Special Issue "Pertussis Toxin and Research on Pertussis Vaccine"

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

Deadline for manuscript submissions: closed (15 September 2021) | Viewed by 10073

Special Issue Editors

Dr. Camille Locht
E-Mail Website
Guest Editor
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 – UMR9017 – CIIL – Center for Infection and Immunity of Lille, F-59000 Lille, France.
Interests: bacterial pathogenesis; bacterial vaccines; immune responses; trained innate immunity
Prof. Dr. Peter Sebo
E-Mail Website
Guest Editor
Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic
Interests: bacterial protein toxin action; cellular and molecular microbiology and immunology; vaccines

Special Issue Information

Dear Colleagues,

Pertussis toxin (PT) is a key immunomodulatory virulence factor of the whooping cough agent Bordetella pertussis. Its action accounts for the severe hyperleukocytosis and immune suppression resulting in the potentially critical course of pertussis illness in infants. Not surprisingly, chemically or genetically inactivated toxoids of PT are used as a key protective antigen component of current acellular pertussis vaccines. Despite several decades of research, many aspects of PT expression and secretion by B. pertussis, as well as the structure–function aspects, intracellular trafficking of the toxin within host cells, as well as the many targets and physiological and immunological consequences of PT’s action in a variety of host cells and tissues remain insufficiently characterized. The ambition of this Special Issue is to re-invigorate the interest in basic studies on the toxin itself and on the use of its toxoids in improved pertussis vaccines that would help to contain the ongoing resurgence of the pertussis disease in the highly vaccinated populations of the most developed countries.

The focus of this Special Issue is on all aspects of research on pertussis toxins and its use. Submissions are welcome on following topics:

  • Expression, secretion, and production of PT by Bordetella pertussis;
  • Structure–function relationships, cellular targets, and mechanism of action of PT;
  • Cellular receptors, intracellular trafficking and translocation and mechanisms of action of PT;
  • Physiological and immunological consequences of PT action and signaling in host interactions of Bordetella pertussis;
  • Production, purification, detoxification, immunogenicity, and vaccine use of toxoids of PT;
  • Immune responses, neutralizing antibody response, and cellular immune response induction by PT-based vaccines and protection against pertussis disease.

Dr. Camille Locht
Prof. Dr. Peter Sebo
Guest Editors

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 2400 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

  • Bordetella pertussis
  • pertussis
  • whooping cough
  • pertussis toxin
  • secretion
  • toxin action
  • toxin regulation
  • toxin expression
  • toxoid preparation
  • toxoid immunogenicity
  • vaccine formulation
  • neutralizing antibodies

Published Papers (8 papers)

