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Toxins
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Leukotoxins
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Leukotoxins

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

Deadline for manuscript submissions: closed (31 August 2018) | Viewed by 38388

Special Issue Editor

Prof. Subramaniam Srikumaran

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Guest Editor
Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040, USA
Interests: Mannheimia haemolytica; Leukotoxins; Host-Pathogen interactions; Strategies for development of disease-resistant animals; Vaccines

Special Issue Information

Dear Colleagues,

Leukotoxins are the critical virulence factors of several Gram-positive and Gram-negative bacteria. Leukotoxin-deletion mutants exhibit drastically reduced virulence, emphasizing the importance of these toxins as virulence factors in the pathogenesis of these bacteria. By targeting all the subsets of leukocytes, they impair the ability of the hosts to mount an effective immune response.  Some of them have haemolytic activity as well.  In some cases, the effects on the target cells are multiple, depending on the concentration. At high concentrations, they cause target cell lysis while at low concentrations they induce the production of immuno-modulatory molecules. The lytic mechanisms include apoptosis and necrosis. Intriguingly, some leukotoxins use the host cell molecules involved in the orchestration of the immune response, as their receptors.  This special issue will focus on recent advances in areas of research, including but not limited to: (i) molecular evolutionary perspectives on leukotoxins; (ii) structure-function relationships; (iii) pathogenetic mechanisms; (iv) leukotoxin-receptor interactions; (v) strategies to prevent binding of leukotoxin to target cells; (vi) immune response to leukotoxins; (vii) vaccines that induce anti-leukotoxin immunity.  We encourage submission of original research articles, perspectives, and review articles.

Prof. Subramaniam Srikumaran
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

  • Leukotoxin
  • Gram-positive
  • Gram-negative
  • host-pathogen interaction
  • pathogenetic mechanisms
  • anti-leukotoxin immunity
  • vaccine

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Published Papers (8 papers)

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Editorial

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2 pages, 181 KiB  
Editorial
Leukotoxins
by Subramaniam Srikumaran
Toxins 2020, 12(4), 231; https://doi.org/10.3390/toxins12040231 - 7 Apr 2020
Viewed by 2266
Abstract
Leukotoxins are the critical virulence factors of several Gram-positive and Gram-negative bacteria [...] Full article
(This article belongs to the Special Issue Leukotoxins)

