The Comprehensive Sourcebook of Bacterial Protein Toxins

The Comprehensive Sourcebook of Bacterial Protein Toxins

4th Edition - May 1, 2015

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  • Authors: Joseph Alouf, Daniel Ladant, Michel Popoff
  • Hardcover ISBN: 9780128001882
  • eBook ISBN: 9780128005897

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The Comprehensive Sourcebook of Bacterial Protein Toxins, Fourth Edition, contains chapters written by internationally known and well-respected specialists. This book contains chapters devoted to individual toxins, as well as chapters that consider the different applications of these toxins. Considerable progress has been made in understanding the structure, function, interaction and trafficking into cells, as well as mechanism of action of toxins. Bacterial toxins are involved in the pathogenesis of many bacteria, some of which are responsible for severe diseases in human and animals, but can also be used as tools in cell biology to dissect cellular processes or used as therapeutic agents. Novel recombinant toxins are already proposed in the treatment of some diseases, as well as new vaccines. Alternatively, certain toxins are also considered as biological weapons or bioterrorism threats. Given the multifaceted aspects of toxin research and the multidisciplinary approaches adopted, toxins are of great interest in many scientific areas from microbiology, virology, cell biology to biochemistry and protein structure. This new edition is written with a multidisciplinary audience in mind and contains 5 new chapters that reflect the latest research in this area. Other chapters have been combined, deleted and fully revised as necessary to deliver relevant and valuable content.

Key Features

  • Descriptions of relevant toxins as well as representative toxins of the main bacterial toxin families to allow for a better comparison between them
  • Focused chapters on toxin applications and common properties or general features of toxins


Scientists and students of toxicology, microbiology, cell biology and biochemistry, as well as medical students, physicians, pathologists and those involved in the management of bioterrorism threats

Table of Contents

  • Introduction to the Fourth Edition

    • In memory of J. E. Alouf (1929–2014)

    Section I: Basic Genomic and Physiological Aspects of Bacterial Protein Toxins

    1. Evolutionary aspects of toxin-producing bacteria

    • Introduction
    • Molecular ecology of toxin-producing bacteria
    • Toxins encoded by plasmids, bacteriophages, and other pathogenicity islands
    • PAI-encoded toxins delivered by specialized secretion systems
    • Molecular evolution of toxins through genetic exchange
    • Modular recombination of bacterial toxins
    • Conclusion
    • References

    2. Mobile genetic elements and pathogenicity islands encoding bacterial toxins

    • Introduction: The genome structure of prokaryotes
    • Protein toxins encoded by mobile genetic elements
    • Gram-negative bacteria
    • Gram-positive bacteria
    • Protein toxins encoded by bacteriophages
    • Gram-negative bacteria
    • Gram-positive bacteria
    • Protein toxin genes and other mobile genetic elements
    • Toxins encoded by PAIs
    • PAI-encoded toxins
    • Other Gram-negative bacteria
    • The bacterial T6SS
    • Gram-positive bacteria
    • Instability of PAIs
    • Conclusion
    • HGT and the evolution of toxin families
    • Acknowledgments
    • References

    3. News and views on protein secretion systems

    • Introduction
    • Type I secretion system
    • Type II secretion system
    • Type III secretion system
    • References

    Section II: Intracellularly Alive Bacterial Protein Toxins

    4. Diphtheria toxin

    • Introduction
    • Diphtheria toxin: from pathology to crystal structure
    • The mechanism of action of DT
    • Conclusion
    • Acknowledgments
    • References

    5. Pseudomonas aeruginosa toxins

    • Introduction
    • T3 secretion in P. aeruginosa
    • Discussion
    • Conclusion
    • References

    6. Bordetella protein toxins

    • PTX
    • Adenylate cyclase toxin
    • DNT
    • References

    7. Vibrio cholerae and Escherichia coli heat-labile enterotoxins and beyond

    • Introduction
    • Cholera then and now
    • Traveler’s diarrhea and other related diseases
    • Structure of cholera toxin and related enterotoxins
    • Intestinal receptors of the enterotoxins
    • How cholera toxin and E. coli heat-labile enterotoxin mediate diarrhea
    • Toxin gene organization, regulation, and biogenesis
    • Cholera toxin and co-regulated pilus (TCP), and ETEC homologues
    • Conclusion
    • References

