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Bacterial Exotoxins and Their Impact on Host–Pathogen Interaction in Animals and Humans

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 22040

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Special Issue Editor

Prof. Dr. Horst Posthaus

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Guest Editor

Institute of Animal Pathology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Interests: pathogenesis and pathology of bacterial infections; host-pathogen interaction; bacterial exotoxins; pore-forming toxins; clostridium perfringens toxins

Special Issue Information

Dear Colleagues,

Bacterial infections are a threat to human and animal health worldwide. In light of the increasing problem of antibiotic resistance, alternative treatments are needed. Understanding the mechanisms underlying host–pathogen interactions is crucial for the development of such alternative approaches. Many bacterial pathogens manipulate host cells and tissues via secreted toxins. A plethora of toxins targeting different cellular structures and functions has thus evolved. Toxic attacks on host cells come in many different flavors, ranging from an attack of the plasma membrane via a secreted enzyme to the internalization of multifunctional protein complexes that specifically target intracellular structures or pathways. In-depth knowledge about the mechanisms of how such specified toxins manipulate not only cellular, but also organ and body functions is central for our understanding of the pathogenesis of animal and human bacterial infections. Likewise, the host's cellular and systemic reactions to such "toxin attacks" contribute to disease and must be considered for the design of alternative treatments.

This Special Issue will focus on mechanisms of toxicity exploited by bacterial exotoxins, their effects on target cells and whole organisms as well as host reactions and defense mechanisms in response to these toxic effects. Original research articles, communications or reviews focused on these bacterial exotoxin–host interactions in animal and human disease are welcome.

Prof. Horst Posthaus
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

bacterial exotoxins
bacterial pathogens
animal
human
host–pathogen interaction
cellular toxicity
cell defense mechanisms
systemic effects

Published Papers (6 papers)

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Research

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18 pages, 4066 KiB

Open AccessEditor’s ChoiceArticle

Susceptibility of Sea Bream (Sparus aurata) to AIP56, an AB-Type Toxin Secreted by Photobacterium damselae subsp. piscicida

by Inês Lua Freitas, Alexandra Teixeira, Inês Loureiro, Johnny Lisboa, Aurélia Saraiva, Nuno Miguel Simões dos Santos and Ana do Vale

Toxins 2022, 14(2), 119; https://doi.org/10.3390/toxins14020119 - 05 Feb 2022

Cited by 4 | Viewed by 2534

Abstract

Photobacterium damselae subsp. piscicida (Phdp) is a Gram-negative bacterium that infects a large number of marine fish species in Europe, Asia, and America, both in aquacultures and in the natural environment. Among the affected hosts are economically important cultured fish, such as sea bream (Sparus aurata), sea bass (Dicentrarchus labrax), yellowtail (Seriola quinqueradiata), and cobia (Rachycentron canadum). The best characterized virulence factor of Phdp is the Apoptosis-Inducing Protein of 56 kDa (AIP56), a secreted AB-type toxin that has been shown to induce apoptosis of sea bass phagocytes during infection. AIP56 has an A subunit that displays metalloprotease activity against NF-kB p65 and a B subunit that mediates binding and internalization of the A subunit in susceptible cells. Despite the fact that the aip56 gene is highly prevalent in Phdp isolates from different fish species, the toxicity of AIP56 has only been studied in sea bass. In the present study, the toxicity of AIP56 for sea bream was evaluated. Ex vivo assays showed that sea bream phagocytes are resistant to AIP56 cytotoxicity and that resistance was associated with an inefficient internalization of the toxin by those cells. Accordingly, in vivo intoxication assays revealed that sea bream is much more resistant to AIP56-induced lethality than sea bass. These findings, showing that the effect of AIP56 is different in sea bass and sea bream, set the basis for future studies to characterize the effects of AIP56 and to fully elucidate its virulence role in different Phdp susceptible hosts. Full article

(This article belongs to the Special Issue Bacterial Exotoxins and Their Impact on Host–Pathogen Interaction in Animals and Humans)

