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Pertussis stability

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...
September 19, 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...
August 31, 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...
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
Ana-Cristina Sotomayor-Pérez, Daniel Ladant, Alexandre Chenal
The past decade has seen a fundamental reappraisal of the protein structure-to-function paradigm because it became evident that a significant fraction of polypeptides are lacking ordered structures under physiological conditions. Ligand-induced disorder-to-order transition plays a key role in the biological functions of many proteins that contain intrinsically disordered regions. This trait is exhibited by RTX (Repeat in ToXin) motifs found in more than 250 virulence factors secreted by Gram-negative pathogenic bacteria...
January 2015: Toxins
Xianzhe Wang, Jennifer A Maynard, Erik L Hewlett, Jennifer A Maynard
The adenylate cyclase toxin (ACT) is a multifunctional virulence factor secreted by Bordetella species. Upon interaction of its C-terminal hemolysin moiety with the cell surface receptor αMβ2 integrin, the N-terminal cyclase domain translocates into the host cell cytosol where it rapidly generates supraphysiological cAMP concentrations, which inhibit host cell anti-bacterial activities. Although ACT has been shown to induce protective immunity in mice, it is not included in any current acellular pertussis vaccines due to protein stability issues and a poor understanding of its role as a protective antigen...
February 6, 2015: Journal of Biological Chemistry
Masako Tanaka, Naoko Inomata, Midori Matsuura, Shuichi Ishida, Aki Suzuki, Mizue Sohara, Michiko Aihara
We report here a 20-year old woman who referred to our clinic for identify the responsible antigen of anaphylaxis. Five days before the reaction, she had a cold and had taken a gel capsule cold medicine, Stona IB Gel®. On the day of the reaction, she took a dose of Stona IB Gel® after eating yogurt. Five minutes after oral administration, she developed a heat sensation and pruritus on her neck, with flushing, abdominal pains, breathing difficulties, and syncope. The specific IgE antibodies measured by ImmunoCAP® were all negative except for gelatin...
November 2014: Arerugī, [Allergy]
Miho Terunuma, Philip G Haydon, Menelas N Pangalos, Stephen J Moss
Gamma-aminobutyric acid B receptors (GABABRs) are heterodimeric G-protein coupled receptors, which mediate slow synaptic inhibition in the brain. Emerging evidence suggests astrocytes also express GABABRs, although their physiological significance remains unknown. To begin addressing this issue, we have used imaging and biochemical analysis to examine the role GABABRs play in regulating astrocytic Ca(2+) signalling. Using live imaging of cultured cortical astrocytes loaded with calcium indicator Fluo-4/AM, we found that astrocytic GABABRs are able to induce astrocytic calcium transients only if they are pre-activated by P2 purinoceptors (P2YRs)...
January 2015: Neuropharmacology
Tzvia I Springer, Erich Goebel, Dinesh Hariraju, Natosha L Finley
Bordetella pertussis, causative agent of whooping cough, produces an adenylate cyclase toxin (CyaA) that is an important virulence factor. In the host cell, the adenylate cyclase domain of CyaA (CyaA-ACD) is activated upon association with calmodulin (CaM), an EF-hand protein comprised of N- and C-lobes (N-CaM and C-CaM, respectively) connected by a flexible tether. Maximal CyaA-ACD activation is achieved through its binding to both lobes of intact CaM, but the structural mechanisms remain unclear. No high-resolution structure of the intact CaM/CyaA-ACD complex is available, but crystal structures of isolated C-CaM bound to CyaA-ACD shed light on the molecular mechanism by which this lobe activates the toxin...
October 10, 2014: Biochemical and Biophysical Research Communications
Haruko Shirato, Yuichi Someya, Masaki Ochiai, Yoshinobu Horiuchi, Motohide Takahashi, Naokazu Takeda, Kengo Wakabayashi, Yasumitsu Ouchi, Yoshihiro Ota, Yoshio Tano, Shinobu Abe, Shudo Yamazaki, Takaji Wakita
As one aspect of its campaign to eradicate poliomyelitis, the World Health Organization (WHO) has encouraged development of the inactivated polio vaccine (IPV) derived from the Sabin strains (sIPV) as an option for an affordable polio vaccine, especially in low-income countries. The Japan Poliomyelitis Research Institute (JPRI) inactivated three serotypes of the Sabin strains and made sIPV preparations, including serotypes 1, 2 and 3 D-antigens in the ratio of 3:100:100. The National Institute of Infectious Diseases, Japan, assessed the immunogenic stability of these sIPV preparations in a rat potency test, according to an evaluation method recommended by the WHO...
September 8, 2014: Vaccine
Edithe Selwa, Marilyne Davi, Alexandre Chenal, Ana-Cristina Sotomayor-Pérez, Daniel Ladant, Thérèse E Malliavin
Adenylyl cyclase (AC) toxin is an essential toxin that allows Bordetella pertussis to invade eukaryotic cells, where it is activated after binding to calmodulin (CaM). Based on the crystal structure of the AC catalytic domain in complex with the C-terminal half of CaM (C-CaM), our previous molecular dynamics simulations (Selwa, E., Laine, E., and Malliavin, T. (2012) Differential role of calmodulin and calcium ions in the stabilization of the catalytic domain of adenyl cyclase CyaA from Bordetella pertussis...
July 25, 2014: Journal of Biological Chemistry
Anthony Yiu-Ho Woo, Krzysztof Jozwiak, Lawrence Toll, Mary J Tanga, Joseph A Kozocas, Lucita Jimenez, Ying Huang, Ying Song, Anita Plazinska, Karolina Pajak, Rajib K Paul, Michel Bernier, Irving W Wainer, Rui-Ping Xiao
Interaction of a given G protein-coupled receptor to multiple different G proteins is a widespread phenomenon. For instance, β2-adrenoceptor (β2-AR) couples dually to Gs and Gi proteins. Previous studies have shown that cAMP-dependent protein kinase (PKA)-mediated phosphorylation of β2-AR causes a switch in receptor coupling from Gs to Gi. More recent studies have demonstrated that phosphorylation of β2-AR by G protein-coupled receptor kinases, particularly GRK2, markedly enhances the Gi coupling. We have previously shown that although most β2-AR agonists cause both Gs and Gi activation, (R,R')-fenoterol preferentially activates β2-AR-Gs signaling...
July 11, 2014: Journal of Biological Chemistry
Ying-Hen Hsieh, Junli Liu, Yun-Huei Tzeng, Jianhong Wu
We develop a deterministic meta-population model to qualitatively capture some key features of disease transmission between a community and its healthcare facility. We consider the disease transmission dynamics within a healthcare facility and between the healthcare facility and its community. The focus of this study is to quantify the roles of the healthcare workers at and visitors to this healthcare facility in shaping the transmission dynamics during a disease outbreak. We stratify the total population into the general population in the community and the healthcare workers and visitors in the healthcare facility, to account for nosocomial transmission in the case when an individual in the community may be exposed to an infection due to a visit to the healthcare facility...
September 7, 2014: Journal of Theoretical Biology
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