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Toxins
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Toxins and Immunology
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Toxins and Immunology

A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 49609

Special Issue Editor

Prof. Dr. Jean Marc Cavaillon

E-Mail Website
Guest Editor
French National Research Agency (ANR, Paris), 75012 Paris, France
Interests: infectious diseases; inflammation; critical care medicine; innate immunity

Special Issue Information

Dear Colleauges,

Toxinology and immunology have been closely linked since their respective births, when Behring and Kitasato demonstrated that serotherapy was effective against diphtheria, when Roux and Yersin discovered its dreadful toxin, and when Ramon described the anatoxin that allowed the elaboration of an effective vaccine, and discovered the use of adjuvant to boost the antibody response. Toxins are part of the bacterial arsenal and are responsible for danger of venoms. As a consequence, they need to be targeted by the immune system. Elaboration of neutralizing specific antibodies is part of the immune defense, and the use of serotherapy remains of great help in the case of venom poisoning. Some toxins behave as superantigens and trigger immune cells in a very specific fashion. Toxins activate the inflammasome and the elaboration of endogenous pyrogens that cause fever, a protective mechanism against infection. However, toxins can also induce a cytokine storm with their pathophysiological consequences. Their toxicity can be directed against the immune leukocytes, weakening the immune defense. However, scientists have also diverted its main property to use it as a weapon against tumor cells. Finally, the existence of IgE against toxins may explain their maintenance through evolution despite their side effect in allergy.

The aim of this Special Issue is to offer an overview of the current knowledge in the interaction between toxins and the immune system.

Prof. Jean Marc Cavaillon
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Antibodies
  • Cancer
  • Cell death
  • Fever
  • IgE
  • Inflammation
  • Innate immunity
  • Leukocytes
  • Serotherapy
  • Superantigens.

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Published Papers (7 papers)