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14 pages, 5418 KiB

Open AccessEditor’s ChoiceArticle

Platelet Endothelial Cell Adhesion Molecule 1 (CD31) Is Essential for Clostridium perfringens Beta-Toxin Mediated Cytotoxicity in Human Endothelial and Monocytic Cells

by Basma Tarek, Julia Bruggisser, Filippo Cattalani and Horst Posthaus

Toxins 2021, 13(12), 893; https://doi.org/10.3390/toxins13120893 - 13 Dec 2021

Cited by 4 | Viewed by 4599

Abstract

Beta toxin (CPB) is a small hemolysin beta pore-forming toxin (β-PFT) produced by Clostridium perfringens type C. It plays a central role in the pathogenesis of necro-hemorrhagic enteritis in young animals and humans via targeting intestinal endothelial cells. We recently identified the membrane protein CD31 (PECAM-1) as the receptor for CPB on mouse endothelial cells. We now assess the role of CD31 in CPB cytotoxicity against human endothelial and monocytic cells using a CRISPR/Cas9 gene knockout and an antibody blocking approach. CD31 knockout human endothelial and monocytic cells were resistant to CPB and CPB oligomers only formed in CD31-expressing cells. CD31 knockout endothelial and monocytic cells could be selectively enriched out of a polyclonal cell population by exposing them to CPB. Moreover, antibody mediated blocking of the extracellular Ig6 domain of CD31 abolished CPB cytotoxicity and oligomer formation in endothelial and monocytic cells. In conclusion, this study confirms the role of CD31 as a receptor of CPB on human endothelial and monocytic cells. Specific interaction with the CD31 molecule can thus explain the cell type specificity of CPB observed in vitro and corresponds to in vivo observations in naturally diseased animals. Full article

(This article belongs to the Special Issue Bacterial Exotoxins and Their Impact on Host–Pathogen Interaction in Animals and Humans)

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13 pages, 2016 KiB

Open AccessArticle

Small Pore-Forming Toxins Different Membrane Area Binding and Ca²⁺ Permeability of Pores Determine Cellular Resistance of Monocytic Cells

by Yu Larpin, Hervé Besançon, Victoriia S. Babiychuk, Eduard B. Babiychuk and René Köffel

Toxins 2021, 13(2), 126; https://doi.org/10.3390/toxins13020126 - 09 Feb 2021

Cited by 7 | Viewed by 1842

Abstract

Pore-forming toxins (PFTs) form multimeric trans-membrane pores in cell membranes that differ in pore channel diameter (PCD). Cellular resistance to large PFTs (>20 nm PCD) was shown to rely on Ca²⁺ influx activated membrane repair mechanisms. Small PFTs (<2 nm PCD) were shown to exhibit a high cytotoxic activity, but host cell response and membrane repair mechanisms are less well studied. We used monocytic immune cell lines to investigate the cellular resistance and host membrane repair mechanisms to small PFTs lysenin (Eisenia fetida) and aerolysin (Aeromonas hydrophila). Lysenin, but not aerolysin, is shown to induce Ca²⁺ influx from the extracellular space and to activate Ca²⁺ dependent membrane repair mechanisms. Moreover, lysenin binds to U937 cells with higher efficiency as compared to THP-1 cells, which is in line with a high sensitivity of U937 cells to lysenin. In contrast, aerolysin equally binds to U937 or THP-1 cells, but in different plasma membrane areas. Increased aerolysin induced cell death of U937 cells, as compared to THP-1 cells, is suggested to be a consequence of cap-like aerolysin binding. We conclude that host cell resistance to small PFTs attack comprises binding efficiency, pore localization, and capability to induce Ca²⁺ dependent membrane repair mechanisms. Full article

(This article belongs to the Special Issue Bacterial Exotoxins and Their Impact on Host–Pathogen Interaction in Animals and Humans)

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31 pages, 5779 KiB

Open AccessArticle

Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes

by Vineet I. Patel, J. Leland Booth, Mikhail Dozmorov, Brent R. Brown and Jordan P. Metcalf