    8. Vibrio parahaemolyticus virulence determinants

    • Introduction
    • V. parahaemolyticus
    • V. parahaemolyticus pandemic O3:K6 clone
    • Virulence factors associated with V. parahaemolyticus pathogenicity in mammals
    • Polar flagellum and surface sensing
    • Quorum sensing
    • Adhesins
    • Capsule
    • MSHA pilus
    • MAM7
    • TDH and TRH toxins
    • T3SS
    • T3SS1
    • VopQ
    • VopS
    • VPA0450
    • VopR
    • T3SS2
    • VopL
    • VopA
    • VopC
    • VopT
    • VopV
    • VopZ
    • VPA1380
    • T6SS
    • T6SS1
    • T6SS2
    • Development of mammalian models for the study of V. parahaemolyticus pathogenicity
    • Parahaemolyticus as a shrimp pathogen
    • Summary and conclusions
    • References

    9. Typhoid toxin

    • Introduction
    • Discovery of typhoid toxin
    • Structure of typhoid toxin
    • Typhoid toxin secretion and export from mammalian cells
    • Typhoid toxin and typhoid fever
    • Typhoid toxin and S. typhi host specificity
    • Concluding remarks
    • References

    10. Shiga toxins: properties and action on cells

    • Introduction
    • Shiga toxins and the bacteria that produce them
    • Detection of Shiga toxins
    • Binding of toxins to cell surface receptors
    • Endocytic uptake of Shiga toxin
    • Transport of Shiga toxin between endosomes and the Golgi apparatus
    • Retrograde Shiga toxin transport to the ER and translocation of the A chain to the cytosol
    • Transport of Shiga toxin across epithelial cells
    • Induction of cytokine production
    • Toxin-induced apoptosis
    • Protection against Shiga toxins
    • Exploitation of Shiga toxins in medicine
    • Conclusions
    • Acknowledgments
    • References

    11. Clostridial neurotoxins: from the cellular and molecular mode of action to their therapeutic use

    • Introduction
    • Various botulinum neurotoxin-producing Clostridium species
    • BoNT and botulinum toxin complexes
    • Clostridium tetani, TeNT gene organization, and TeNT
    • Mode of action of clostridial neurotoxins
    • BoNT-induced muscle paralysis triggers sprouting and differentiation of new endplates
    • Botulinum toxin and neurotoxin in therapy
    • Toxin formulations and units
    • From pioneering studies to approved indications
    • Concluding remarks
    • References

    12. Uptake and transport of clostridial neurotoxins

    • Introduction
    • Mechanism of action
    • Structure-Function relationship
    • Neurospecific binding and uptake of CNT
    • APRs as CNT binding sites
    • Polysialoangliosides as cell surface receptors for CNTs
    • Future perspectives
    • Acknowledgments
    • References

    13. Bacillus anthracis toxins

    • Introduction
    • The genetics of toxin and virulence
    • The proteins
    • Toxin action on cells and animals
    • Concluding remarks
    • References

    14. ADP-ribosylating toxins modifying the actin cytoskeleton

    • Introduction
    • Actin cytoskeleton and regulation of actin polymerization
    • ADP-ribosylating toxins targeting RHO-GTPases
    • ADP-ribosylating toxins targeting actin
    • Salmonella SpvB
    • Concluding remarks
    • References

    15. Large clostridial cytotoxins modifying small GTpases: structural aspects

    • Introduction
    • Binding of the toxins to target cells: the C-terminal CROP domain
    • Pore formation and translocation of the toxins
    • CPD
    • The N-terminal glycosyltransferase domain
    • Mechanism of the toxin-catalyzed glycosylation reaction
    • Substrate recognition
    • Holotoxin structure of TcdA and TcdB
    • Conclusions
    • References

    16. Large clostridial glycosylating toxins modifying small GTPases: cellular aspects

    • Introduction
    • Cell entry
    • Activities of the glycosyltransferase domain: UDP-hexose hydrolysis and glycosyltransferase activities
    • Biological effects of the LCGTs in cell culture models
    • Large clostridial glycosylating toxins in pathogenesis
    • Treatment of CDAD and new approaches of LCGT inhibition
    • Exploiting the large clostridial glycosylating toxins as tools in cell biology
    • References

    17. Pasteurella multocida toxin

    • Introduction
    • Molecular and cellular mechanisms of PMT action
    • PMT activation of heterotrimeric G proteins and their effectors
    • PMT-induced activation of Gαi
    • PMT-stimulated Gβγ signaling
    • Cellular effects of PMT
    • PMT characterization
    • PMT production and release
    • PMT protein purification and characterization
    • PMT structure and functional organization
    • Localization of functional domains
    • PMT crystal structure
    • Comparison of PMT with related toxins
    • PMT interaction with and entry into mammalian cells
    • Cellular uptake
    • Translocation into the cytoplasm
    • Conclusion
    • Acknowledgments
    • References