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Research

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Article
The CHO Cell Clustering Response to Pertussis Toxin: History of Its Discovery and Recent Developments in Its Use
Toxins 2021, 13(11), 815; https://doi.org/10.3390/toxins13110815 - 19 Nov 2021
Cited by 2 | Viewed by 728
Abstract
Chinese hamster ovary (CHO) cells respond to pertussis toxin (PT) with a novel clustering pattern, which is dependent on biologically active PT. Since its description in 1983, this cellular response has been refined and used extensively for detection and quantification of PT activity, [...] Read more.
Chinese hamster ovary (CHO) cells respond to pertussis toxin (PT) with a novel clustering pattern, which is dependent on biologically active PT. Since its description in 1983, this cellular response has been refined and used extensively for detection and quantification of PT activity, as well as anti-PT antibodies. There are limitations, however, in the use of this phenomenon as originally described. They are: (1) a subjective, observer-dependent scoring system; (2) the requirement for 16–24 h incubation in order for the response to be clearly detectable; and (3) apparent interference from non-toxin materials. To overcome these limitations, a number of alternative in vitro assays for PT, using CHO cells or other cell types, have been developed and are described elsewhere in this publication. In addressing the challenges associated with the CHO cell assay, we discovered that changes in the electrical impedance-based “normalized cell index” of PT-treated CHO cells obtained with the ACEA xCELLigence instrument enable objective detection/quantification of the PT-induced effect in as little as 3–4 h. To the best of our knowledge, the molecular basis for this intriguing response remains unknown. We present here electron microscopic (EM) images of control and PT-treated cells, which suggest some potential molecular mechanisms. Full article
(This article belongs to the Special Issue Pertussis Toxin and Research on Pertussis Vaccine)
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Article
Design of a Quantitative LC-MS Method for Residual Toxins Adenylate Cyclase Toxin (ACT), Dermonecrotic Toxin (DNT) and Tracheal Cytotoxin (TCT) in Bordetella pertussis Vaccines
Toxins 2021, 13(11), 763; https://doi.org/10.3390/toxins13110763 - 28 Oct 2021
Viewed by 929
Abstract
The antigens for acellular pertussis vaccines are made up of protein components that are purified directly from Bordetella pertussis (B. pertussis) bacterial fermentation. As such, there are additional B. pertussis toxins that must be monitored as residuals during process optimization. This paper describes [...] Read more.
The antigens for acellular pertussis vaccines are made up of protein components that are purified directly from Bordetella pertussis (B. pertussis) bacterial fermentation. As such, there are additional B. pertussis toxins that must be monitored as residuals during process optimization. This paper describes a liquid chromatography mass spectrometry (LC-MS) method for simultaneous analysis of residual protein toxins adenylate cyclase toxin (ACT) and dermonecrotic toxin (DNT), as well as a small molecule glycopeptide, tracheal cytotoxin (TCT) in a Pertussis toxin vaccine antigen. A targeted LC-MS technique called multiple reaction monitoring (MRM) is used for quantitation of ACT and TCT, which have established limits in drug product formulations. However, DNT is currently monitored in an animal test, which does not have an established quantitative threshold. New approaches for DNT testing are discussed, including a novel standard based on concatenated quantitation sequences for ACT and DNT. Collectively, the method represents a “3-in-1” analytical simplification for monitoring process-related residuals during development of B. pertussis vaccines. Full article
