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Pertussis stability

Darragh P O'Brien, Dominique Durand, Alexis Voegele, Véronique Hourdel, Marilyne Davi, Julia Chamot-Rooke, Patrice Vachette, Sébastien Brier, Daniel Ladant, Alexandre Chenal
Once translocated into the cytosol of target cells, the catalytic domain (AC) of the adenylate cyclase toxin (CyaA), a major virulence factor of Bordetella pertussis, is potently activated by binding calmodulin (CaM) to produce supraphysiological levels of cAMP, inducing cell death. Using a combination of small-angle X-ray scattering (SAXS), hydrogen/deuterium exchange mass spectrometry (HDX-MS), and synchrotron radiation circular dichroism (SR-CD), we show that, in the absence of CaM, AC exhibits significant structural disorder, and a 75-residue-long stretch within AC undergoes a disorder-to-order transition upon CaM binding...
December 29, 2017: PLoS Biology
Christian W Johns, Natosha L Finley
Site I inactivation of calmodulin (CaM) was used to examine the importance of aspartic acid 22 at position 3 in CaM calcium binding, protein folding, and activation of the Bordetella pertussis adenylate cyclase toxin domain (CyaA-ACD). NMR calcium titration experiments showed that site I in the CaM mutant (D22A) remained largely unperturbed, while sites II, III, and IV exhibited calcium-induced conformational changes similar to wild-type CaM (CaMWt). Circular dichroism analyses revealed that D22A had comparable α-helical content to CaMWt, and only modest differences in α-helical composition were detected between CaMWt-CyaA-ACD and D22A-CyaA-ACD complexes...
November 30, 2017: Toxins
Shilratna Walke, Gopal Srivastava, Chinmayee Bar Routaray, Dilip Dhavale, Kalpana Pai, Jignesh Doshi, Rakesh Kumar, Pooja Doshi
The paper explained the microencapsulation of three different antigenic materials viz. Diphtheria toxoid (DT), whole cell pertussis antigens (PT and FHA) and tetanus toxoid (TT) by coacervation method using water soluble chitosan as a polymer crosslinked by vanillin/TPP co-crosslinkers for the development of oral trivalent DwPT vaccine. Instrumental characterization of chitosan microspheres suggested specific interaction with vanillin/TPP, higher thermal stability, amorphous nature, spherical morphology with size less than 2μm along with positive charge density offering mucoadhesive properties...
October 13, 2017: International Journal of Biological Macromolecules
Irina Gates, Marina DuVall, Hong Ju, M Lucia Tondella, Lucia Pawloski
Bordetella pertussis infection has been increasing in the US, with reported cases reaching over 50,000 in 2012, a number last observed in the 1950s. Concurrently, B. pertussis lacking the pertactin protein, one of the immunogens included in the acellular vaccine formulations, has rapidly emerged since 2010, and has become the predominant circulating phenotype. Monitoring the production of the remaining acellular vaccine immunogens, such as pertussis toxin (Pt), is a critical next step. To date, methods for screening Pt have been either through genomic sequencing means or by conventional ELISAs...
2017: PloS One
Catherine Arsenault, Mira Johri, Arijit Nandi, José M Mendoza Rodríguez, Peter M Hansen, Sam Harper
BACKGROUND: Important inequalities in childhood vaccination coverage persist between countries and population groups. Understanding why some countries achieve higher and more equitable levels of coverage is crucial to redress these inequalities. In this study, we explored the country-level determinants of (1) coverage of the third dose of diphtheria-tetanus-pertussis- (DTP3) containing vaccine and (2) within-country inequalities in DTP3 coverage in 45 countries supported by Gavi, the Vaccine Alliance...
April 25, 2017: Vaccine
Sarah Skye Gilbert, Neeraj Thakare, Arun Ramanujapuram, Anup Akkihal
BACKGROUND: Immunization supply chains in low resource settings do not always reach children with necessary vaccines. Digital information systems can enable real time visibility of inventory and improve vaccine availability. In 2014, a digital, mobile/web-based information system was implemented in two districts of Uttar Pradesh, India. This retrospective investigates improvements and stabilization of supply chain performance following introduction of the digital information system. METHODS: All data were collected via the digital information system between March 2014 and September 2015...
April 19, 2017: Vaccine
Chattip Kurehong, Chalermpol Kanchanawarin, Busaba Powthongchin, Panchika Prangkio, Gerd Katzenmeier, Chanan Angsuthanasombat
The Bordetella pertussis CyaA-hemolysin (CyaA-Hly) domain was previously demonstrated to be an important determinant for hemolysis against target erythrocytes and ion-channel formation in planar lipid bilayers (PLBs). Here, net-charge variations in the pore-lining helix of thirteen related RTX cytolysins including CyaA-Hly were revealed by amino acid sequence alignments, reflecting their different degrees of hemolytic activity. To analyze possible functional effects of net-charge alterations on hemolytic activity and channel formation of CyaA-Hly, specific mutations were made at Gln(574) or Glu(581) in its pore-lining α3 of which both residues are highly conserved Lys in the three highly active RTX cytolysins (i...