    18. Deamidase toxins

    • Introduction
    • The growing family of deamidase toxins and activating Rho GTPases
    • Host cell reaction to Rho GTPase activation
    • Acknowledgments
    • References

    19. Helicobacter pylori vacuolating toxin

    • Introduction
    • The vacA gene and its product
    • VacA structure
    • Interaction with host cells
    • Biological activities of VacA
    • Conclusion
    • Acknowledgments
    • References

    20. Bacterial genotoxins

    • Introduction
    • CDT gene organization and distribution
    • CDT structure and enzymatic activity
    • Secretion from the producing bacterium
    • Cellular internalization in the target cells
    • Cellular responses to intoxication
    • CDTs and bacterial pathogenesis
    • CDTs as tools in basic and medical research
    • Colibactin
    • Concluding remarks
    • Acknowledgments
    • References

    Section III: Bacterial Protein Toxins Active on the Surface of Target Cells

    21. Basic mechanism of pore-forming toxins

    • Introduction
    • Structure of PFTs
    • PFTs formed by α-helices
    • Conclusions and further perspectives
    • References

    22. Membrane-damaging and cytotoxic sphingomyelinases and phospholipases

    • Introduction
    • Bacterial SMases
    • Bacterial PLases
    • Complementary or redundant roles of PLases and SMases in pathogenesis of selected diseases
    • Concluding remarks
    • References

    23. Structure and function of RTX toxins

    • Introduction: an overview of RTX proteins
    • Common features of RTX toxins
    • RTX-repeats: motifs and structures
    • T1SS
    • Assembly of the T1SS apparatus
    • Main RTX toxins
    • E. coli α-hemolysin (HlyA)
    • Other RTX toxins
    • The AC toxin, CyaA, from Bordetella species
    • MARTX toxins
    • Molecular mode of action of RTX toxins: some key issues
    • Concluding remarks
    • Acknowledgments
    • References

    24. Perfringolysin O and related cholesterol-dependent cytolysins: mechanism of pore formation

    • Introduction to CDC family
    • General features of the CDC structure and brief overview of the pore-forming mechanism
    • Detailed pore-forming mechanism
    • Amino-terminal extensions to the core CDC structure
    • Cellular mechanisms of membrane repair after CDC attack
    • CDCs in gram-negative bacteria
    • Conclusion
    • Acknowledgments
    • References

    25. The staphylococcal alpha-toxin and leukotoxins

    • Introduction
    • Alpha-helix cytolysins: delta-hemolysin and phenol-soluble modulins
    • A beta-barrel pore formingtoxin prototype: alpha hemolysin
    • Staphylococcal bicomponent leukotoxins
    • Staphylococcal pore-forming toxins challenged in pathogenesis
    • Applications and engineered PFTS in perspective
    • Conclusion
    • References

    26. Aerolysin and Related Aeromonas Toxins

    • Introduction
    • Production, purification, and primary sequence
    • Structure of proaerolysin
    • Secretion of proaerolysin
    • Receptor binding
    • From the precursor to the active toxin
    • Heptamer formation
    • Membrane insertion and channel properties
    • Cellular consequences of aerolysin
    • Aerolysin as a tool
    • Concluding remarks
    • Acknowledgments
    • References

    27. Structural relationships between small β-pore-forming toxins from Clostridium perfringens

    • Introduction
    • βPFTs
    • C. perfringens toxins
    • Aerolysin-like toxins
    • C. septicum α-toxin
    • Shared mechanisms of cytotoxicity
    • CPE
    • Pore formation in aerolysin-like toxins
    • Hemolysin-like toxins
    • β-Toxin
    • Relationship between C. perfringens and S. aureus hemolysin-like β-PFTs
    • Conclusion
    • Acknowledgments
    • References

    28. Clostridium perfringens enterotoxin

    • Introduction
    • The genetics and expression of CPE
    • The intestinal action of CPE
    • The cellular action of CPE
    • Summary: a current model for CPE action
    • CPE structure/function relationships
    • Development of a CPE vaccine?
    • Potential applications of CPE: cancer and more
    • Concluding remarks
    • Acknowledgments
    • References

    29. Bacillus cereus phospholipases, enterotoxins, and other hemolysins

    • Introduction
    • Toxins of B. cereus s.l.
    • Regulation of transcription and secretion of toxins
    • Conclusion
    • References

    30. Mechanism of action of Bacillus thuringiensis insecticidal toxins and their use in the control of insect pests

    • Introduction
    • Cry toxin family
    • Cyt toxin family
    • Vip toxin family
    • Mechanism of action of 3d-Cry toxins
    • Concluding remarks
    • References

