits of mutant holotoxins or the unique CTA1-DD adjuvant for future prospects of developing effective mucosal vaccines in general and oral vaccines, in particular.
Mobile Genetic Elements as Carriers for Bacterial Virulence Genes
José R Penadés and J. Ross Fitzgerald
The identification of accessory genetic elements (plasmids, bacteriophages, and 'pathogenicity islands') encoding virulence-associated genes has led to enhanced understanding of the evolution of pathogenic bacteria and how they adapt to new host environments. It is evident that mobile genetic elements (MGE) have had a profound influence on the emergence and spread of pathogenic bacteria. Furthermore, an understanding of the mechanisms of horizontal acquisition of virulence genes may lead to the identification of alternative approaches for preventing the emergence of new pathogenic clones or for controlling existing ones. In this chapter, we provide examples of MGE, which confer determinants of pathogenicity to selected bacterial species, and summarise current knowledge regarding their mechanisms of transmission.
The Staphylococcal Superantigen-like Toxins
Ries J. Langley and John D. Fraser
Staphylococcus aureus is a serious human pathogen responsible for a wide range of hospital and community acquired infections and deaths. It produces many virulence factors with functions involved first in invasion and then establishment and persistence within the body. Immune evasion is essential for survival of S. aureus in the host. The Staphylococcal Superantigen-like Proteins (SSLs), a family of recently discovered proteins expressed by all strains, play key roles in immune evasion by targeting important components of innate immunity. For example SSL7 blocks IgA from binding its Fc receptor on immune cells. IgA is the bodies' first line of defence against invading pathogens. SSL7 also binds the complement component C5 and prevents the cleavage of this molecule into its active fragments. The active fragment C5a has been shown to be of great importance in clearance of S. aureus. The binding of SSL10 to IgG1 prevents effector functions of this important class of antibody. Another sub-group of SSLs bind immune cell receptor proteins in a glycan-dependent manner to inhibit host immune defence against S. aureus. It is becoming clear that the SSLs are among the important arsenal of proteins that are responsible for immune evasion in S. aureus.
Botulinum Neurotoxins as Therapeutics
Botulinum neurotoxins (BoNTs) cause flaccid paralysis by interfering with vesicle fusion and neurotransmitter release in the neuronal cells. Due to their high efficacy, prolonged activity and satisfactory safety profile, BoNTs are now the most widely used therapeutic proteins. BoNT/A was approved by the U.S. FDA to treat strabismus, blepharospam, hemifacial spasm, cervical dystonia, glabellar facial lines, axillary hyperhidrosis and chronic migraine and for cosmetic use. The efficacy of BoNT/A in treating dystonia and other neuronal disorders, coupled with the satisfactory safety profile, has prompted its empirical use in a variety of indications. Currently available BoNT therapies have certain limitations such as the neuronal specific indications and immunoresistance issues resulting from periodic injections. Recent studies on the structure-function characterization of HCs and LCs of Botulinum Neurotoxins have advanced our knowledge on the mechanisms of BoNT receptor binding, internalization and substrate recognition. Advanced understanding in these areas has opened up new opportunities to engineer recombinant proteins to treat diseases that are not amenable to therapy with native neurotoxins, or to give better outcome than with the native neurotoxins. In conclusion, the future of BoNTs in medical applications is bright, yet more research is needed to improve their medical uses.
Microbial Toxins as Tools in Cell Biology
Julie Claudinon, Gustaf E. Rydell and Winfried Römer
Microbial toxins are important virulence factors of many bacteria and still a significant threat to human health. Over the years, many toxins have attracted remarkable attention not only from microbiologists, but also in particular from the field of cell biology, where they have become valuable tools to manipulate and investigate fundamental cellular and physiological processes. In this review, we highlight the use of microbial toxins by life scientists for permeabilizing cell membranes, targeting cell surface receptors, elucidating intracellular trafficking pathways and signaling mechanisms, and for specifically inactivating DNA and protein functions, amongst others. The use of microbial toxins as important cell biology tools for a multitude of applications benefits from many of the characteristics that they have naturally acquired through interactions with their hosts during co-evolution. Microbial toxins have emerged from being the patient's 'foe' to becoming a highly useful scientist's 'friend'.
The Toxins of Clostridium difficile
Glen P. Carter, Milena M. Awad, Julian I. Rood and Dena Lyras
Clostridium difficile infections represent a range of antibiotic-associated diarrhoea syndromes that are caused by the Gram-positive, spore-forming anaerobe C. difficile. This bacterium is the most significant cause of hospital-acquired diarrhoea in many countries and the emergence of variant strains with enhanced virulence capacity over the last decade has intensified this problem, resulting in major worldwide epidemics. Upon colonisation of a susceptible host C. difficile produces two large clostridial cytotoxins, toxin A (TcdA) and toxin B (TcdB), which are monoglucosyltransferases that irreversibly modify members of the Rho family of host regulatory proteins, leading to disruption of downstream signalling pathways and cell death, with disease manifesting as diarrhoea. Recent studies have indicated that toxin B plays a much more important role in disease than early studies had suggested. Comparison of the more recent epidemic isolates with historical strains has identified numerous differences that may contribute to increased virulence, including the production of binary toxin (CDT), which is an actin-specific ADP-ribosyltransferase. However, the role of CDT in disease pathogenesis remains unclear. This review will discuss our current understanding of the role of the C. difficile toxins in disease, with a particular emphasis on results obtained from studying these toxins using animal disease models.
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(EAN: 9781908230287 Subjects: [microbiology] [bacteriology] [molecular microbiology] )