March 16, 2017: Toxins
Sara E Cannella, Véronique Yvette Ntsogo Enguéné, Marilyne Davi, Christian Malosse, Ana Cristina Sotomayor Pérez, Julia Chamot-Rooke, Patrice Vachette, Dominique Durand, Daniel Ladant, Alexandre Chenal
Bordetella pertussis, the causative agent of whooping cough, secretes an adenylate cyclase toxin, CyaA, which invades eukaryotic cells and alters their physiology by cAMP overproduction. Calcium is an essential cofactor of CyaA, as it is the case for most members of the Repeat-in-ToXins (RTX) family. We show that the calcium-bound, monomeric form of CyaA, hCyaAm, conserves its permeabilization and haemolytic activities, even in a fully calcium-free environment. In contrast, hCyaAm requires sub-millimolar calcium in solution for cell invasion, indicating that free calcium in solution is involved in the CyaA toxin translocation process...
February 10, 2017: Scientific Reports
Alberta Di Pasquale, Paolo Bonanni, Nathalie Garçon, Lawrence R Stanberry, Mostafa El-Hodhod, Fernanda Tavares Da Silva
Vaccines are different from most medicines in that they are administered to large and mostly healthy populations including infants and children, so there is a low tolerance for potential risks or side-effects. In addition, the long-term benefits of immunisation in reducing or eliminating infectious diseases may induce complacency due to the absence of cases. However, as demonstrated in recent measles outbreaks in Europe and United States, reappearance of the disease occurs as soon as vaccine coverage falls...
December 20, 2016: Vaccine
Tuhina Banerjee, Lucia Cilenti, Michael Taylor, Adrienne Showman, Suren A Tatulian, Ken Teter
Pertussis toxin (PT) moves from the host cell surface to the endoplasmic reticulum (ER) by retrograde vesicular transport. The catalytic PTS1 subunit dissociates from the rest of the toxin in the ER and then shifts to a disordered conformation which may trigger its export to the cytosol through the quality control mechanism of ER-associated degradation (ERAD). Functional roles for toxin instability and ERAD in PTS1 translocation have not been established. We addressed these issues with the use of a surface plasmon resonance system to quantify the cytosolic pool of PTS1 from intoxicated cells...
December 2016: Infection and Immunity
Alberto Maltz, Gabriel Fabricius
An epidemic model with births and deaths is considered on a two-dimensional L×L lattice. Each individual can have global infective contacts according to the standard susceptible-infected-recovered (SIR) model rules or local infective contacts with their nearest neighbors. We propose a deterministic approach to this model and, for the parameters corresponding to pertussis and rubella in the prevaccine era, verify that there is a close agreement with the stochastic simulations when epidemic spread or endemic stationarity is considered...
December 2016: Theoretical Population Biology
E Lesne, E-M Krammer, E Dupre, C Locht, M F Lensink, R Antoine, F Jacob-Dubuisson
UNLABELLED: The two-component system BvgAS controls the expression of the virulence regulon of Bordetella pertussis. BvgS is a prototype of bacterial sensor kinases with extracytoplasmic Venus flytrap perception domains. Following its transmembrane segment, BvgS harbors a cytoplasmic Per-Arnt-Sim (PAS) domain and then a predicted 2-helix coiled coil that precede the dimerization-histidine-phosphotransfer domain of the kinase. BvgS homologs have a similar domain organization, or they harbor only a predicted coiled coil between the transmembrane and the dimerization-histidine-phosphotransfer domains...
March 1, 2016: MBio
R Silvestri, F Marchetti
BACKGROUND: Antigens contained in vaccines are inherently unstable biologically; such a characteristic is conferred by their three-dimensional structure. Preserving the ability of the vaccines to protect against disease is necessary to ensure the supervision and monitoring of all steps of the cold chain. DTPa-HBV-IPV/Hib vaccine (Infanrix hexaTM, GSK Vaccines, Belgium) is designed to prevent disease due to diphtheria, tetanus, pertussis (DTP), hepatitis B virus (HBV), poliomyelitis and Haemophilus influenzae type b (Hib); it was first licensed for use in Europe in 2000 and is currently licensed in at least 95 countries...