Research

Jump to: Editorial

16 pages, 1825 KiB  
Article
Panton-Valentine Leucocidin Proves Direct Neuronal Targeting and Its Early Neuronal and Glial Impacts a Rabbit Retinal Explant Model
by XuanLi Liu, Michel J Roux, Serge Picaud, Daniel Keller, Arnaud Sauer, Pauline Heitz, Gilles Prévost and David Gaucher
Toxins 2018, 10(11), 455; https://doi.org/10.3390/toxins10110455 - 4 Nov 2018
Cited by 6 | Viewed by 2946
Abstract
Panton-Valentine leukocidin (PVL) retinal intoxication induces glial activation and inflammatory response via the interaction with retinal neurons. In this study, rabbit retinal explant was used as a model to study neuronal and glial consequences of PVL intoxication. Retinal explants were treated with different [...] Read more.
Panton-Valentine leukocidin (PVL) retinal intoxication induces glial activation and inflammatory response via the interaction with retinal neurons. In this study, rabbit retinal explant was used as a model to study neuronal and glial consequences of PVL intoxication. Retinal explants were treated with different concentrations of PVL. PVL location and neuronal and glial changes were examined using immunohistochemistry. Some inflammatory factors were quantified using RT-qPCR at 4 and 8 h. These results were compared with those of control explants. PVL co-localized rapidly with retinal ganglion cells and with horizontal cells. PVL induced Müller and microglial cell activation. Retinal structure was altered and some amacrine and microglial cells underwent apoptosis. Glial activation and cell apoptosis increased in a PVL concentration- and time-dependent manner. IL-6 and IL-8 expression increased in PVL-treated explants but less than in control explants, which may indicate that other factors were responsible for glial activation and retinal apoptosis. On retinal explants, PVL co-localized with neuronal cells and induced glial activation together with microglial apoptosis, which confirms previous results observed in in vivo model. Rabbit retinal explant seems to be suitable model to further study the process of PVL leading to glial activation and retinal cells apoptosis. Full article
(This article belongs to the Special Issue Leukotoxins)
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18 pages, 4620 KiB  
Article
Aggregatibacter actinomycetemcomitans Leukotoxin Is Delivered to Host Cells in an LFA-1-Indepdendent Manner When Associated with Outer Membrane Vesicles
by Justin B. Nice, Nataliya V. Balashova, Scott C. Kachlany, Evan Koufos, Eric Krueger, Edward T. Lally and Angela C. Brown
Toxins 2018, 10(10), 414; https://doi.org/10.3390/toxins10100414 - 13 Oct 2018
Cited by 40 | Viewed by 5608
Abstract
The Gram-negative bacterium, Aggregatibacter actinomycetemcomitans, has been associated with localized aggressive periodontitis (LAP). In particular, highly leukotoxic strains of A. actinomycetemcomitans have been more closely associated with this disease, suggesting that LtxA is a key virulence factor for A. actinomycetemcomitans. LtxA is [...] Read more.
The Gram-negative bacterium, Aggregatibacter actinomycetemcomitans, has been associated with localized aggressive periodontitis (LAP). In particular, highly leukotoxic strains of A. actinomycetemcomitans have been more closely associated with this disease, suggesting that LtxA is a key virulence factor for A. actinomycetemcomitans. LtxA is secreted across both the inner and outer membranes via the Type I secretion system, but has also been found to be enriched within outer membrane vesicles (OMVs), derived from the bacterial outer membrane. We have characterized the association of LtxA with OMVs produced by the highly leukotoxic strain, JP2, and investigated the interaction of these OMVs with host cells to understand how LtxA is delivered to host cells in this OMV-associated form. Our results demonstrated that a significant fraction of the secreted LtxA exists in an OMV-associated form. Furthermore, we have discovered that in this OMV-associated form, the toxin is trafficked to host cells by a cholesterol- and receptor-independent mechanism in contrast to the mechanism by which free LtxA is delivered. Because OMV-associated toxin is trafficked to host cells in an entirely different manner than free toxin, this study highlights the importance of studying both free and OMV-associated forms of LtxA to understand A. actinomycetemcomitans virulence. Full article
(This article belongs to the Special Issue Leukotoxins)
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16 pages, 3018 KiB  
Article
A Critical Role for HlgA in Staphylococcus aureus Pathogenesis Revealed by A Switch in the SaeRS Two-Component Regulatory System
by Arundhathi Venkatasubramaniam, Tulasikumari Kanipakala, Nader Ganjbaksh, Rana Mehr, Ipsita Mukherjee, Subramaniam Krishnan, Taeok Bae, M. Javad Aman and Rajan P. Adhikari
Toxins 2018, 10(9), 377; https://doi.org/10.3390/toxins10090377 - 18 Sep 2018
Cited by 19 | Viewed by 5462
Abstract
Cytolytic pore-forming toxins including alpha hemolysin (Hla) and bicomponent leukotoxins play an important role in the pathogenesis of Staphylococcus aureus. These toxins kill the polymorphonuclear phagocytes (PMNs), disrupt epithelial and endothelial barriers, and lyse erythrocytes to provide iron for bacterial growth. The [...] Read more.