    31. Escherichia coli heat-stable enterotoxins

    • Introduction
    • Diarrhea caused by ETEC
    • Heat-stable enterotoxins
    • STa enterotoxin
    • Biochemical characteristics
    • estA gene
    • Secretion of STa and formation of disulfide bonds
    • Structure of STa and identification of the toxic domain
    • Receptors
    • Receptor distribution
    • Mechanism of action
    • STa and TJs
    • STb toxin
    • Biochemical characteristics
    • estB gene
    • Secretion of STb and disulfide bond formation
    • STb receptors
    • Toxic domain and 3D structure of STb
    • Mechanism of action
    • Pore formation and internalization
    • STb and TJs
    • EAST1 toxin
    • EAST1 polypeptide
    • astA gene
    • EAST1 variants
    • EAST1 toxicity
    • Relative importance of ETEC toxins in pathogenesis
    • Concluding remarks
    • Acknowledgments
    • References

    32. Bacterial superantigens and superantigen-like toxins

    • Introduction
    • Group a streptococcal superantigens
    • Staphylococcal SAgs
    • Protein structures of streptococcal and staphylococcal SAgs
    • Biochemical properties of streptococcal and staphylococcal SAgs
    • The SAgs of Yersinia pseudotuberculosis
    • The SAg of Mycoplasma arthritidis
    • Biological activities of SAgs
    • SAgs and human disease
    • Clinical and experimental therapeutic interventions
    • Why do bacteria produce SAgs?
    • The staphylococcal SAg-like toxins
    • Acknowledgments
    • References

    Section IV: Clinical Aspects, Applications of Bacterial Protein Toxins in Cell Biology and Therapy, and Toxin Inhibitors

    33. Clostridial toxins in the pathogenesis of gas gangrene

    • Introduction
    • Major histotoxic clostridial infections
    • The role of exotoxins in C. perfringens gas gangrene
    • Stage 4: Progression of local and regional tissue destruction
    • Conclusion
    • Acknowledgments
    • References

    34. Engineering of botulinum neurotoxins as novel therapeutic tools

    • Background
    • Strategy for successfully generating recombinant BoNTs as SCs in E. coli
    • Insights gained into devising BoNT-based neurotherapeutics with long durations of action
    • Engineering a long-acting antinociceptive by harnessing therapeutic advantageous features of two BoNT serotypes
    • Engineered hybrids of BoNT and TeTx as tools to establish the domains responsible for their respective local or retrograde trafficking
    • Retargeting of BoNT variants to selected secretory cells for additional therapeutic applications
    • Concluding Remarks
    • Acknowledgements
    • References

    35. Engineering of bacterial toxins for research and medicine

    • Introduction
    • Engineering receptor-binding activities
    • Engineering toxin activation
    • Exploiting membrane binding and translocation
    • Engineering C domains
    • Engineering of alpha toxin from Staphylococcus aureus
    • Conclusion
    • References

    36. Toxins as tools

    • Introduction
    • Inactivation of Rho GTPases by bacterial protein toxins
    • Rho-activating toxins
    • ADP-ribosylating toxins to study actin
    • Clostridial neurotoxins as tools to study exocytosis
    • Toxins for intracellular protein delivery
    • Conclusion
    • References

    37. Exploiting endocytic pathways to prevent bacterial toxin infection

    • Introduction
    • Mode of entry utilized by toxins
    • CME
    • IL-2 receptor endocytic pathway
    • Toxins exploiting multiple entry mechanisms
    • Lipid-binding toxins
    • Synaptic vesicle recycling and toxin entry into neurons
    • Toxins with undefined intra/extracellular pore-forming activity
    • The availability of SMIs
    • Inhibitors of clathrin and CME
    • Other inhibitors of toxin endocytosis and trafficking
    • Competitive inhibitors and antibodies (targeting the toxin)
    • Development and testing of SMIs in the future
    • Conclusion
    • References

    38. Inhibitors of pore-forming toxins

    • Introduction
    • Pore-forming bacterial toxins and their inhibitors
    • Anthrax toxin of B. anthracis
    • Clostridial binary toxin B subunits are close orthologs of the PA of anthrax
    • Small-molecule cationic pore blockers
    • Polyvalent cationic pore blockers
    • Inhibiting staphylococcal membrane-perforating toxins
    • Inhibiting ETX of C. perfringens
    • Concluding remarks
    • Acknowledgments
    • References