September 2015: Annali di Igiene: Medicina Preventiva e di Comunità
Liang Zhang, Anneliese J Morrison, Patrick H Thibodeau
The serralysin family of bacterial metalloproteases is associated with virulence in multiple modes of infection. These extracellular proteases are members of the Repeats-in-ToXin (RTX) family of toxins and virulence factors, which mediated virulence in E. coli, B. pertussis, and P. aeruginosa, as well as other animal and plant pathogens. The serralysin proteases are structurally dynamic and their folding is regulated by calcium binding to a C-terminal domain that defines the RTX family of proteins. Previous studies have suggested that interactions between N-terminal sequences and this C-terminal domain are important for the high thermal and chemical stabilities of the RTX proteases...
2015: PloS One
Michael Gabl, Malene Winther, Amanda Welin, Anna Karlsson, Tudor Oprea, Johan Bylund, Claes Dahlgren, Huamei Forsman
Functional selectivity, a process by which G-protein coupled receptors (GPCRs) can activate one signaling route while avoiding another, is regulated by ligand-mediated stabilization of specific receptor states that modulate different downstream signaling events. We propose a novel mechanism for functional selectivity, induced by the endogenous P2Y2R agonist ATP and regulated at the signaling interface by the cytoskeleton. Upon ATP stimulation of human neutrophils, a transient rise in the cytosolic concentration of free Ca(2+) was not followed by activation of the superoxide anion-generating NADPH-oxidase...
August 15, 2015: Experimental Cell Research
Michal Česnek, Petr Jansa, Markéta Šmídková, Helena Mertlíková-Kaiserová, Martin Dračínský, Tarsis F Brust, Petr Pávek, František Trejtnar, Val J Watts, Zlatko Janeba
Novel small-molecule agents to treat Bordetella pertussis infections are highly desirable, as pertussis (whooping cough) remains a serious health threat worldwide. In this study, a series of 2-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, adefovir), in their isopropyl ester bis(L-phenylalanine) prodrug form, were designed and synthesized as potent inhibitors of adenylate cyclase toxin (ACT) isolated from B. pertussis. The series consists of PMEA analogues bearing either a linear or branched aliphatic chain or a heteroatom at the C2 position of the purine moiety...
August 2015: ChemMedChem
William G Robichaux, Sukru S Oner, Stephen M Lanier, Joe B Blumer
Group II activator of G-protein signaling (AGS) proteins contain one or more G-protein regulatory motifs (GPR), which serve as docking sites for GαiGDP independent of Gβγ and stabilize the GDP-bound conformation of Gαi, acting as guanine nucleotide dissociation inhibitors. The GαGPR interaction is regulated by seven-transmembrane-spanning (7TM) receptors in the intact cell as determined by bioluminescence resonance energy transfer (BRET). It is hypothesized that a 7TM receptor directly couples to the GαGPR complex in a manner analogous to receptor coupling to the Gαβγ heterotrimer...
August 2015: Molecular Pharmacology
Seon Min Woo, Kyoung-jin Min, Taeg Kyu Kwon
Melatonin is involved in many physiological functions, and it has differential effects on apoptosis in normal and cancer cells. However, the mechanism of its antitumor roles is not well understood. In this study, we show that melatonin enhances tunicamycin-induced apoptosis in human breast carcinoma MDA-MB-231 cells. Melatonin up-regulates pro-apoptotic protein Bim expression at the transcriptional levels in the presence of tunicamycin. Melatonin inhibits tunicamycin-induced COX-2 expression in MDA-MB-231 cells...
April 2015: Journal of Pineal Research
Boying Liang, Yue Ju, James R Joubert, Erin J Kaleta, Rodrigo Lopez, Ian W Jones, Henry K Hall, Saliya N Ratnayaka, Vicki H Wysocki, S Scott Saavedra
Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) coupled with affinity capture is a well-established method to extract biological analytes from complex samples followed by label-free detection and identification. Many bioanalytes of interest bind to membrane-associated receptors; however, the matrices and high-vacuum conditions inherent to MALDI-TOF MS make it largely incompatible with the use of artificial lipid membranes with incorporated receptors as platforms for detection of captured proteins and peptides...
April 2015: Analytical and Bioanalytical Chemistry
Honggang Xue, Bangling Yang, Debra D Kristensen, Dexiang Chen
Inadvertent vaccine freezing often occurs in the cold chain and may cause damage to freeze‑sensitive vaccines. Liquid vaccines that contain aluminum salt adjuvants are particularly vulnerable. Polyol cryoprotective excipients have been shown to prevent freeze damage to hepatitis B vaccine. In this study, we examined the freeze-protective effect of propylene glycol on diphtheria-tetanus-pertussis-whole-cell (DTwP) and acellular (DTaP) vaccines. Pilot lots of DTwP and DTaP formulated with 7.5% propylene glycol underwent 3 freeze-thaw treatments...
2014: Human Vaccines & Immunotherapeutics
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