Toxins 2020, 12(7), 464; https://doi.org/10.3390/toxins12070464 - 20 Jul 2020

Cited by 4 | Viewed by 3786

Abstract

Bacillus anthracis, the causative agent of inhalation anthrax, is a serious concern as a bioterrorism weapon. The vegetative form produces two exotoxins: Lethal toxin (LT) and edema toxin (ET). We recently characterized and compared six human airway and alveolar-resident phagocyte (AARP) subsets at the transcriptional and functional levels. In this study, we examined the effects of LT and ET on these subsets and human leukocytes. AARPs and leukocytes do not express high levels of the toxin receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). Less than 20% expressed surface TEM8, while less than 15% expressed CMG2. All cell types bound or internalized protective antigen, the common component of the two toxins, in a dose-dependent manner. Most protective antigen was likely internalized via macropinocytosis. Cells were not sensitive to LT-induced apoptosis or necrosis at concentrations up to 1000 ng/mL. However, toxin exposure inhibited B. anthracis spore internalization. This inhibition was driven primarily by ET in AARPs and LT in leukocytes. These results support a model of inhalation anthrax in which spores germinate and produce toxins. ET inhibits pathogen phagocytosis by AARPs, allowing alveolar escape. In late-stage disease, LT inhibits phagocytosis by leukocytes, allowing bacterial replication in the bloodstream. Full article

(This article belongs to the Special Issue Bacterial Exotoxins and Their Impact on Host–Pathogen Interaction in Animals and Humans)

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Review

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22 pages, 1472 KiB

Open AccessReview

Aggregatibacter actinomycetemcomitans as the Aetiological Cause of Rheumatoid Arthritis: What Are the Unsolved Puzzles?

by Sung Cheng Looh, Zoey May Pheng Soo, Jia Jia Wong, Hok Chai Yam, Sook Khuan Chow and Jung Shan Hwang

Toxins 2022, 14(1), 50; https://doi.org/10.3390/toxins14010050 - 11 Jan 2022

Cited by 8 | Viewed by 3148

Abstract

Leukotoxin A (LtxA) is the major virulence factor of an oral bacterium known as Aggregatibacter actinomycetemcomitans (Aa). LtxA is associated with elevated levels of anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients. LtxA targets leukocytes and triggers an influx of extracellular calcium into cytosol. The current proposed model of LtxA-mediated hypercitrullination involves the dysregulated activation of peptidylarginine deiminase (PAD) enzymes to citrullinate proteins, the release of hypercitrullinated proteins through cell death, and the production of autoantigens recognized by ACPA. Although model-based evidence is yet to be established, its interaction with the host’s immune system sparked interest in the role of LtxA in RA. The first part of this review summarizes the current knowledge of Aa and LtxA. The next part highlights the findings of previous studies on the association of Aa or LtxA with RA aetiology. Finally, we discuss the unresolved aspects of the proposed link between LtxA of Aa and RA. Full article

(This article belongs to the Special Issue Bacterial Exotoxins and Their Impact on Host–Pathogen Interaction in Animals and Humans)

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22 pages, 2247 KiB

Open AccessReview

Spatiotemporal Regulation of Vibrio Exotoxins by HlyU and Other Transcriptional Regulators

by Byoung Sik Kim

Toxins 2020, 12(9), 544; https://doi.org/10.3390/toxins12090544 - 22 Aug 2020

Cited by 9 | Viewed by 3990

Abstract

After invading a host, bacterial pathogens secrete diverse protein toxins to disrupt host defense systems. To ensure successful infection, however, pathogens must precisely regulate the expression of those exotoxins because uncontrolled toxin production squanders energy. Furthermore, inappropriate toxin secretion can trigger host immune responses that are detrimental to the invading pathogens. Therefore, bacterial pathogens use diverse transcriptional regulators to accurately regulate multiple exotoxin genes based on spatiotemporal conditions. This review covers three major exotoxins in pathogenic Vibrio species and their transcriptional regulation systems. When Vibrio encounters a host, genes encoding cytolysin/hemolysin, multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin, and secreted phospholipases are coordinately regulated by the transcriptional regulator HlyU. At the same time, however, they are distinctly controlled by a variety of other transcriptional regulators. How this coordinated but distinct regulation of exotoxins makes Vibrio species successful pathogens? In addition, anti-virulence strategies that target the coordinating master regulator HlyU and related future research directions are discussed. Full article

(This article belongs to the Special Issue Bacterial Exotoxins and Their Impact on Host–Pathogen Interaction in Animals and Humans)

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