Cytolytic pore-forming toxins including alpha hemolysin (Hla) and bicomponent leukotoxins play an important role in the pathogenesis of Staphylococcus aureus. These toxins kill the polymorphonuclear phagocytes (PMNs), disrupt epithelial and endothelial barriers, and lyse erythrocytes to provide iron for bacterial growth. The expression of these toxins is regulated by the two-component sensing systems Sae and Agr. Here, we report that a point mutation (L18P) in SaeS, the histidine kinase sensor of the Sae system, renders the S. aureus Newman hemolytic activity fully independent of Hla and drastically increases the PMN lytic activity. Furthermore, this Hla-independent activity, unlike Hla itself, can lyse human erythrocytes. The Hla-independent activity towards human erythrocytes was also evident in USA300, however, under strict agr control. Gene knockout studies revealed that this Hla-independent Sae-regulated activity was entirely dependent on gamma hemolysin A subunit (HlgA). In contrast, hemolytic activity of Newman towards human erythrocytes from HlgAB resistant donors was completely dependent on agr. The culture supernatant from Newman S. aureus could be neutralized by antisera against two vaccine candidates based on LukS and LukF subunits of Panton-Valentine leukocidin but not by an anti-Hla neutralizing antibody. These findings display the complex involvement of Sae and Agr systems in regulating the virulence of S. aureus and have important implications for vaccine and immunotherapeutics development for S. aureus disease in humans. Full article
(This article belongs to the Special Issue Leukotoxins)
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15 pages, 1795 KiB  
Article
Synergistic Effects of Influenza and Staphylococcus aureus Toxins on Inflammation Activation and Cytotoxicity in Human Monocytic Cell Lines
by Marion Jeannoel, Jean-Sebastien Casalegno, Michèle Ottmann, Cédric Badiou, Oana Dumitrescu, Bruno Lina and Gérard Lina
Toxins 2018, 10(7), 286; https://doi.org/10.3390/toxins10070286 - 11 Jul 2018
Cited by 13 | Viewed by 4295
Abstract
In patients with influenza, morbidity and mortality are strongly influenced by infections with Staphylococcus aureus producing high amounts of certain toxins. Here we tested the impact of influenza virus on the pro-inflammatory and cytotoxic actions of a panel of S. aureus virulence factors, [...] Read more.
In patients with influenza, morbidity and mortality are strongly influenced by infections with Staphylococcus aureus producing high amounts of certain toxins. Here we tested the impact of influenza virus on the pro-inflammatory and cytotoxic actions of a panel of S. aureus virulence factors, including Panton-Valentine Leucocidin (PVL), phenol-soluble modulin α1 (PSMα1) and 3 (PSMα3), α-hemolysin (Hla), and cell wall components, i.e., heat-killed S. aureus (HKSA) and protein A. We initially screened for potential synergic interactions using a standardized in vitro model in influenza-infected continuous human monocytic cell lines. Then we tested the identified associations using an ex vivo model in influenza-infected human monocytes freshly isolated from blood. Co-exposure to influenza virus and HKSA, PVL, PSMα1, and PSMα3 increased NF-κB/AP-1 pathway activation in THP1-XBlue cells, and co-exposure to influenza virus and PVL increased cytotoxicity in U937 cells. In monocytes isolated from blood, the synergy between influenza virus and HKSA was confirmed based on cytokine production (TNF-α, IL-1β, IL-6), and co-exposure to influenza virus and Hla-increased cytotoxicity. Our findings suggest that influenza virus potentiates the pro-inflammatory action of HKSA and contributes to the cytotoxicity of Hla on monocytes. Synergic interactions identified in the cell-line model must be cautiously interpreted since few were relevant in the ex vivo model. Full article
(This article belongs to the Special Issue Leukotoxins)
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8 pages, 951 KiB  
Article
Leukotoxin of Bibersteinia trehalosi Contains a Unique Neutralizing Epitope, and a Non-Neutralizing Epitope Shared with Mannheimia haemolytica Leukotoxin
by Arumugam Murugananthan, Sudarvili Shanthalingam, Sai Arun Batra, Sitara Alahan and Subramaniam Srikumaran
Toxins 2018, 10(6), 220; https://doi.org/10.3390/toxins10060220 - 30 May 2018
Cited by 10 | Viewed by 5214
Abstract
Bibersteinia trehalosi and Mannheimia haemolytica, originally classified as Pasteurella haemolytica biotype T and biotype A, respectively, under Genus Pasteurella has now been placed under two different Genera, Bibersteinia and Mannheimia, based on DNA-DNA hybridization and 16S RNA studies. While M. haemolytica [...] Read more.
Bibersteinia trehalosi and Mannheimia haemolytica, originally classified as Pasteurella haemolytica biotype T and biotype A, respectively, under Genus Pasteurella has now been placed under two different Genera, Bibersteinia and Mannheimia, based on DNA-DNA hybridization and 16S RNA studies. While M. haemolytica has been the predominant pathogen of pneumonia in ruminants, B. trehalosi is emerging as an important pathogen of ruminant pneumonia. Leukotoxin is the critical virulence factor of these two pathogens. While the leukotoxin of M. haemolytica has been well studied, the characterization of B. trehalosi leukotoxin has lagged behind. As the first step towards addressing this problem, we developed monoclonal antibodies (mAbs) against B. trehalosi leukotoxin and used them to characterize the leukotoxin epitopes. Two mAbs that recognized sequential epitopes on the leukotoxin were developed. One of them, AM113, neutralized B. trehalosi leukotoxin while the other, AM321, did not. The mAb AM113 revealed the existence of a neutralizing epitope on B. trehalosi leukotoxin that is not present on M. haemolytica leukotoxin. A previously developed mAb, MM601, revealed the presence of a neutralizing epitope on M. haemolytica leukotoxin that is not present on B. trehalosi leukotoxin. The mAb AM321 recognized a non-neutralizing epitope shared by the leukotoxins of B. trehalosi and M. haemolytica. The mAb AM113 should pave the way for mapping the leukotoxin-neutralizing epitope on B. trehalosi leukotoxin and the development of subunit vaccines and/or virus-vectored vaccines against this economically important respiratory pathogen of ruminants. Full article
