Special Issue "Gram Positive Toxins Producing Organisms"

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Molecular Microbiology and Immunology".

Deadline for manuscript submissions: 31 December 2022 | Viewed by 6235

Special Issue Editors

Dr. Shashi Sharma
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Chief Guest Editor
Division of Microbiology, Office of Regulatory Science, CFSAN/US Food and Drug Administration, MD 20740, USA
Interests: select agent research; toxins; bacteria; gram positive
Dr. Stephen A. Morse
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Co-Guest Editor
IHRC, Inc., 2 Ravinia Drive, Suite 1200, Atlanta, GA 30346, USA
Interests: all aspect of select agent research; gram positive bacterial and other toxins
Dr. Sabine Pellett
E-Mail Website
Co-Guest Editor
Department of Bacteriology, Botulinum Toxins Laboratory, University of Wisconsin, 1550 Linden Drive, Madison, WI 53706, USA
Interests: botulinum toxins; food safety; plasmids; transposons; bacteriophages
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Special Issue Information

Dear Colleagues,

Many bacteria produce toxins of considerable medical importance. Vaccines have been developed for some of the toxin-mediated diseases (e.g., tetanus, diphtheria) and continue to be important in the prevention of disease. Over the past few decades, great strides have been made in our understanding of the structure and function of bacterial toxins and their role in disease.  These advances reflect the productive interactions of disciplines such as protein chemistry and crystallography, molecular genetics, molecular biology, genomics, immunology, neurobiology, pharmacology, and biophysics.  Remarkable progress has been made in the elucidation of the molecular mechanisms of a wide range of toxins with increasing numbers found to have enzymatic activities, including those that ADP-ribosylate (e.g., diphtheria toxin) and glycosylate novel targets, and Zn-proteinases with exquisite specificities (e.g., botulinum A neurotoxin and SNAP-25).    The host immune system is not only the primary defense against colonization and sometimes invasion by toxigenic bacteria, but it also constitutes a major target for bacterial toxins that can act either directly by cytotoxicity towards immune effector cells, or indirectly by deregulation of cytokine production. 

Toxin genes and other virulence determinants are frequently encoded by mobile genetic elements, which are located on pathogenicity islands and/or on mobilizable genetic elements such as plasmids, transposons, and bacteriophages.  These genetic elements with the capacity to be spread by horizontal gene transfer contribute to the rapid evolution of bacterial pathogens as the rearrangement, excision and acquisition of large genomic regions creates new pathogenic variants.  The occurrence of toxin-encoding genes on various interdepending genetic elements, their ability to delete from and integrate into chromosomal DNA and the existence of toxin families among a wide variety of bacterial species demonstrate that toxigenic pathogen evolution is connected to the transfer of foreign DNA harboring toxin determinants. 

The aim of this issue is to provide a collection of articles that highlights research on bacterial toxins.  The editors chose to focus this issue on Gram positive bacterial toxins.  Submissions reflecting all aspects of toxin research are welcome from applied (novel diagnostics, countermeasures, vaccines) to more basic areas related to the biology of the toxin, genomics, and pathogenesis.  Gram positive toxins include, but are not limited to, tetanus toxin, botulinum toxins, staphylococcal toxins, diphtheria toxin, streptococcal toxins, Listeria toxin, anthrax toxins, Bacillus cereus toxins, pneumolysin, enterococcal toxins, and other clostridial toxins (e.g., perfringolysin O).  Each of these toxins has a unique story to tell but needs a storyteller.  We hope you will be able to contribute to this special issue on Gram positive toxins. 