(This article belongs to the Special Issue Pertussis Toxin and Research on Pertussis Vaccine)
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Article
PTX Instructs the Development of Lung-Resident Memory T Cells in Bordetella pertussis Infected Mice
Toxins 2021, 13(9), 632; https://doi.org/10.3390/toxins13090632 - 08 Sep 2021
Viewed by 883
Abstract
Whooping cough is a severe, highly contagious disease of the human respiratory tract, caused by Bordetellapertussis. The pathogenicity requires several virulence factors, including pertussis toxin (PTX), a key component of current available vaccines. Current vaccines do not induce mucosal immunity. Tissue-resident [...] Read more.
Whooping cough is a severe, highly contagious disease of the human respiratory tract, caused by Bordetellapertussis. The pathogenicity requires several virulence factors, including pertussis toxin (PTX), a key component of current available vaccines. Current vaccines do not induce mucosal immunity. Tissue-resident memory T cells (Trm) are among the first lines of defense against invading pathogens and are involved in long-term protection. However, the factors involved in Trm establishment remain unknown. Comparing two B.pertussis strains expressing PTX (WT) or not (ΔPTX), we show that the toxin is required to generate both lung CD4+ and CD8+ Trm. Co-administering purified PTX with ΔPTX is sufficient to generate these Trm subsets. Importantly, adoptive transfer of lung CD4+ or CD8+ Trm conferred protection against B. pertussis in naïve mice. Taken together, our data demonstrate for the first time a critical role for PTX in the induction of mucosal long-term protection against B. pertussis. Full article
(This article belongs to the Special Issue Pertussis Toxin and Research on Pertussis Vaccine)
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Article
Human Peptides α-Defensin-1 and -5 Inhibit Pertussis Toxin
Toxins 2021, 13(7), 480; https://doi.org/10.3390/toxins13070480 - 11 Jul 2021
Cited by 1 | Viewed by 1196
Abstract
Bordetella pertussis causes the severe childhood disease whooping cough, by releasing several toxins, including pertussis toxin (PT) as a major virulence factor. PT is an AB5-type toxin, and consists of the enzymatic A-subunit PTS1 and five B-subunits, which facilitate binding to [...] Read more.
Bordetella pertussis causes the severe childhood disease whooping cough, by releasing several toxins, including pertussis toxin (PT) as a major virulence factor. PT is an AB5-type toxin, and consists of the enzymatic A-subunit PTS1 and five B-subunits, which facilitate binding to cells and transport of PTS1 into the cytosol. PTS1 ADP-ribosylates α-subunits of inhibitory G-proteins (Gαi) in the cytosol, which leads to disturbed cAMP signaling. Since PT is crucial for causing severe courses of disease, our aim is to identify new inhibitors against PT, to provide starting points for novel therapeutic approaches. Here, we investigated the effect of human antimicrobial peptides of the defensin family on PT. We demonstrated that PTS1 enzyme activity in vitro was inhibited by α-defensin-1 and -5, but not β-defensin-1. The amount of ADP-ribosylated Gαi was significantly reduced in PT-treated cells, in the presence of α-defensin-1 and -5. Moreover, both α-defensins decreased PT-mediated effects on cAMP signaling in the living cell-based interference in the Gαi-mediated signal transduction (iGIST) assay. Taken together, we identified the human peptides α-defensin-1 and -5 as inhibitors of PT activity, suggesting that these human peptides bear potential for developing novel therapeutic strategies against whooping cough. Full article
(This article belongs to the Special Issue Pertussis Toxin and Research on Pertussis Vaccine)
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Review

