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Toxins Sep 2021Besides the typical whooping cough syndrome, infection with or immunization with whole-cell vaccines can result in a wide variety of physiological manifestations,... (Review)
Review
Besides the typical whooping cough syndrome, infection with 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.
Topics: Antigens; History, 20th Century; History, 21st Century; Humans; Immunization; Pertussis Toxin; Pertussis Vaccine
PubMed: 34564627
DOI: 10.3390/toxins13090623 -
Toxins Mar 2022Pertussis, also known as whooping cough, is a respiratory disease caused by infection with , which releases several virulence factors, including the AB-type pertussis... (Review)
Review
Pertussis, also known as whooping cough, is a respiratory disease caused by infection with , which releases several virulence factors, including the AB-type pertussis toxin (PT). The characteristic symptom is severe, long-lasting paroxysmal coughing. Especially in newborns and infants, pertussis symptoms, such as leukocytosis, can become life-threatening. Despite an available vaccination, increasing case numbers have been reported worldwide, including Western countries such as Germany and the USA. Antibiotic treatment is available and important to prevent further transmission. However, antibiotics only reduce symptoms if administered in early stages, which rarely occurs due to a late diagnosis. Thus, no causative treatments against symptoms of whooping cough are currently available. The AB-type protein toxin PT is a main virulence factor and consists of a binding subunit that facilitates transport of an enzyme subunit into the cytosol of target cells. There, the enzyme subunit ADP-ribosylates inhibitory α-subunits of G-protein coupled receptors resulting in disturbed cAMP signaling. As an important virulence factor associated with severe symptoms, such as leukocytosis, and poor outcomes, PT represents an attractive drug target to develop novel therapeutic strategies. In this review, chaperone inhibitors, human peptides, small molecule inhibitors, and humanized antibodies are discussed as novel strategies to inhibit PT.
Topics: Anti-Bacterial Agents; Bordetella pertussis; Humans; Infant; Infant, Newborn; Leukocytosis; Peptides; Pertussis Toxin; Whooping Cough
PubMed: 35324684
DOI: 10.3390/toxins14030187 -
Toxins Aug 2021Production and secretion of pertussis toxin (PT) is essential for the virulence of . Due to the large oligomeric structure of PT, transport of the toxin across bacterial... (Review)
Review
Production and secretion of pertussis toxin (PT) is essential for the virulence of . 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.
Topics: Biological Transport; Bordetella pertussis; Membrane Transport Proteins; Pertussis Toxin; Virulence Factors, Bordetella
PubMed: 34437445
DOI: 10.3390/toxins13080574 -
Toxins Jul 2019Pertussis toxin (PT) is a multimeric complex of six proteins. The PTS1 subunit is an ADP-ribosyltransferase that inactivates the alpha subunit of heterotrimeric G/... (Review)
Review
Pertussis toxin (PT) is a multimeric complex of six proteins. The PTS1 subunit is an ADP-ribosyltransferase that inactivates the alpha subunit of heterotrimeric G/ proteins. The remaining PT subunits form a pentamer that positions PTS1 in and above the central cavity of the triangular structure. Adhesion of this pentamer to glycoprotein or glycolipid conjugates on the surface of a target cell leads to endocytosis of the PT holotoxin. Vesicle carriers then deliver the holotoxin to the endoplasmic reticulum (ER) where PTS1 dissociates from the rest of the toxin, unfolds, and exploits the ER-associated degradation pathway for export to the cytosol. Refolding of the cytosolic toxin allows it to regain an active conformation for the disruption of cAMP-dependent signaling events. This review will consider the intracellular trafficking of PT and the order-disorder-order transitions of PTS1 that are essential for its cellular activity.
Topics: Animals; Cytosol; Humans; Pertussis Toxin; Protein Subunits; Protein Transport
PubMed: 31349590
DOI: 10.3390/toxins11080437 -
Toxins Sep 2019is a human-specific pathogen and the causative agent of whooping cough. The ongoing resurgence in pertussis incidence in high income countries is likely due to faster... (Review)
Review
is a human-specific pathogen and the causative agent of whooping cough. The ongoing resurgence in pertussis incidence in high income countries is likely due to faster waning of immunity and increased asymptomatic colonization in individuals vaccinated with acellular pertussis (aP) vaccine relative whole-cell pertussis (wP)-vaccinated individuals. This has renewed interest in developing more effective vaccines and treatments and, in support of these efforts, defining pertussis vaccine correlates of protection and the role of vaccine antigens and toxins in disease. Pertussis and its toxins have been investigated by scientists for over a century, yet we still do not have a clear understanding of how pertussis toxin (PT) contributes to disease symptomology or how anti-PT immune responses confer protection. This review covers PT's role in disease and evidence for its protective role in vaccines. Clinical data suggest that PT is a defining and essential toxin for pathogenesis and, when formulated into a vaccine, can prevent disease. Additional studies are required to further elucidate the role of PT in disease and vaccine-mediated protection, to inform the development of more effective treatments and vaccines.