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Research

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18 pages, 1911 KiB  
Article
Intradermal Application of Crotamine Induces Inflammatory and Immunological Changes In Vivo
by Ana Vitória Pupo Silvestrini, Luana Henrique de Macedo, Thiago Antônio Moretti de Andrade, Maíra Felonato Mendes, Acácio Antônio Pigoso and Maurício Ventura Mazzi
Toxins 2019, 11(1), 39; https://doi.org/10.3390/toxins11010039 - 14 Jan 2019
Cited by 10 | Viewed by 3895
Abstract
Crotamine is a single-chain polypeptide with cell-penetrating properties, which is considered a promising molecule for clinical use. Nevertheless, its biosafety data are still scarce. Herein, we assessed the in vivo proinflammatory properties of crotamine, including its local effect and systemic serum parameters. Sixty [...] Read more.
Crotamine is a single-chain polypeptide with cell-penetrating properties, which is considered a promising molecule for clinical use. Nevertheless, its biosafety data are still scarce. Herein, we assessed the in vivo proinflammatory properties of crotamine, including its local effect and systemic serum parameters. Sixty male Wistar rats were intradermically injected with 200, 400 and 800 µg crotamine and analyzed after 1, 3 and 7 days. Local effect of crotamine was assessed by determination of MPO and NAG activities, NO levels and angiogenesis. Systemic inflammatory response was assessed by determination of IL-10, TNF-α, CRP, NO, TBARS and SH groups. Crotamine induced macrophages and neutrophils chemotaxis as evidenced by the upregulation of both NAG (0.5–0.6 OD/mg) and MPO (0.1–0.2 OD/mg) activities, on the first and third day of analysis, respectively. High levels of NO were observed for all concentrations and time-points. Moreover, 800 μg crotamine resulted in serum NO (64.7 μM) and local tissue NO (58.5 μM) levels higher or equivalent to those recorded for their respective histamine controls (55.7 μM and 59.0 μM). Crotamine also induced a significant angiogenic response compared to histamine. Systemically, crotamine induced a progressive increase in serum CRP levels up to the third day of analysis (22.4–45.8 mg/mL), which was significantly greater than control values. Crotamine (400 μg) also caused an increase in serum TNF-α, in the first day of analysis (1095.4 pg/mL), however a significant increase in IL-10 (122.2 pg/mL) was also recorded for the same time-point, suggesting the induction of an anti-inflammatory effect. Finally, crotamine changed the systemic redox state by inducing gradual increase in serum levels of TBARS (1.0–1.8 μM/mL) and decrease in SH levels (124.7–19.5 μM/mL) throughout the experimental period of analysis. In summary, rats intradermally injected with crotamine presented local and systemic acute inflammatory responses similarly to histamine, which limits crotamine therapeutic use on its original form. Full article
(This article belongs to the Special Issue Toxins and Immunology)
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11 pages, 1218 KiB  
Article
SS1P Immunotoxin Induces Markers of Immunogenic Cell Death and Enhances the Effect of the CTLA-4 Blockade in AE17M Mouse Mesothelioma Tumors
by Yasmin Leshem, Emily M. King, Ronit Mazor, Yoram Reiter and Ira Pastan
Toxins 2018, 10(11), 470; https://doi.org/10.3390/toxins10110470 - 14 Nov 2018
Cited by 29 | Viewed by 4286
Abstract
SS1P is an anti-mesothelin immunotoxin composed of a targeting antibody fragment genetically fused to a truncated fragment of Pseudomonas exotoxin A. Delayed responses reported in mesothelioma patients receiving SS1P suggest that anti-tumor immunity is induced. The goal of this study is to evaluate [...] Read more.
SS1P is an anti-mesothelin immunotoxin composed of a targeting antibody fragment genetically fused to a truncated fragment of Pseudomonas exotoxin A. Delayed responses reported in mesothelioma patients receiving SS1P suggest that anti-tumor immunity is induced. The goal of this study is to evaluate if SS1P therapy renders mesothelioma tumors more sensitive to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade. We evaluated the ability of SS1P to induce adenosine triphosphate (ATP) secretion and calreticulin expression on the surface of AE17M mouse mesothelioma cells. Both properties are associated with immunogenic cell death. Furthermore, we treated these tumors with intra-tumoral SS1P and systemic CTLA-4. We found that SS1P increased the release of ATP from AE17M cells in a dose and time-dependent manner. In addition, SS1P induced calreticulin expression on the surface of AE17M cells. These results suggest that SS1P promotes immunogenic cell death and could sensitize tumors to anti-CTLA-4 based therapy. In mouse studies, we found that the combination of anti-CTLA-4 with intra-tumoral SS1P induced complete regressions in most mice and provided a statistically significant survival benefit compared to monotherapy. The surviving mice were protected from tumor re-challenge, indicating the development of anti-tumor immunity. These findings support the use of intra-tumoral SS1P in combination with anti-CTLA-4. Full article
(This article belongs to the Special Issue Toxins and Immunology)
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Review

