Microbial Toxins: Current Research and Future Trends | Book
Caister Academic Press
Thomas Proft The Maurice Wilkins Centre for Molecular Biodiscovery and School of Medical Sciences, University of Auckland, New Zealand
viii + 192
May 2009Buy hardback
GB £159 or US $319
Toxins are important virulence determinants responsible for microbial pathogenicity and/or evasion of the host immune response. Understanding toxin molecular and cellular biology is critical for the development of new anti-toxin strategies, particularly for those with bioterrorism capability. Indeed potential applications of toxin research extend beyond simply combating microbial virulence and include the development of novel anti-cancer drugs and other front-line medicines, use of toxins as tools in neurobiology and cellular biology, etc. This timely volume serves as an update on the most important recent advances. Written by internationally respected scientists, topics reviewed include: toxins carried by mobile genetic elements, botulinum neurotoxins, anthrax, subtilase cytotoxin, Pasteurella multocida toxin, RTX toxins of vibrios, vacA toxin, staphylococcal immune evasion toxins and fungal ribotoxins.
Essential reading for everyone with an interest in microbial toxins and recommended reading for other scientists with an interest in bioterrorism, microbial pathogenesis, and microbial genomics.
"This is a book of reference that comprises unlimited information on microbial toxins! This well crafted book not only provides a general overview of toxins but elucidates in detail recent molecular approaches, achievements and refreshing perspective on the future studies of these molecules ... an invaluable reference for scientists ... This is a book of reference to learn more about the molecular mechanisms employed by pathogenic microbes to survive and evade immunosurveillance of the host." from Expert Review of Anti-infective Therapy (August 2009)
"from leading experts all over the world ... leading-edge research" from SciTech Book News June 2009 p. 65
"a collection of expert reviews of microbial toxins ... a very good overview of the state of the art ... The diagrams are useful and informative. The book will be of use to anyone that wants an up-to-date summary of microbial toxins. It will be of use to PhD students and postdoctoral scientists working on pathogenicity or toxin biochemistry ... I would like to see several copies in our University library." from Tim Mitchell, University of Glasgow, UK writing in Microbiology Today (2009)
"[chapter 9 is] of special interest to mycologists" from David L. Hawksworth writing in Mycological Research (2009) 113: 908-910.
"the book serves well the molecular microbiologist ... not only well-documented but timely and inspiring" from Robert D. Johnson (St. George's University, NJ, USA) writing in Inoculum (2010) 61: 21-22
"timely and inspiring" (Mycological Society) "from leading experts all over the world ... leading-edge research" (SciTech Book News)
Toxins Carried by Mobile Genetic Elements
José R Penadés and J. Ross Fitzgerald
The identification of accessory genetic elements (plasmids, bacteriophages, and 'pathogenicity islands') encoding virulence-associated genes has facilitated our efforts to understand the evolution of pathogenic microorganisms. In many cases, toxigenic bacteria including Vibrio cholerae, Escherichia coli and Staphylococcus aureus, acquired virulence by acquisition of toxin genes carried in mobile genetic elements. In fact, mobile genetic elements have had a profound influence on the emergence of pathogenic clones of these bacteria. In order to trace the evolution of pathogens from their non-pathogenic progenitors, it is important to identify and characterize the genetic elements that mediate lateral acquisition of virulence genes. Understanding the evolutionary events that lead to the emergence of pathogenic clones may provide new approaches to the control of infectious diseases.
Botulinum Neurotoxins: Structure and Mechanism of Action
Roshan Kukreja and Bal Ram Singh
Botulinum neurotoxins (BoNTs) are the most potent natural toxins known to humankind. The family of BoNTs comprises of seven antigenically distinct serotypes (A to G) that are produced by various toxigenic strains of spore-forming anaerobic Clostridium botulinum
. They act as metalloproteinases that enter peripheral cholinergic nerve terminals and cleave proteins that are crucial components of the neuroexocytosis apparatus, causing a persistent but reversible inhibition of neurotransmitter release resulting in flaccid muscle paralysis.
Apart from being the sole causative agent of the deadly food poisoning disease, botulism, BoNTs pose a major biological warfare threat due to their extreme toxicity and easy production. Interestingly they also serve as powerful tools to treat an ever expanding list of medical conditions. A better understanding of the structure-function relationship of clostridial neurotoxins will not only help decipher their molecular mode of action but will also provide a greater understanding of the potential use of their individual domains in answering more fundamental questions of neuroexocytosis. It is also critical for designing effective specific inhibitors to counter botulism biothreat, and for the development of new therapeutics.
Francisco J. Maldonado-Arocho, Kathleen M. Averette-Mirrashidi, and Kenneth A. Bradley
Bacillus anthracis produces two major virulence factors, a tripartite exotoxin referred to as anthrax toxin, and an antiphagocytic capsule. These virulence factors mediate pathogen survival and, in the case of toxin, directly induce damage to the host. Two distinct enzymatic activities are associated with anthrax toxin, each encoded by a separate protein. The enzymatic subunits are lethal factor (LF), a zinc-dependent metalloproteinase, and oedema factor (EF), a calcium- and calmodulin-dependent adenylate cyclase. (Leppla, 1982; 1984; Vitale et al., 1998; 1999). LF and EF gain access to the host cytosol by binding to and translocating through a pore formed by the shared binding subunit, protective antigen (PA) (Blaustein et al., 1989; Milne et al., 1994; Zhang et al., 2004a; 2004b). The combination of LF and PA is called lethal toxin (LT), and this toxin inactivates MAPK signaling in the host. Oedema toxin (ET), formed by the combination of EF and PA, produces high cAMP levels in host cells. Early during infection, systemic toxin levels are low, and likely modulate the host immune response locally, thereby allowing for establishment of infection. Late in infection, toxin concentrations increase causing organ damage, vascular leakage, and ultimately death of the host. Indeed, both LT and ET are capable of inducing mortality in animal models when injected as purified toxins. This chapter will focus on current trends in LT and ET research aimed at understanding the mechanisms by which they affect the host and alter disease outcome.