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Review
The History of Pertussis Toxin
Toxins 2021, 13(9), 623; https://doi.org/10.3390/toxins13090623 - 05 Sep 2021
Cited by 2 | Viewed by 1445
Abstract
Besides the typical whooping cough syndrome, infection with Bordetella pertussis or immunization with whole-cell vaccines can result in a wide variety of physiological manifestations, including leukocytosis, hyper-insulinemia, and histamine sensitization, as well as protection against disease. Initially believed to be associated with different [...] Read more.
Besides the typical whooping cough syndrome, infection with Bordetella pertussis or immunization with whole-cell vaccines can result in a wide variety of physiological manifestations, including leukocytosis, hyper-insulinemia, and histamine sensitization, as well as protection against disease. Initially believed to be associated with different molecular entities, decades of research have provided the demonstration that these activities are all due to a single molecule today referred to as pertussis toxin. The three-dimensional structure and molecular mechanisms of pertussis toxin action, as well as its role in protective immunity have been uncovered in the last 50 years. In this article, we review the history of pertussis toxin, including the paradigm shift that occurred in the 1980s which established the pertussis toxin as a single molecule. We describe the role molecular biology played in the understanding of pertussis toxin action, its role as a molecular tool in cell biology and as a protective antigen in acellular pertussis vaccines and possibly new-generation vaccines, as well as potential therapeutical applications. Full article
(This article belongs to the Special Issue Pertussis Toxin and Research on Pertussis Vaccine)
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Review
Secretion of Pertussis Toxin from Bordetella pertussis
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Toxins 2021, 13(8), 574; https://doi.org/10.3390/toxins13080574 - 18 Aug 2021
Viewed by 1164
Abstract
Production and secretion of pertussis toxin (PT) is essential for the virulence of Bordetella pertussis. Due to the large oligomeric structure of PT, transport of the toxin across bacterial membrane barriers represents a significant hurdle that the bacteria must overcome in order [...] Read more.
Production and secretion of pertussis toxin (PT) is essential for the virulence of Bordetella pertussis. Due to the large oligomeric structure of PT, transport of the toxin across bacterial membrane barriers represents a significant hurdle that the bacteria must overcome in order to maintain pathogenicity. During the secretion process, PT undergoes a two-step transport process. The first step involves transport of the individual polypeptide chains of PT across the inner membrane utilizing a generalized secretion pathway, most likely the bacterial Sec system. The second step involves the use of a specialized apparatus to transport the toxin across the outer membrane of the bacterial cell. This apparatus, which has been termed the Ptl transporter and which is unique to the PT secretion pathway, is a member of the type IV family of bacterial transporters. Here, the current understanding of the PT secretion process is reviewed including a description of the Ptl proteins that assemble to form the transporter, the general structure of type IV transporters, the known similarities and differences between canonical type IV substrate transport and Ptl-mediated transport of PT, as well as the known sequence of events in the assembly and secretion of PT. Full article
(This article belongs to the Special Issue Pertussis Toxin and Research on Pertussis Vaccine)
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Review
In Vivo Models and In Vitro Assays for the Assessment of Pertussis Toxin Activity
Toxins 2021, 13(8), 565; https://doi.org/10.3390/toxins13080565 - 12 Aug 2021
Cited by 3 | Viewed by 1367
Abstract
One of the main virulence factors produced by Bordetella pertussis is pertussis toxin (PTx) which, in its inactivated form, is the major component of all marketed acellular pertussis vaccines. PTx ADP ribosylates Gαi proteins, thereby affecting the inhibition of adenylate cyclases and [...] Read more.
One of the main virulence factors produced by Bordetella pertussis is pertussis toxin (PTx) which, in its inactivated form, is the major component of all marketed acellular pertussis vaccines. PTx ADP ribosylates Gαi proteins, thereby affecting the inhibition of adenylate cyclases and resulting in the accumulation of cAMP. Apart from this classical model, PTx also activates some receptors and can affect various ADP ribosylation- and adenylate cyclase-independent signalling pathways. Due to its potent ADP-ribosylation properties, PTx has been used in many research areas. Initially the research primarily focussed on the in vivo effects of the toxin, including histamine sensitization, insulin secretion and leukocytosis. Nowadays, PTx is also used in toxicology research, cell signalling, research involving the blood–brain barrier, and testing of neutralizing antibodies. However, the most important area of use is testing of acellular pertussis vaccines for the presence of residual PTx. In vivo models and in vitro assays for PTx often reflect one of the toxin’s properties or details of its mechanism. Here, the established and novel in vivo and in vitro methods used to evaluate PTx are reviewed, their mechanisms, characteristics and limitations are described, and their application for regulatory and research purposes are considered. Full article
(This article belongs to the Special Issue Pertussis Toxin and Research on Pertussis Vaccine)
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Review
Evaluation of Anti-PT Antibody Response after Pertussis Vaccination and Infection: The Importance of Both Quantity and Quality
Toxins 2021, 13(8), 508; https://doi.org/10.3390/toxins13080508 - 21 Jul 2021
Cited by 1 | Viewed by 1007
Abstract
Pertussis toxin (PT) is considered the main virulence factor causing whooping cough or pertussis. The protein is widely studied and its composition was revealed and sequenced already during the 1980s. The human immune system creates a good response against PT when measured in [...] Read more.
Pertussis toxin (PT) is considered the main virulence factor causing whooping cough or pertussis. The protein is widely studied and its composition was revealed and sequenced already during the 1980s. The human immune system creates a good response against PT when measured in quantity. However, the serum anti-PT antibodies wane rapidly, and only a small amount of these antibodies are found a few years after vaccination/infection. Therefore, multiple approaches to study the functionality (quality) of these antibodies, e.g., avidity, neutralizing capacity, and epitope specificity, have been investigated. In addition, the long-term B cell memory (Bmem) to PT is crucial for good protection throughout life. In this review, we summarize the findings from functional PT antibody and Bmem studies. These results are discussed in line with the quantity of serum anti-PT antibodies. PT neutralizing antibodies and anti-PT antibodies with proper avidity are crucial for good protection against the disease, and certain epitopes have been identified to have multiple functions in the protection. Although PT-specific Bmem responses are detectable at least five years after vaccination, long-term surveillance is lacking. Variation of the natural boosting of circulating Bordetella pertussis in communities is an important confounding factor in these memory studies. Full article
(This article belongs to the Special Issue Pertussis Toxin and Research on Pertussis Vaccine)
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