scholarly journals A cocktail of humanized anti–pertussis toxin antibodies limits disease in murine and baboon models of whooping cough

2015 ◽  
Vol 7 (316) ◽  
pp. 316ra195-316ra195 ◽  
Author(s):  
Annalee W. Nguyen ◽  
Ellen K. Wagner ◽  
Joshua R. Laber ◽  
Laura L. Goodfield ◽  
William E. Smallridge ◽  
...  
Keyword(s):  
Pertussis Toxin ◽  
Whooping Cough

scholarly journals Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katharina Ernst ◽  
Ann-Katrin Mittler ◽  
Veronika Winkelmann ◽  
Carolin Kling ◽  
Nina Eberhardt ◽  
...  
Keyword(s):  
Pertussis Toxin ◽  
Airway Epithelium ◽  
Whooping Cough ◽  
Apical Surface ◽  
Basal Cells ◽  
Pharmacological Chaperone ◽  
Infant Mouse ◽  
Novel Therapeutic Strategies

AbstractWhooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, a role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is demonstrated. PTS1 specifically and directly interacts with chaperones in vitro and in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing intracellular PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough.

Purification and immunological characterization of HPLC-purified pertussis toxin subunits

1991 ◽  
Vol 69 (5-6) ◽  
pp. 336-340
Author(s):  
Pele Chong ◽  
Stephen Cockle ◽  
Heather Boux ◽  
Michel Klein
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Pertussis Toxin ◽  
High Performance ◽  
Whooping Cough ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Active Immunization ◽  
Single Step ◽  
Nad Glycohydrolase

Pertussis toxin (PT), an oligomeric exotoxin of Bordetella pertussis containing five dissimilar subunits, is considered to be an essential immunogen in acellular and component pertussis vaccines against whooping cough. A rapid single-step procedure for isolating PT subunits was developed using reverse-phase high-performance liquid chromatography. Recoveries of individual subunits were 75% (S1), 70% (S2), > 90% (S3), > 90% (S4), and 50% (S5), as judged by SDS-PAGE and amino acid analysis. Lyophilized subunits were solubilized in urea followed by step-wise dialysis to remove the urea. All subunits were inactive in histamine sensitization, lymphocytosis, and hemagglutination assays. However, purified S1 retained residual NAD-glycohydrolase and ADP-ribosyltransferase activity. A partially active holotoxin could be generated by mixing the five individual subunits. All subunits were immunogenic in rabbits and mice. Monospecific antisera raised in both animal species were able to neutralize the PT-mediated clustering of Chinese hamster ovary cells, but active immunization of mice with single subunits failed to protect them in the intracerebral challenge assay. These subunit preparations therefore retained neutralizing determinants, but did not contain protective epitopes.Key words: pertussis toxin, high-performance liquid chromatography, purification, pertussis vaccine.

scholarly journals Pertussis Toxin: A Key Component in Pertussis Vaccines?

Toxins ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 557
Author(s):  
Kelsey A. Gregg ◽  
Tod J. Merkel
Keyword(s):  
Immune Responses ◽  
Pertussis Toxin ◽  
Whooping Cough ◽  
Protective Role ◽  
Clear Understanding ◽  
Correlates Of Protection ◽  
Vaccine Antigens ◽  
Specific Pathogen ◽  
Human Specific

B. pertussis 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 B. pertussis 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.

Neutralizing Antibodies to Pertussis Toxin in Whooping Cough

1985 ◽  
Vol 151 (4) ◽  
pp. 646-649 ◽  
Author(s):  
M. Granstrom ◽  
G. Granstrom ◽  
P. Gillenius ◽  
P. Askelof
Keyword(s):  
Pertussis Toxin ◽  
Neutralizing Antibodies ◽  
Whooping Cough

scholarly journals G Proteins Gαi1/3Are Critical Targets for Bordetella pertussis Toxin-Induced Vasoactive Amine Sensitization

2013 ◽  
Vol 82 (2) ◽  
pp. 773-782 ◽  
Author(s):  
Sean A. Diehl ◽  
Benjamin McElvany ◽  
Rajkumar Noubade ◽  
Nathan Seeberger ◽  
Brock Harding ◽  
...  
Keyword(s):  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Inflammatory Responses ◽  
Whooping Cough ◽  
Differential Susceptibility ◽  
Inbred Strains ◽  
Content Type ◽  
Multiple Loci ◽  
Inbred Strains Of Mice

