Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following active service during the 1990/1991 Gulf Conflict, a number of UK and US veterans presented with a diverse range of symptoms, collectively known as Gulf Veterans Illnesses (GVI). The administration of vaccines and/or the pretreatment against possible nerve agent poisoning, pyridostigmine bromide (PB), given to Armed Forces personnel during the Gulf Conflict has been implicated as a possible factor in the aetiology of these illnesses. The possibility that adverse health effects may result from the administration of these vaccines (anthrax, pertussis, plague, yellow fever, polio, typhoid, tetanus, hepatitis B, meningococcal meningitis and cholera) and/or PB, have been investigated over an eighteen month period, in a non-human primate model, the common marmoset. This study reports immunological indices, including leukocyte phenotypes, intracellular cytokines IFN-gamma and IL-4 and antibody responses against vaccine antigens. Using human isotyping reagents previously shown to cross react with marmoset immunoglobulins (ibid) it was shown that marmosets responded strongly against anthrax PA and pertussis and weakly against killed whole cell plague, cholera and typhoid. At the end of the study the immune response to a previously unseen T-cell dependent antigen, keyhole limpet haemocyanin (KLH), was examined in order to determine whether immune function had been compromised by the compounds administered. Statistically equivalent, robust antibody responses were measured against KLH in all treatment groups indicating that the immune system had not been compromised by any of the treatments. In addition, urinary cortisol was measured at key points throughout the study as an index of physiological stress which may have been induced by the treatments. There were no effects of treatment on urinary cortisol secretion. With respect to the other immunological indices measured, there were no statistical differences between the treatment groups during the period of the study.
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PMID:Multiple vaccine and pyridostigmine bromide interactions in the common marmoset Callithrix jacchus: immunological and endocrinological effects. 1705 67

We describe a microfluidic genetic analysis system that represents a previously undescribed integrated microfluidic device capable of accepting whole blood as a crude biological sample with the endpoint generation of a genetic profile. Upon loading the sample, the glass microfluidic genetic analysis system device carries out on-chip DNA purification and PCR-based amplification, followed by separation and detection in a manner that allows for microliter samples to be screened for infectious pathogens with sample-in-answer-out results in < 30 min. A single syringe pump delivers sample/reagents to the chip for nucleic acid purification from a biological sample. Elastomeric membrane valving isolates each distinct functional region of the device and, together with resistive flow, directs purified DNA and PCR reagents from the extraction domain into a 550-nl chamber for rapid target sequence PCR amplification. Repeated pressure-based injections of nanoliter aliquots of amplicon (along with the DNA sizing standard) allow electrophoretic separation and detection to provide DNA fragment size information. The presence of Bacillus anthracis (anthrax) in 750 nl of whole blood from living asymptomatic infected mice and of Bordetella pertussis in 1 microl of nasal aspirate from a patient suspected of having whooping cough are confirmed by the resultant genetic profile.
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PMID:A fully integrated microfluidic genetic analysis system with sample-in-answer-out capability. 1715 53

The adenylyl cyclase toxins produced by bacteria (such as the edema factor (EF) of Bacillus anthracis and CyaA of Bordetella pertussis) are important virulence factors in anthrax and whooping cough. Co-crystal structures of these proteins differ in the number and positioning of metal ions in the active site. Metal ions bound only to the ligands in the crystal structures are not included during the docking. To determine what effect these "missing" metals have on docking results, the AutoDock, LigandFit/Cerius2, and FlexX programs were compared for their ability to correctly place substrate analogues and inhibitors into the active sites of the crystal structures of EF, CyaA, and mammalian adenylate cyclase. Protonating the phosphates of substrate analogues improved the accuracy of docking into the active site of CyaA, where the grid did not account for one of the three Mg2+ ions in the crystal structure. The AutoDock ranking (based on docking energies) of a test group of compounds was relatively unaffected by protonation of carboxyl groups. However, the ranking by FlexX-ChemScore varied significantly, especially for docking to CyaA, suggesting that alternate protonation states should be tested when screening compound libraries with this program. When the charges on the bound metal were set correctly, AutoDock was the most reliable program of the three tested with respect to positioning substrate analogues and ranking compounds according to their experimentally determined ability to inhibit EF.
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PMID:Accounting for ligand-bound metal ions in docking small molecules on adenylyl cyclase toxins. 1731 51