Subtilase Cytotoxin: A New Bacterial AB5 Toxin Family
Adrienne W. Paton and James C. Paton
Subtilase cytotoxin (SubAB) is the recently-recognised prototype of a new AB5 toxin family secreted by Shiga toxigenic Escherichia coli (STEC). Its A subunit is a subtilase-like serine protease and cytotoxicity for eukaryotic cells is due to a highly specific, single-site cleavage of BiP/GRP78, an essential Hsp70 family chaperone located in the ER. This cleavage triggers a severe ER stress response, ultimately resulting in apoptosis. The B subunit has specificity for glycans terminating in the sialic acid N-glycolylneuraminic acid. Although its actual role in human disease remains to be established, SubAB is lethal for mice and induces pathological features overlapping those seen in the haemolytic uraemic syndrome, a life-threatening complication of STEC infection.
Pasteurella multocida Toxin
Joachim H.C. Orth
Pasteurella multocida toxin (PMT) is the major pathogenic deteriment of Pasteurella multocida. The species Pasteurella multocida leads to various diseases of animals and humans. The toxin is the causative agent of the economically important atrophic rhinitis in swine. Stimulation of several signalling pathways is induced by PMT. Most remarkable is a potent mitogenic effect. Phospholipase Cβ and the small GTPase Rho are activated due to stimulation of heterotrimeric G proteins of the Gαq and Gα12/13 family. Here most recent results on studies of PMT are presented.
The Multifunctional-Autoprocessing RTX toxins of Vibrios
Karla J. F. Satchell and Brett Geissler
Multifunctional-Autoprocessing RTX toxins are a unique family of secreted proteins toxins, predominantly produced by the Vibrio sp. The best characterized of these toxins is produced by V. cholerae, for which aspects of the regulation, secretion, and mechanism of toxicity have been defined. Within the eukaryotic cell, this toxin has three distinct biochemical activities resulting in autoprocessing, covalent crosslinking of actin, and inactivation of Rho-family GTPases, ultimately resulting in destruction of the actin cytoskeleton. Related toxins produced by V. vulnificus and V. anguillarum have also been characterized and found to have some similar, but also distinct mechanisms of action. For each Vibrio sp., the toxins have been linked to virulence and it is possible that these toxins function to assist the bacterium to evade host immune defenses in some cases.
Helicobacter pylori VacA Toxin
Timothy L. Cover and John C. Atherton
Helicobacter pylori, a Gram-negative bacterium that colonizes the human stomach, secretes a toxin known as VacA. This toxin was initially identified based on its ability to cause vacuolation in cultured gastric epithelial cells. More recent studies have shown that VacA also causes several other alterations in gastric epithelial cells and that VacA targets multiple types of immune cells. Most VacA-induced cellular alterations are attributable to insertion of the toxin into cellular membranes and the formation of membrane channels. In this chapter, we highlight recent progress in understanding three features of VacA: (i) structural properties of VacA, (ii) targeting of T lymphocytes by VacA, and (iii) diversity among VacA proteins expressed by different H. pylori strains.
Staphylococcal Immune Evasion Toxins
Ries J. Langley, Thomas Proft, and John D. Fraser
With the advent of complete microbial genomes, the identification and characterisation of novel immune evasion proteins from Staphylococcus aureus has increased significantly. Studies of these proteins have revealed significant conservation of protein structures and a range of activities that are all directed at the two key elements of host immunity, complement and neutrophils. This chapter focuses on some of these secreted virulence factors and the ways in which they assist the bacterium to surivive in the face of a hostile immune response. In particular, the chapter discusses the structure and function of complement inhibiting molecules SSL7, CHIPS, Efb, Ehp, SCIN, and Sbi and the leukocyte inhibiting SAgs, SSLs, CHIPS, and Eap.
Fungal Ribotoxins: Structure, Function and Evolution
Elías Herrero-Galán, Elisa Álvarez-García, Nelson Carreras-Sangrà, Javier Lacadena, Jorge Alegre-Cebollada, Álvaro Martínez del Pozo, Mercedes Oñaderra, and José G. Gavilanes
Ribotoxins are a family of fungal extracellular ribonucleases which inactivate ribosomes by specifically cleaving a single phosphodiester bond located at the universally conserved sarcin/ricin loop of the large rRNA. The subsequent inhibition of protein biosynthesis is followed by cell death via apoptosis. Ribotoxins are also able to interact with membranes containing acid phospholipids, their cytotoxicity being preferentially directed towards cells showing altered membrane permeability, e.g. transformed or virus infected cells. Many features of their cytotoxic action and their ribonucleolytic mechanism have been elucidated by comparison with other extracellular non toxic fungal RNases, best represented by RNase T1. The study of structure-function relationships in ribotoxins is of particular interest, since they are postulated as potential therapeutic agents against different human pathologies. The production of hypoallergenic variants with application in several Aspergillus-related allergic syndromes and the construction of immunotoxins against different carcinomas are promising examples of such potential therapeutic utilisation.
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(EAN: 9781904455448 Subjects: [bacteriology] [microbiology] [medical microbiology] [molecular microbiology])