Dr. Shashi Sharma
Dr. Stephen A. Morse
Dr. Sabine Pellett
Guest Editors

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Published Papers (7 papers)

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Research

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Article
Streptococcus pyogenes NAD+-Glycohydrolase Reduces Skeletal Muscle βNAD+ Levels Independently of Streptolysin O
Microorganisms 2022, 10(7), 1476; https://doi.org/10.3390/microorganisms10071476 - 21 Jul 2022
Viewed by 253
Abstract
Necrotizing soft tissue infections caused by Streptococcus pyogenes (group A streptococcus [GAS]) are characterized by rapid and extensive necrosis of fascia and muscle. Molecular epidemiological studies have demonstrated a positive correlation between GAS isolates that cause invasive infections and the production of S. [...] Read more.
Necrotizing soft tissue infections caused by Streptococcus pyogenes (group A streptococcus [GAS]) are characterized by rapid and extensive necrosis of fascia and muscle. Molecular epidemiological studies have demonstrated a positive correlation between GAS isolates that cause invasive infections and the production of S. pyogenes NAD+-glycohydrolase (SPN), an NADase secreted by GAS, but the effect of SPN on muscle cells has not been described. Thus, using standard βNAD+ and ATP quantification assays, we investigated the effects of SPN on cultured human skeletal muscle cell (SkMC) βNAD+ and ATP with and without streptolysin O (SLO)–a secreted cholesterol-dependent cytolysin known to act synergistically with SPN. We found that culture supernatants from GAS strains producing SLO and SPN depleted intracellular βNAD+ and ATP, while exotoxins from a GAS strain producing SLO and an enzymatically-inactive form of SPN had no effect on βNAD+ or ATP. Addition of purified, enzymatically-active SPN to NADase-negative culture supernatants or sterile media reconstituted βNAD+ depletion but had no effect ATP levels. Further, SPN-mediated βNAD+ depletion could be augmented by SLO or the homologous cholesterol-dependent cytolysin, perfringolysin O (PFO). Remarkably, SPN-mediated βNAD+ depletion was SkMC-specific, as purified SPN had minimal effect on epithelial cell βNAD+. Taken together, this study identifies a previously unrecognized role for SPN as a major disruptor of skeletal muscle βNAD+. Such activity could contribute to the rapid and widespread myonecrosis characteristic of severe GAS soft tissue infections. Full article
(This article belongs to the Special Issue Gram Positive Toxins Producing Organisms)
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Article
Comparative Genomics of Clostridium baratii Reveals Strain-Level Diversity in Toxin Abundance
Microorganisms 2022, 10(2), 213; https://doi.org/10.3390/microorganisms10020213 - 20 Jan 2022
Cited by 2 | Viewed by 714
Abstract
Clostridium baratii strains are rare opportunistic pathogens associated with botulism intoxication. They have been isolated from foods, soil and be carried asymptomatically or cause botulism outbreaks. Is not taxonomically related to Clostridium botulinum, but some strains are equipped with BoNT/F7 cluster. Despite [...] Read more.
Clostridium baratii strains are rare opportunistic pathogens associated with botulism intoxication. They have been isolated from foods, soil and be carried asymptomatically or cause botulism outbreaks. Is not taxonomically related to Clostridium botulinum, but some strains are equipped with BoNT/F7 cluster. Despite their relationship with diseases, our knowledge regarding the genomic features and phylogenetic characteristics is limited. We analyzed the pangenome of C. baratii to understand the diversity and genomic features of this species. We compared existing genomes in public databases, metagenomes, and one newly sequenced strain isolated from an asymptomatic subject. The pangenome was open, indicating it comprises genetically diverse organisms. The core genome contained 28.49% of the total genes of the pangenome. Profiling virulence factors confirmed the presence of phospholipase C in some strains, a toxin capable of disrupting eukaryotic cell membranes. Furthermore, the genomic analysis indicated significant horizontal gene transfer (HGT) events as defined by the presence of prophage genomes. Seven strains were equipped with BoNT/F7 cluster. The active site was conserved in all strains, identifying a missing 7-aa region upstream of the active site in C. baratii genomes. This analysis could be important to advance our knowledge regarding opportunistic clostridia and better understand their contribution to disease. Full article