    39. Bacterial protein toxins as biological weapons

    • Introduction
    • The beginning of U.S. bioterrorism awareness
    • Dual-use research of concern (DURC)
    • Bacterial protein toxins as biological weapons
    • BoNT as a bioweapon
    • SEB as a bioweapon
    • SEB diagnosis and treatment
    • C. perfringens epsilon toxin
    • Concluding remarks
    • Disclaimer
    • References

Product details

  • No. of pages: 1200
  • Language: English
  • Copyright: © Elsevier 2015
  • Published: May 1, 2015
  • Imprint: Elsevier
  • Hardcover ISBN: 9780128001882
  • eBook ISBN: 9780128005897

About the Authors

Joseph Alouf

Joseph E. Alouf is Professor of Microbiology at the Pasteur Institute of Lille. He is former Head of the Department of Bacteriology and Mycology at the Pasteur Institute at Paris and Chairman of its Scientific Council. He served as Secretary General of the French Society of Immunology from 1984-1986 and President of the Federation of the European Microbiological Societies from 1989-1992. His 40-year research work relates to the field of bacterial protein toxins and immunology of infectious diseases. He is also the co-editor of several books.

Affiliations and Expertise

Institute Pasteur de Lille, France

Daniel Ladant

Daniel Ladant is Director of Research at French CNRS (National Center for Scientific Research) and head of the “Biochemistry of Macromolecular Interactions” unit at Institut Pasteur, Paris, France. He obtained a Ph.D. in Microbiology in 1989 and a « Habilitation à Diriger des Recherches » (HDR), in 1999 from the Université Paris Diderot, Paris, France. His research has been mainly focused on the study of the molecular mechanisms that underlie protein-protein and protein-membrane interactions, using as a model system a bacterial toxin, the adenylate cyclase (CyaA) produced by Bordetella pertussis, the causative agent of whooping cough. CyaA is an essential virulence factor from B. pertussis, and belongs to the large family of RTX (Repeat in ToXins) cytolysins produced by diverse Gram-negative bacteria. By combining molecular genetics, biochemical and biophysical approaches, he has characterized the structure, function and biogenesis of the CyaA toxin, with a particular emphasis on deciphering the molecular basis of its original entry pathway that involves a direct translocation of its catalytic domain across the plasma membrane. Basic knowledge gained on the mechanisms of CyaA entry into eukaryotic target cells and its interaction with cellular effectors has been used to develop various applications in vaccinology and biotechnology. In particular, the natural property of the CyaA toxin to target immune cells has been exploited to create innovative vaccines capable of stimulating potent cell-mediated immune responses against specific antigens. Two CyaA-based recombinant vaccines are currently evaluated in clinical trials. D. Ladant also designed a CyaA-based two-hybrid (BACTH) technology that has been exploited for studying, in bacteria, the assembly of protein complexes, and particularly to analyze membrane associated machineries such as bacterial secretion systems or the bacterial cell division apparatus. His other research interests include the other class II bacterial adenylate cyclase toxins, such as Edema Factor (EF) from Bacillus anthracis and ExoY toxin from Pseudomonas aeruginosa, in particular to explore of the allosteric mechanisms implicated in the activation of these enzymes by eukaryotic factors.

He has published more than 90 articles in peer-reviewed journals, 20 review articles or Book chapters and co-authored 11 patents.

Affiliations and Expertise

PhD, Director of Research at French CNRS (National Center for Scientific Research) and head of the Biochemistry of Macromolecular Interactions unit at Institut Pasteur, Paris, France

Michel Popoff

Michel R. Popoff, D.V.M., Ph.D. (Microbiology) from the University of Paris (1985), Habilitation à Diriger des Recherches (HDR) from the University of Paris (1990), is the Head of the Anaerobic Bacteria and Toxins Unit and the Director of the National Reference Center for Anaerobic Bacteria and Botulism at Pasteur Institute, Paris, France. He is member of the French Veterinary Academy. His laboratory is focused on Clostridium toxins through genetic and biological activity analysis and has investigated the regulation of toxin synthesis in Clostridium botulinum and Clostridium tetani. In the recent years, we have analyzed the molecular mechanism of the actin depolymerizing C. sordellii lethal toxin and clostridial binary toxins, the pore-forming C. perfringens epsilon toxin, and the passage of botulinum neurotoxin through the intestinal barrier. He was co-editor of the 3° edition of the Sourcebook of Bacterial Protein Toxins Academic Press (2006).

Affiliations and Expertise

CNR Anaerobies et Botulisme, Unite Bacteries anaerobies et Toxines, Institut Pasteur, FRANCE

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