Topics: Animals; Hemagglutinins; Humans; Immunoglobulins, Intravenous; Pertussis Toxin; Pertussis Vaccine; Vaccination
PubMed: 31546599
DOI: 10.3390/toxins11100557 -
Toxins Jun 2019Pertussis, caused by respiratory tract infection with the bacterial pathogen , has long been considered to be a toxin-mediated disease. Bacteria adhere and multiply... (Review)
Review
Pertussis, caused by respiratory tract infection with the bacterial pathogen , has long been considered to be a toxin-mediated disease. Bacteria adhere and multiply extracellularly in the airways and release several toxins, which have a variety of effects on the host, both local and systemic. Predominant among these toxins is pertussis toxin (PT), a multi-subunit protein toxin that inhibits signaling through a subset of G protein-coupled receptors in mammalian cells. PT activity has been linked with severe and lethal pertussis disease in young infants and a detoxified version of PT is a common component of all licensed acellular pertussis vaccines. The role of PT in typical pertussis disease in other individuals is less clear, but significant evidence supporting its contribution to pathogenesis has been accumulated from animal model studies. In this review we discuss the evidence indicating a role for PT in pertussis disease, focusing on its contribution to severe pertussis in infants, modulation of immune and inflammatory responses to infection, and the characteristic paroxysmal cough of pertussis.
Topics: Animals; Humans; Pertussis Toxin; Whooping Cough
PubMed: 31252532
DOI: 10.3390/toxins11070373 -
PLoS Pathogens Jun 2022The adenylate cyclase (ACT) and the pertussis (PT) toxins of Bordetella pertussis exert potent immunomodulatory activities that synergize to suppress host defense in the...
The adenylate cyclase (ACT) and the pertussis (PT) toxins of Bordetella pertussis exert potent immunomodulatory activities that synergize to suppress host defense in the course of whooping cough pathogenesis. We compared the mouse lung infection capacities of B. pertussis (Bp) mutants (Bp AC- or Bp PT-) producing enzymatically inactive toxoids and confirm that ACT action is required for maximal bacterial proliferation in the first days of infection, whereas PT action is crucial for persistence of B. pertussis in mouse lungs. Despite accelerated and near complete clearance from the lungs by day 14 of infection, the PT- bacteria accumulated within the lymphoid tissue of lung-draining mediastinal lymph nodes (mLNs). In contrast, the wild type or AC- bacteria colonized the lungs but did not enter into mLNs. Lung infection by the PT- mutant triggered an early arrival of migratory conventional dendritic cells with associated bacteria into mLNs, where the PT- bacteria entered the T cell-rich paracortex of mLNs by day 5 and proliferated in clusters within the B-cell zone (cortex) of mLNs by day 14, being eventually phagocytosed by infiltrating neutrophils. Finally, only infection by the PT- bacteria triggered an early production of anti-B. pertussis serum IgG antibodies already within 14 days of infection. These results reveal that action of the pertussis toxin blocks DC-mediated delivery of B. pertussis bacteria into mLNs and prevents bacterial colonization of mLNs, thus hampering early adaptive immune response to B. pertussis infection.
Topics: Animals; Bordetella pertussis; Dendritic Cells; Lung; Lymph Nodes; Mice; Mice, Inbred BALB C; Pertussis Toxin; Whooping Cough
PubMed: 35666769
DOI: 10.1371/journal.ppat.1010577 -
Immunity Jul 2003Peripheral blood monocytes are a heterogeneous population of circulating leukocytes. Using a murine adoptive transfer system to probe monocyte homing and differentiation...