(This article belongs to the Special Issue Leukotoxins)
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10 pages, 1165 KiB  
Article
High Production of LukMF’ in Staphylococcus aureus Field Strains Is Associated with Clinical Bovine Mastitis
by Jurriaan Hoekstra, Victor Rutten, Laura Sommeling, Tine Van Werven, Mirlin Spaninks, Birgitta Duim, Lindert Benedictus and Gerrit Koop
Toxins 2018, 10(5), 200; https://doi.org/10.3390/toxins10050200 - 15 May 2018
Cited by 28 | Viewed by 5607
Abstract
Staphylococcus aureus, a major cause of bovine mastitis, produces a wide range of immune-evasion molecules. The bi-component leukocidin LukMF’ is a potent killer of bovine neutrophils in vitro. Since the role of LukMF’ in development of bovine mastitis has not been studied [...] Read more.
Staphylococcus aureus, a major cause of bovine mastitis, produces a wide range of immune-evasion molecules. The bi-component leukocidin LukMF’ is a potent killer of bovine neutrophils in vitro. Since the role of LukMF’ in development of bovine mastitis has not been studied in natural infections, we aimed to clarify whether presence of the lukM-lukF’ genes and production levels of LukMF’ are associated with clinical severity of the disease. Staphylococcus aureus was isolated from mastitis milk samples (38 clinical and 17 subclinical cases) from 33 different farms. The lukM-lukF’ genes were present in 96% of the isolates. Remarkably, 22% of the lukM-lukF’-positive S. aureus isolates displayed a 10-fold higher in vitro LukMF’ production than the average of the lower-producing ones. These high producing isolates were cultured significantly more frequently from clinical than subclinical mastitis cases. Also, the detection of LukM protein in milk samples was significantly associated with clinical mastitis and high production in vitro. The high producing LukMF’ strains all belonged to the same genetic lineage, spa-type t543. Analysis of their global toxin gene regulators revealed a point mutation in the Repressor of toxins (rot) gene which results in a non-functional start codon, preventing translation of rot. This mutation was only identified in high LukMF’ producing isolates and not in low LukMF’ producing isolates. Since rot suppresses the expression of various toxins including leukocidins, this mutation is a possible explanation for increased LukMF’ production. Identification of high LukMF’ producing strains is of clinical relevance and can potentially be used as a prognostic marker for severity of mastitis. Full article
(This article belongs to the Special Issue Leukotoxins)
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7 pages, 1814 KiB  
Article
β-Hemolysis May Not Be a Reliable Indicator of Leukotoxicity of Mannheimia haemolytica Isolates
by Jegarubee Bavananthasivam, Sudarvili Shanthalingam, Abirami Kugadas, Bindu Raghavan, Sai Batra and Subramaniam Srikumaran
Toxins 2018, 10(5), 173; https://doi.org/10.3390/toxins10050173 - 25 Apr 2018
Cited by 2 | Viewed by 5419
Abstract
Mannheimia (Pasteurella) haemolytica causes bronchopneumonia in domestic and wild ruminants. Leukotoxin is the critical virulence factor of M. haemolytica. Since β-hemolysis is caused by a large number of leukotoxin-positive M. haemolytica isolates, all β-hemolytic M. haemolytica isolates are considered to [...] Read more.
Mannheimia (Pasteurella) haemolytica causes bronchopneumonia in domestic and wild ruminants. Leukotoxin is the critical virulence factor of M. haemolytica. Since β-hemolysis is caused by a large number of leukotoxin-positive M. haemolytica isolates, all β-hemolytic M. haemolytica isolates are considered to be leukotoxic as well. However, conflicting reports exist in literature as to the leukotoxic and hemolytic properties of M. haemolytica. One group of researchers reported their leukotoxin-deletion mutants to be hemolytic while another reported their mutants to be non-hemolytic. The objective of this study was to determine whether β-hemolysis is a reliable indicator of leukotoxicity of M. haemolytica isolates. Ninety-five isolates of M. haemolytica were first confirmed for presence of leukotoxin gene (lktA) by a leukotoxin-specific PCR assay. Culture supernatant fluids from these isolates were then tested for presence of leukotoxin protein by an ELISA, and for leukotoxic activity by a cytotoxicity assay. All isolates were tested for β-hemolysis by culture on blood agar plates. Sixty-two isolates (65%) produced leukotoxin protein while 33 isolates (35%) did not. Surprisingly, 18 of the 33 isolates (55%), that did not produce leukotoxin protein, were hemolytic. Of the 62 isolates that produced leukotoxin, 55 (89%) were leukotoxic while 7 (11%) were not. All except one of the 55 leukotoxic isolates (98%) were also hemolytic. All seven isolates that were not leukotoxic were hemolytic. Taken together, these results suggest that β-hemolysis may not be a reliable indicator of leukotoxicity of M. haemolytica isolates. Furthermore, all M. haemolytica isolates that possess lktA gene may not secrete active leukotoxin. Full article
(This article belongs to the Special Issue Leukotoxins)
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