(This article belongs to the Special Issue Gram Positive Toxins Producing Organisms)
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Article
Extensive Genome Exploration of Clostridium botulinum Group III Field Strains
Microorganisms 2021, 9(11), 2347; https://doi.org/10.3390/microorganisms9112347 - 13 Nov 2021
Viewed by 678
Abstract
In animals, botulism is commonly sustained by botulinum neurotoxin C, D or their mosaic variants, which are produced by anaerobic bacteria included in Clostridium botulinum group III. In this study, a WGS has been applied to a large collection of C. botulinum group [...] Read more.
In animals, botulism is commonly sustained by botulinum neurotoxin C, D or their mosaic variants, which are produced by anaerobic bacteria included in Clostridium botulinum group III. In this study, a WGS has been applied to a large collection of C. botulinum group III field strains in order to expand the knowledge on these BoNT-producing Clostridia and to evaluate the potentiality of this method for epidemiological investigations. Sixty field strains were submitted to WGS, and the results were analyzed with respect to epidemiological information and compared to published sequences. The strains were isolated from biological or environmental samples collected in animal botulism outbreaks which occurred in Italy from 2007 to 2016. The new sequenced strains belonged to subspecific groups, some of which were already defined, while others were newly characterized, peculiar to Italian strains and contained genomic features not yet observed. This included, in particular, two new flicC types (VI and VII) and new plasmids which widen the known plasmidome of the species. The extensive genome exploration shown in this study improves the C. botulinum and related species classification scheme, enriching it with new strains of rare genotypes and permitting the highest grade of discrimination among strains for forensic and epidemiological applications. Full article
(This article belongs to the Special Issue Gram Positive Toxins Producing Organisms)
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Article
A Rapid and Simple Assay Correlates In Vitro NetB Activity with Clostridium perfringens Pathogenicity in Chickens
Microorganisms 2021, 9(8), 1708; https://doi.org/10.3390/microorganisms9081708 - 11 Aug 2021
Cited by 1 | Viewed by 1077
Abstract
Necrotic enteritis is an important enteric disease in poultry, caused by NetB-producing Clostridium (C.) perfringens strains. As no straight-forward method to assess the NetB activity of C. perfringens was available, we aimed to develop an easy, high-throughput method to measure the NetB activity [...] Read more.
Necrotic enteritis is an important enteric disease in poultry, caused by NetB-producing Clostridium (C.) perfringens strains. As no straight-forward method to assess the NetB activity of C. perfringens was available, we aimed to develop an easy, high-throughput method to measure the NetB activity produced by C. perfringens. First, the appearance of C. perfringens on different avian blood agar plates was assessed. Based on the size of the haemolysis surrounding the C. perfringens colonies, NetB-positive strains could phenotypically be discriminated from NetB-negative strains on both chicken and duck blood agar. Additionally, strains producing the consensus NetB protein induced more pronounced haemolysis on chicken blood agar as compared to the weak outer haemolysis induced by A168T NetB-variant-producing C. perfringens strains. Next, a 96-well plate-based haemolysis assay to screen NetB activity in the C. perfringens culture supernatants was developed. Using this assay, a positive correlation between the in vitro NetB activity and virulence of the C. perfringens strains was shown. The developed activity assay allows us to screen novel C. perfringens isolates for their in vitro NetB activity, which could give valuable information on their disease-inducing potential, or identify molecules and (bacterial) metabolites that affect NetB expression and activity. Full article
(This article belongs to the Special Issue Gram Positive Toxins Producing Organisms)
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Review