ABSTRACTPertussis toxin (PTX) is an AB5-type exotoxin produced by the bacteriumBordetella pertussis, the causative agent of whooping cough.In vivointoxication with PTX elicits a variety of immunologic and inflammatory responses, including vasoactive amine sensitization (VAAS) to histamine (HA), serotonin (5-HT), and bradykinin (BDK). Previously, by using a forward genetic approach, we identified the HA H1receptor (Hrh1/H1R) as the gene in mice that controls differential susceptibility toB. pertussisPTX-induced HA sensitization (Bphs). Here we show, by using inbred strains of mice, F1hybrids, and segregating populations, that, unlike Bphs, PTX-induced 5-HT sensitivity (Bpss) and BDK sensitivity (Bpbs) are recessive traits and are separately controlled by multiple loci unlinked to 5-HT and BDK receptors, respectively. Furthermore, we found that PTX sensitizes mice to HA independently of Toll-like receptor 4, a purported receptor for PTX, and that the VAAS properties of PTX are not dependent upon endothelial caveolae or endothelial nitric oxide synthase. Finally, by using mice deficient in individual Gαi/oG-protein subunits, we demonstrate that Gαi1and Gαi3are the criticalin vivotargets of ADP-ribosylation underlying VAAS elicited by PTX exposure.

scholarly journals Characterization of Individual Human Antibodies That Bind Pertussis Toxin Stimulated by Acellular Immunization

2018 ◽  
Vol 86 (6) ◽  
pp. e00004-18 ◽  
Author(s):  
Edith Acquaye-Seedah ◽  
Elizabeth E. Reczek ◽  
Hugh H. Russell ◽  
Andrea M. DiVenere ◽  
Sara O. Sandman ◽  
...  
Keyword(s):  
Pertussis Toxin ◽  
Protective Antigen ◽  
Whooping Cough ◽  
Structural Explanation ◽  
Booster Immunization ◽  
Human Antibodies ◽  
B Subunit ◽  
Individual Human

ABSTRACTDespite high vaccination rates, the incidence of whooping cough has steadily been increasing in developing countries for several decades. The current acellular pertussis (aP) vaccines all include the major protective antigen pertussis toxin (PTx) and are safer, but they appear to be less protective than infection or older, whole-cell vaccines. To better understand the attributes of individual antibodies stimulated by aP, we isolated plasmablast clones recognizing PTx after booster immunization of two donors. Five unique antibody sequences recognizing native PTx were recovered and expressed as recombinant human IgG1 antibodies. The antibodies all bind different epitopes on the PTx S1 subunit, B oligomer, or S1-B subunit interface, and just one clone neutralized PTx in anin vitroassay. To better understand the epitopes bound by the nonneutralizing S1-subunit antibodies, comprehensive mutagenesis with yeast display provided a detailed map of the epitope recognized by antibodies A8 and E12. Residue R76 is required for antibody A8 binding and is present on the S1 surface but is only partially exposed in the holotoxin, providing a structural explanation for A8's inability to neutralize holotoxin. The B-subunit-specific antibody D8 inhibited PTx binding to a model receptor and neutralized PTxin vitroas well as in anin vivoleukocytosis assay. This is the first study, to our knowledge, to identify individual human antibodies stimulated by the acellular pertussis vaccine and demonstrates the feasibility of using these approaches to address outstanding issues in pertussis vaccinology, including mechanisms of accelerated waning of protective immunity despite repeated aP immunization.

Induction of humoral immunity in response to immunization with recombinantMycobacterium bovisBCG expressing the S1 subunit ofBordetella pertussistoxin

2005 ◽  
Vol 51 (12) ◽  
pp. 1015-1020 ◽  
Author(s):  
Marco A Medeiros ◽  
Geraldo R.G Armôa ◽  
Odir A Dellagostin ◽  
Douglas McIntosh
Keyword(s):  
Immune Responses ◽  
Pertussis Toxin ◽  
Whooping Cough ◽  
Low Cost ◽  
Long Term Memory ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Specific Igg

Two recombinant Mycobacterium bovis BCG (rBCG) vaccine strains were developed for the expression of cytoplasmically located S1 subunit of pertussis toxin, with expression driven by the hsp60 promoter of M. bovis (rBCG/pPB10) or the pAN promoter of Mycobacterium paratuberculosis (rBCG/pPB12). Both strains showed stable expression of equivalent levels of recombinant S1 in vitro and induced long-term (up to 8 months) humoral immune responses in BALB/c mice, although these responses differed quantitatively and qualitatively. Specifically, rBCG/pPB12 induced markedly higher levels of IgG1 than did rBCG/pPB10, and mice immunized with the former strain developed specific long-term memory to S1, as indicated by the production of high levels of S1-specific IgG in response to a sublethal challenge with pertussis toxin 15 months after initial immunization. When considered in combination with previous studies, our data encourage further evaluation of rBCG as a potential means of developing a low-cost whooping cough vaccine based on defined antigens.Key words: recombinant BCG, humoral immune response, B. pertussis.

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