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26 pages, 1928 KiB  
Review
Roles of Shiga Toxins in Immunopathology
by Moo-Seung Lee and Vernon L. Tesh
Toxins 2019, 11(4), 212; https://doi.org/10.3390/toxins11040212 - 9 Apr 2019
Cited by 63 | Viewed by 11453
Abstract
Shigella species and Shiga toxin-producing Escherichia coli (STEC) are agents of bloody diarrhea that may progress to potentially lethal complications such as diarrhea-associated hemolytic uremic syndrome (D+HUS) and neurological disorders. The bacteria share the ability to produce virulence factors called Shiga toxins (Stxs). [...] Read more.
Shigella species and Shiga toxin-producing Escherichia coli (STEC) are agents of bloody diarrhea that may progress to potentially lethal complications such as diarrhea-associated hemolytic uremic syndrome (D+HUS) and neurological disorders. The bacteria share the ability to produce virulence factors called Shiga toxins (Stxs). Research over the past two decades has identified Stxs as multifunctional toxins capable of inducing cell stress responses in addition to their canonical ribotoxic function inhibiting protein synthesis. Notably, Stxs are not only potent inducers of cell death, but also activate innate immune responses that may lead to inflammation, and these effects may increase the severity of organ injury in patients infected with Stx-producing bacteria. In the intestines, kidneys, and central nervous system, excessive or uncontrolled host innate and cellular immune responses triggered by Stxs may result in sensitization of cells to toxin mediated damage, leading to immunopathology and increased morbidity and mortality in animal models (including primates) and human patients. Here, we review studies describing Stx-induced innate immune responses that may be associated with tissue damage, inflammation, and complement activation. We speculate on how these processes may contribute to immunopathological responses to the toxins. Full article
(This article belongs to the Special Issue Toxins and Immunology)
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19 pages, 640 KiB  
Review
Staphylococcal Superantigens: Pyrogenic Toxins Induce Toxic Shock
by Teresa Krakauer
Toxins 2019, 11(3), 178; https://doi.org/10.3390/toxins11030178 - 23 Mar 2019
Cited by 83 | Viewed by 9708
Abstract
Staphylococcal enterotoxin B (SEB) and related superantigenic toxins produced by Staphylococcus aureus are potent activators of the immune system. These protein toxins bind to major histocompatibility complex (MHC) class II molecules and specific Vβ regions of T-cell receptors (TCRs), resulting in the activation [...] Read more.
Staphylococcal enterotoxin B (SEB) and related superantigenic toxins produced by Staphylococcus aureus are potent activators of the immune system. These protein toxins bind to major histocompatibility complex (MHC) class II molecules and specific Vβ regions of T-cell receptors (TCRs), resulting in the activation of both monocytes/macrophages and T lymphocytes. The bridging of TCRs with MHC class II molecules by superantigens triggers an early “cytokine storm” and massive polyclonal T-cell proliferation. Proinflammatory cytokines, tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 elicit fever, inflammation, multiple organ injury, hypotension, and lethal shock. Upon MHC/TCR ligation, superantigens induce signaling pathways, including mitogen-activated protein kinase cascades and cytokine receptor signaling, which results in NFκB activation and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. In addition, gene profiling studies have revealed the essential roles of innate antimicrobial defense genes in the pathogenesis of SEB. The genes expressed in a murine model of SEB-induced shock include intracellular DNA/RNA sensors, apoptosis/DNA damage-related molecules, endoplasmic reticulum/mitochondrial stress responses, immunoproteasome components, and IFN-stimulated genes. This review focuses on the signaling pathways induced by superantigens that lead to the activation of inflammation and damage response genes. The induction of these damage response genes provides evidence that SEB induces danger signals in host cells, resulting in multiorgan injury and toxic shock. Therapeutics targeting both host inflammatory and cell death pathways can potentially mitigate the toxic effects of staphylococcal superantigens. Full article
(This article belongs to the Special Issue Toxins and Immunology)
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23 pages, 4453 KiB  
Review
Serotherapy against Voltage-Gated Sodium Channel-Targeting α-Toxins from Androctonus Scorpion Venom
by Marie-France Martin-Eauclaire, Sonia Adi-Bessalem, Djelila Hammoudi-Triki, Fatima Laraba-Djebari and Pierre E. Bougis
Toxins 2019, 11(2), 63; https://doi.org/10.3390/toxins11020063 - 23 Jan 2019
Cited by 18 | Viewed by 7116
Abstract