Peripheral blood monocytes are a heterogeneous population of circulating leukocytes. Using a murine adoptive transfer system to probe monocyte homing and differentiation in vivo, we identified two functional subsets among murine blood monocytes: a short-lived CX(3)CR1(lo)CCR2(+)Gr1(+) subset that is actively recruited to inflamed tissues and a CX(3)CR1(hi)CCR2(-)Gr1(-) subset characterized by CX(3)CR1-dependent recruitment to noninflamed tissues. Both subsets have the potential to differentiate into dendritic cells in vivo. The level of CX(3)CR1 expression also defines the two major human monocyte subsets, the CD14(+)CD16(-) and CD14(lo)CD16(+) monocytes, which share phenotype and homing potential with the mouse subsets. These findings raise the potential for novel therapeutic strategies in inflammatory diseases.
Topics: Animals; Cell Differentiation; Cell Movement; Dendritic Cells; Humans; Mice; Mice, Inbred C57BL; Monocytes; Pertussis Toxin; Receptors, CCR2; Receptors, Chemokine; Receptors, Interleukin-8A
PubMed: 12871640
DOI: 10.1016/s1074-7613(03)00174-2 -
Toxins Jun 2023toxin (PT) and C2 toxin are ADP-ribosylating toxins causing severe diseases in humans and animals. They share a common translocation mechanism requiring the cellular...
toxin (PT) and C2 toxin are ADP-ribosylating toxins causing severe diseases in humans and animals. They share a common translocation mechanism requiring the cellular chaperones Hsp90 and Hsp70, cyclophilins, and FK506-binding proteins to transport the toxins' enzyme subunits into the cytosol. Inhibitors of chaperone activities have been shown to reduce the amount of transported enzyme subunits into the cytosol of cells, thus protecting cells from intoxication by these toxins. Recently, domperidone, an approved dopamine receptor antagonist drug, was found to inhibit Hsp70 activity. Since Hsp70 is required for cellular toxin uptake, we hypothesized that domperidone also protects cells from intoxication with PT and C2. The inhibition of intoxication by domperidone was demonstrated by analyzing the ADP-ribosylation status of the toxins' specific substrates. Domperidone had no inhibitory effect on the receptor-binding or enzyme activity of the toxins, but it inhibited the pH-driven membrane translocation of the enzyme subunit of the C2 toxin and reduced the amount of PTS1 in cells. Taken together, our results indicate that domperidone is a potent inhibitor of PT and C2 toxins in cells and therefore might have therapeutic potential by repurposing domperidone to treat diseases caused by bacterial toxins that require Hsp70 for their cellular uptake.
Topics: Animals; Humans; Bordetella pertussis; Domperidone; Botulinum Toxins; Bacterial Toxins; Pertussis Toxin; ADP Ribose Transferases
PubMed: 37505681
DOI: 10.3390/toxins15070412 -
Pathogens and Disease Oct 2016The significant and sometimes dramatic rise in the number of circulating white blood cells (leukocytosis) in infants suffering from pertussis (whooping cough) has been... (Review)
Review
The significant and sometimes dramatic rise in the number of circulating white blood cells (leukocytosis) in infants suffering from pertussis (whooping cough) has been recognized for over a century. Although pertussis is a disease that afflicts people of all ages, it can be particularly severe in young infants, and these are the individuals in whom leukocytosis is most pronounced. Very high levels of leukocytosis are associated with poor outcome in infants hospitalized with pertussis and modern treatments are often aimed at reducing the number of leukocytes. Pertussis leukocytosis is caused by pertussis toxin, a soluble protein toxin released by Bordetella pertussis during infection, but the exact mechanisms by which this occurs are still unclear. In this minireview, I discuss the history of clinical and experimental findings on pertussis leukocytosis, possible contributing mechanisms causing this condition and treatments aimed at reducing leukocytosis in hospitalized infants. Since recent studies have detailed significant associations between specific levels of pertussis leukocytosis and fatal outcome, this is a timely review that may stimulate new thinking on how to understand and combat this problem.
Topics: Antibodies, Monoclonal; Bordetella pertussis; Exchange Transfusion, Whole Blood; Extracorporeal Membrane Oxygenation; History, 19th Century; History, 20th Century; History, 21st Century; Host-Pathogen Interactions; Humans; Infant; Leukocytes; Leukocytosis; Lymph Nodes; Pertussis Toxin; Survival Analysis; Whooping Cough
PubMed: 27609461
DOI: 10.1093/femspd/ftw087