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Annual Review of Biochemistry Jun 2019Botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) are the most potent toxins known and cause botulism and tetanus, respectively. BoNTs are also widely utilized... (Review)
Review
Botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) are the most potent toxins known and cause botulism and tetanus, respectively. BoNTs are also widely utilized as therapeutic toxins. They contain three functional domains responsible for receptor-binding, membrane translocation, and proteolytic cleavage of host proteins required for synaptic vesicle exocytosis. These toxins also have distinct features: BoNTs exist within a progenitor toxin complex (PTC), which protects the toxin and facilitates its absorption in the gastrointestinal tract, whereas TeNT is uniquely transported retrogradely within motor neurons. Our increasing knowledge of these toxins has allowed the development of engineered toxins for medical uses. The discovery of new BoNTs and BoNT-like proteins provides additional tools to understand the evolution of the toxins and to engineer toxin-based therapeutics. This review summarizes the progress on our understanding of BoNTs and TeNT, focusing on the PTC, receptor recognition, new BoNT-like toxins, and therapeutic toxin engineering.
Topics: Animals; Botulinum Toxins; Humans; Metalloendopeptidases; Protein Conformation; Protein Engineering; Tetanus Toxin
PubMed: 30388027
DOI: 10.1146/annurev-biochem-013118-111654 -
Toxins Jan 2021Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal... (Review)
Review
Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal dystonia, despite short-term clinical benefits and the risks of adverse effects. To cater for the high demand across various medical specialties, at least six US Food and Drug Administration (FDA)-approved formulations of BoNT are currently available for diverse labelled indications. The toxo-pharmacological properties of these formulations are not uniform and thus should not be used interchangeably. Synthetic BoNTs and BoNTs from non-clostridial sources are not far from clinical use. Moreover, the study of mutations in naturally occurring toxins has led to modulation in the toxo-pharmacokinetic properties of BoNTs, including the duration and potency. We present an overview of the toxo-pharmacology of conventional and novel BoNT preparations, including those awaiting imminent translation from the laboratory to the clinic.
Topics: Bacterial Toxins; Botulinum Toxins; Drug Compounding; Drug Development; Drug Prescriptions; Humans; Nervous System Diseases; Neuromuscular Agents; Neuromuscular Junction; Recombinant Proteins
PubMed: 33466571
DOI: 10.3390/toxins13010058 -
Toxins Sep 2020Toxins are the major pathogenicity factors produced by numerous bacteria involved in severe diseases in humans and animals. Certain pathogenic bacteria synthesize only...
Toxins are the major pathogenicity factors produced by numerous bacteria involved in severe diseases in humans and animals. Certain pathogenic bacteria synthesize only one toxin which is responsible for all the symptoms and outcome of the disease. For example, botulinum toxins (BoNTs) and tetanus toxin (TeNT) are the unique causal factors of botulism and tetanus, respectively. Other bacteria attack the host organism by a set of multiple toxins which synergistically act to promote the disease. This is the case of and strains which secrete wide ranges of toxins such as pore-forming toxins, membrane phospholipid damaging toxins, and other cytotoxins and toxins interacting with the immune system involved in gangrene lesion generation.
Topics: Acetylcholine Release Inhibitors; Animals; Bacterial Toxins; Botulinum Toxins; Clostridium; Humans; Insecticides; Pore Forming Cytotoxic Proteins; Staphylococcus
PubMed: 32899816
DOI: 10.3390/toxins12090570 -
Cell Mar 2022Enterococci are a part of human microbiota and a leading cause of multidrug resistant infections. Here, we identify a family of Enterococcus pore-forming toxins (Epxs)...
Enterococci are a part of human microbiota and a leading cause of multidrug resistant infections. Here, we identify a family of Enterococcus pore-forming toxins (Epxs) in E. faecalis, E. faecium, and E. hirae strains isolated across the globe. Structural studies reveal that Epxs form a branch of β-barrel pore-forming toxins with a β-barrel protrusion (designated the top domain) sitting atop the cap domain. Through a genome-wide CRISPR-Cas9 screen, we identify human leukocyte antigen class I (HLA-I) complex as a receptor for two members (Epx2 and Epx3), which preferentially recognize human HLA-I and homologous MHC-I of equine, bovine, and porcine, but not murine, origin. Interferon exposure, which stimulates MHC-I expression, sensitizes human cells and intestinal organoids to Epx2 and Epx3 toxicity. Co-culture with Epx2-harboring E. faecium damages human peripheral blood mononuclear cells and intestinal organoids, and this toxicity is neutralized by an Epx2 antibody, demonstrating the toxin-mediated virulence of Epx-carrying Enterococcus.
Topics: Animals; Bacterial Toxins; Cattle; Enterococcus; Horses; Leukocytes, Mononuclear; Mice; Microbial Sensitivity Tests; Swine; Virulence Factors
PubMed: 35259335
DOI: 10.1016/j.cell.2022.02.002 -
Journal of Leukocyte Biology Sep 2020Discussion on lethal toxin-induced acute IL-1β production as dependent on NLRP1b and caspase-1, PAD4, cell-free DNA and neutrophils.
Discussion on lethal toxin-induced acute IL-1β production as dependent on NLRP1b and caspase-1, PAD4, cell-free DNA and neutrophils.