Because of their venom lethality towards mammals, scorpions of the Androctonus genus are considered a critical threat to human health in North Africa. Several decades of exploration have led to a comprehensive inventory of their venom components at chemical, pharmacological, and immunological levels. [...] Read more.
Because of their venom lethality towards mammals, scorpions of the Androctonus genus are considered a critical threat to human health in North Africa. Several decades of exploration have led to a comprehensive inventory of their venom components at chemical, pharmacological, and immunological levels. Typically, these venoms contain selective and high affinity ligands for the voltage-gated sodium (Nav) and potassium (Kv) channels that dictate cellular excitability. In the well-studied Androctonus australis and Androctonus mauretanicus venoms, almost all the lethality in mammals is due to the so-called α-toxins. These peptides commonly delay the fast inactivation process of Nav channels, which leads to increased sodium entry and a subsequent cell membrane depolarization. Markedly, their neutralization by specific antisera has been shown to completely inhibit the venom’s lethal activity, because they are not only the most abundant venom peptide but also the most fatal. However, the structural and antigenic polymorphisms in the α-toxin family pose challenges to the design of efficient serotherapies. In this review, we discuss past and present accomplishments to improve serotherapy against Androctonus scorpion stings. Full article
(This article belongs to the Special Issue Toxins and Immunology)
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11 pages, 573 KiB  
Review
Pseudomonas Exotoxin Immunotoxins and Anti-Tumor Immunity: From Observations at the Patient’s Bedside to Evaluation in Preclinical Models
by Yasmin Leshem and Ira Pastan
Toxins 2019, 11(1), 20; https://doi.org/10.3390/toxins11010020 - 5 Jan 2019
Cited by 39 | Viewed by 5071
Abstract
Immunotoxins are protein drugs composed of a targeting domain genetically fused to a protein toxin. One killing domain being explored is a truncated Pseudomonas exotoxin A (PE). PE based immunotoxins are designed to kill cells directly by inhibiting their ability to synthesize proteins. [...] Read more.
Immunotoxins are protein drugs composed of a targeting domain genetically fused to a protein toxin. One killing domain being explored is a truncated Pseudomonas exotoxin A (PE). PE based immunotoxins are designed to kill cells directly by inhibiting their ability to synthesize proteins. However, observations from clinical trials suggest that this alone cannot explain their anti-tumor activity. Here we discuss patterns of clinical responses suggesting that PE immunotoxins can provoke anti-tumor immunity, and review murine models that further support this ability. In addition, we describe our preclinical effort to develop a combination therapy of local PE immunotoxins with a systemic anti-CTLA-4 immune check point blocking antibody. The combination eradicated murine tumors and prolonged the survival of mice. Clinical trials that test the ability of immunotoxins to augment immunotherapy have been recently opened. Full article
(This article belongs to the Special Issue Toxins and Immunology)
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13 pages, 1466 KiB  
Review
Interaction between Insects, Toxins, and Bacteria: Have We Been Wrong So Far?
by Guillaume Tetreau
Toxins 2018, 10(7), 281; https://doi.org/10.3390/toxins10070281 - 6 Jul 2018
Cited by 16 | Viewed by 6820
Abstract
Toxins are a major virulence factor produced by many pathogenic bacteria. In vertebrates, the response of hosts to the bacteria is inseparable from the response to the toxins, allowing a comprehensive understanding of this tripartite host-pathogen-toxin interaction. However, in invertebrates, this interaction has [...] Read more.
Toxins are a major virulence factor produced by many pathogenic bacteria. In vertebrates, the response of hosts to the bacteria is inseparable from the response to the toxins, allowing a comprehensive understanding of this tripartite host-pathogen-toxin interaction. However, in invertebrates, this interaction has been investigated by two complementary but historically distinct fields of research: toxinology and immunology. In this article, I highlight how such dichotomy between these two fields led to a biased, or even erroneous view of the ecology and evolution of the interaction between insects, toxins, and bacteria. I focus on the reason behind such a dichotomy, on how to bridge the fields together, and on confounding effects that could bias the outcome of the experiments. Finally, I raise four questions at the border of the two fields on the cross-effects between toxins, bacteria, and spores that have been largely underexplored to promote a more comprehensive view of this interaction. Full article
(This article belongs to the Special Issue Toxins and Immunology)
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