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Review
Recent Developments in Botulinum Neurotoxins Detection
Microorganisms 2022, 10(5), 1001; https://doi.org/10.3390/microorganisms10051001 - 10 May 2022
Viewed by 650
Abstract
Botulinum neurotoxins (BoNTs) are produced as protein complexes by bacteria of the genus Clostridium that are Gram-positive, anaerobic and spore forming (Clostridium botulinum, C. butyricum, C. baratii and C. argentinense spp.). BoNTs show a high immunological and genetic diversity. Therefore, [...] Read more.
Botulinum neurotoxins (BoNTs) are produced as protein complexes by bacteria of the genus Clostridium that are Gram-positive, anaerobic and spore forming (Clostridium botulinum, C. butyricum, C. baratii and C. argentinense spp.). BoNTs show a high immunological and genetic diversity. Therefore, fast, precise, and more reliable detection methods are still required to monitor outbreaks and ensure surveillance of botulism. The botulinum toxin field also comprises therapeutic uses, basic research studies and biodefense issues. This review presents currently available detection methods, and new methods offering the potential of enhanced precision and reproducibility. While the immunological methods offer a range of benefits, such as rapid analysis time, reproducibility and high sensitivity, their implementation is subject to the availability of suitable tools and reagents, such as specific antibodies. Currently, the mass spectrometry approach is the most sensitive in vitro method for a rapid detection of active or inactive forms of BoNTs. However, these methods require inter-laboratory validation before they can be more widely implemented in reference laboratories. In addition, these surrogate in vitro models also require full validation before they can be used as replacement bioassays of potency. Cell-based assays using neuronal cells in culture recapitulate all functional steps of toxin activity, but are still at various stages of development; they are not yet sufficiently robust, due to high batch-to-batch cell variability. Cell-based assays have a strong potential to replace the mouse bioassay (MBA) in terms of BoNT potency determination in pharmaceutical formulations; they can also help to identify suitable inhibitors while reducing the number of animals used. However, the development of safe countermeasures still requires the use of in vivo studies to complement in vitro immunological or cell-based approaches. Full article
(This article belongs to the Special Issue Gram Positive Toxins Producing Organisms)
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Review
Preclinical Evidence for the Role of Botulinum Neurotoxin A (BoNT/A) in the Treatment of Peripheral Nerve Injury
Microorganisms 2022, 10(5), 886; https://doi.org/10.3390/microorganisms10050886 - 24 Apr 2022
Viewed by 579
Abstract
Traumatic peripheral nerve injuries tend to be more common in younger, working age populations and can lead to long-lasting disability. Peripheral nerves have an impressive capacity to regenerate; however, successful recovery after injury depends on a number of factors including the mechanism and [...] Read more.
Traumatic peripheral nerve injuries tend to be more common in younger, working age populations and can lead to long-lasting disability. Peripheral nerves have an impressive capacity to regenerate; however, successful recovery after injury depends on a number of factors including the mechanism and severity of the trauma, the distance from injury to the reinnervation target, connective tissue sheath integrity, and delay between injury and treatment. Even though modern surgical procedures have greatly improved the success rate, many peripheral nerve injuries still culminate in persistent neuropathic pain and incomplete functional recovery. Recent studies in animals suggest that botulinum neurotoxin A (BoNT/A) can accelerate nerve regeneration and improve functional recovery after injury to peripheral nerves. Possible mechanisms of BoNT/A action include activation or proliferation of support cells (Schwann cells, mast cells, and macrophages), increased angiogenesis, and improvement of blood flow to regenerating nerves. Full article
(This article belongs to the Special Issue Gram Positive Toxins Producing Organisms)
Review
Clostridial Neurotoxins: Structure, Function and Implications to Other Bacterial Toxins
Microorganisms 2021, 9(11), 2206; https://doi.org/10.3390/microorganisms9112206 - 23 Oct 2021
Cited by 3 | Viewed by 885
Abstract
Gram-positive bacteria are ancient organisms. Many bacteria, including Gram-positive bacteria, produce toxins to manipulate the host, leading to various diseases. While the targets of Gram-positive bacterial toxins are diverse, many of those toxins use a similar mechanism to invade host cells and exert [...] Read more.
Gram-positive bacteria are ancient organisms. Many bacteria, including Gram-positive bacteria, produce toxins to manipulate the host, leading to various diseases. While the targets of Gram-positive bacterial toxins are diverse, many of those toxins use a similar mechanism to invade host cells and exert their functions. Clostridial neurotoxins produced by Clostridial tetani and Clostridial botulinum provide a classical example to illustrate the structure–function relationship of bacterial toxins. Here, we critically review the recent progress of the structure–function relationship of clostridial neurotoxins, including the diversity of the clostridial neurotoxins, the mode of actions, and the flexible structures required for the activation of toxins. The mechanism clostridial neurotoxins use for triggering their activity is shared with many other Gram-positive bacterial toxins, especially molten globule-type structures. This review also summarizes the implications of the molten globule-type flexible structures to other Gram-positive bacterial toxins. Understanding these highly dynamic flexible structures in solution and their role in the function of bacterial toxins not only fills in the missing link of the high-resolution structures from X-ray crystallography but also provides vital information for better designing antidotes against those toxins. Full article
(This article belongs to the Special Issue Gram Positive Toxins Producing Organisms)
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