Topics: Antigens, Bacterial; Apoptosis Regulatory Proteins; Bacterial Toxins; Caspase 1; Macrophages
PubMed: 32401416
DOI: 10.1002/JLB.4CE0320-101R -
Microbiology (Reading, England) Mar 2022Pore-forming toxins (PFTs) are widely distributed in both Gram-negative and Gram-positive bacteria. PFTs can act as virulence factors that bacteria utilise in...
Pore-forming toxins (PFTs) are widely distributed in both Gram-negative and Gram-positive bacteria. PFTs can act as virulence factors that bacteria utilise in dissemination and host colonisation or, alternatively, they can be employed to compete with rival microbes in polymicrobial niches. PFTs transition from a soluble form to become membrane-embedded by undergoing large conformational changes. Once inserted, they perforate the membrane, causing uncontrolled efflux of ions and/or nutrients and dissipating the protonmotive force (PMF). In some instances, target cells intoxicated by PFTs display additional effects as part of the cellular response to pore formation. Significant progress has been made in the mechanistic description of pore formation for the different PFTs families, but in several cases a complete understanding of pore structure remains lacking. PFTs have evolved recognition mechanisms to bind specific receptors that define their host tropism, although this can be remarkably diverse even within the same family. Here we summarise the salient features of PFTs and highlight where additional research is necessary to fully understand the mechanism of pore formation by members of this diverse group of protein toxins.
Topics: Bacteria; Bacterial Toxins; Cell Membrane; Humans; Pore Forming Cytotoxic Proteins; Virulence Factors
PubMed: 35333704
DOI: 10.1099/mic.0.001154 -
Microbiology Spectrum Jul 2019The pathogenesis of clostridial myonecrosis or gas gangrene involves an interruption to the blood supply to the infected tissues, often via a traumatic wound, anaerobic...
The pathogenesis of clostridial myonecrosis or gas gangrene involves an interruption to the blood supply to the infected tissues, often via a traumatic wound, anaerobic growth of the infecting clostridial cells, the production of extracellular toxins, and toxin-mediated cell and tissue damage. This review focuses on host-pathogen interactions in -mediated and -mediated myonecrosis. The major toxins involved are α-toxin, which has phospholipase C and sphingomyelinase activity, and α-toxin, a β-pore-forming toxin that belongs to the aerolysin family. Although these toxins are cytotoxic, their effects on host cells are quite complex, with a range of intracellular cell signaling pathways induced by their action on host cell membranes.
Topics: Anaerobiosis; Bacterial Toxins; Clostridium perfringens; Clostridium septicum; Gas Gangrene; Host-Pathogen Interactions; Humans; Wounds and Injuries
PubMed: 31350831
DOI: 10.1128/microbiolspec.GPP3-0024-2018 -
International Journal of Molecular... Nov 2022The huge advances in genomics and molecular biology in the past two decades have made now an exciting time to study bacterial toxins, in particular, the most potent...
The huge advances in genomics and molecular biology in the past two decades have made now an exciting time to study bacterial toxins, in particular, the most potent bacterial toxin known to humankind, botulinum neurotoxins (BoNTs) [...].
Topics: Neurotoxins; Clostridium; Botulinum Toxins; Bacterial Toxins; Genomics
PubMed: 36430554
DOI: 10.3390/ijms232214076 -
Frontiers in Cellular and Infection... 2021The dynamic host environment presents a significant hurdle that pathogenic bacteria must overcome to survive and cause diseases. Consequently, these organisms have... (Review)
Review
The dynamic host environment presents a significant hurdle that pathogenic bacteria must overcome to survive and cause diseases. Consequently, these organisms have evolved molecular mechanisms to facilitate adaptation to environmental changes within the infected host. Small RNAs (sRNAs) have been implicated as critical regulators of numerous pathways and systems in pathogenic bacteria, including that of bacterial Toxin-Antitoxin (TA) systems. TA systems are typically composed of two factors, a stable toxin, and a labile antitoxin which functions to protect against the potentially deleterious activity of the associated toxin. Of the six classes of bacterial TA systems characterized to date, the toxin component is always a protein. Type I and Type III TA systems are unique in that the antitoxin in these systems is an RNA molecule, whereas the antitoxin in all other TA systems is a protein. Though hotly debated, the involvement of TA systems in bacterial physiology is recognized by several studies, with the Type II TA system being the most extensively studied to date. This review focuses on RNA-regulated TA systems, highlighting the role of Type I and Type III TA systems in several pathogenic bacteria.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; RNA; Toxin-Antitoxin Systems
PubMed: 34084755
DOI: 10.3389/fcimb.2021.661026 -
Current Opinion in Microbiology Feb 2022Clostridioides difficile produces toxins TcdA and TcdB during infection. Since the severity of the illness is directly correlated with the level of toxins produced,... (Review)
Review
Clostridioides difficile produces toxins TcdA and TcdB during infection. Since the severity of the illness is directly correlated with the level of toxins produced, researchers have long been interested in the regulation mechanisms of toxin production. The advent of new genetics and mutagenesis technologies in C. difficile has allowed a slew of new investigations in the last decade, which considerably improved our understanding of this crucial regulatory network. The current body of work shows that the toxin regulatory network overlaps with the regulatory networks of sporulation, motility, and key metabolic pathways. This implies that toxin production is a complicated process initiated by bacteria in response to numerous host factors during infection. We summarize the existing knowledge about the toxin gene regulatory network here.
Topics: Bacterial Proteins; Bacterial Toxins; Clostridioides difficile; Enterotoxins
PubMed: 34781095
DOI: 10.1016/j.mib.2021.10.018