Calmodulin (CaM), a eukaryotic calcium sensor that regulates diverse biological activities, consists of N- and C-terminal globular domains (N-CaM and C-CaM, respectively). CaM serves as the activator of CyaA, a 188-kDa adenylyl cyclase toxin secreted by Bordetella pertussis, which is the etiologic agent for whooping cough. Upon insertion of the N-terminal adenylyl cyclase domain (ACD) of CyaA to its targeted eukaryotic cells, CaM binds to this domain tightly ( approximately 200 pm affinity). This interaction activates the adenylyl cyclase activity of CyaA, leading to a rise in intracellular cAMP levels to disrupt normal cellular signaling. We recently solved the structure of CyaA-ACD in complex with C-CaM to elucidate the mechanism of catalytic activation. However, the structure of the interface between N-CaM and CyaA, the formation of which contributes a 400-fold increase of binding affinity between CyaA and CaM, remains elusive. Here, we used site-directed mutations and molecular dynamic simulations to generate several working models of CaM-bound CyaA-ACD. The validity of these models was evaluated by disulfide bond cross-linking, point mutations, and fluorescence resonance energy transfer experiments. Our study reveals that a beta-hairpin region (amino acids 259-273) of CyaA-ACD likely makes contacts with the second calcium binding motif of the extended CaM. This mode of interaction differs from the interaction of N-CaM with anthrax edema factor, which binds N-CaM via its helical domain. Thus, two structurally conserved, bacterial adenylyl cyclase toxins have evolved to utilize distinct binding surfaces and modes of activation in their interaction with CaM, a highly conserved eukaryotic signaling protein.
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PMID:Protein-protein docking and analysis reveal that two homologous bacterial adenylyl cyclase toxins interact with calmodulin differently. 1858 46

The enzymatic activity of the three most studied bacterial toxins that increase the cytosolic cAMP level: pertussis toxin (PT), cholera toxin (CT), and anthrax edema toxin (ET), was imaged by fluorescence videomicroscopy. Three different cell lines were transfected with a fluorescence resonance energy transfer biosensor based on the PKA regulatory and catalytic subunits fused to CFP and YFP, respectively. Real-time imaging of cells expressing this cAMP biosensor provided time and space resolved pictures of the toxins action. The time course of the PT-induced cAMP increase suggests that its active subunit enters the cytosol more rapidly than that deduced by biochemical experiments. ET generated cAMP concentration gradients decreasing from the nucleus to the cell periphery. On the contrary, CT, which acts on the plasma membrane adenylate cyclase, did not. The potential of imaging methods in studying the mode of entry and the intracellular action of bacterial toxins is discussed.
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PMID:cAMP imaging of cells treated with pertussis toxin, cholera toxin, and anthrax edema toxin. 1879 14

There are countless bacterial pathogens that cause disease in humans. Many of these bacterial infections not only cause significant morbidity and mortality in the human population but also cause a significant economic impact on society. Vaccines allow for reduction and potential eradication of such diseases. This article will review the currently approved antibacterial vaccines, which are vaccines for pertussis, tetanus, diphtheria, meningococcus, pneumococcus, Haemophilus influenza, cholera, typhoid, and anthrax.
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PMID:Existing antibacterial vaccines. 1933 24

Adverse events following immunization (AEFI) are not uncommon, with injection site reactions (ISRs) being the most common. Predictors of injection site reactions are vaccine factors (antigen characteristics, antigen dose, dose number of antigen, antigen adjuvanting and type of diluent), vaccine administration factors (site and route of administration) and vaccinee factors (age and sex, the latter the subject of this review). 1,074 studies which reported ISRs were retrieved by searching of on line journals and databases. Analysis of these data for sex-difference was only reported in 57 studies, with 54 of these studies reporting a sex-difference (42 in subjects >17 years and 12 in subjects <17 years). In accord with the well documented greater pain sensitivity in females compared with males, in all studies with vaccines which reported pain during and post vaccination [hepatitis A, B, diphtheria/tetanus toxoid, diphtheria/tetanus/pertussis(DTaP and Tdap), anthrax and inactivated influenza], females reported a greater rate of pain than males. The pathophysiology of the sex-difference in local reactions (induration, tenderness, erythema, pruritus) following vaccination is clearly multifactorial with hypersensitivity reaction (type III, Arthus reaction-antigen/antibody immune complex formation), route of administration and hormonal factors being suggested. The data presented in this review demonstrate that studies of AEFI should recruit similar numbers of females and males and that these data should be analyzed for sex-difference. Additionally, unlike as at present, reporting of analysis of AEFI data by sex should become standard practice.
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PMID:Sex differences in injection site reactions with human vaccines. 1937 79

Bacillus anthracis, the etiologic agent for anthrax, secretes edema factor (EF) to disrupt intracellular signaling pathways. Upon translocation into host cells and association with a calcium sensor, calmodulin (CaM), EF becomes a highly active adenylyl cyclase (AC) that raises the intracellular concentration of cyclic AMP (cAMP). Growing evidence shows that EF plays a key role in anthrax pathogenesis by affecting cellular functions vital for host defense. This strategy is also used by Bordetella pertussis, a bacterium that causes whooping cough. Pertussis bacteria secrete the bifunctional toxin CyaA which raises the intracellular cAMP. Here, we discuss recent advances from structural analyses that reveal the molecular basis of the conserved mechanism of activation and catalysis of EF and CyaA by CaM even though these two toxins use the completely different sequences to bind CaM. Comparison of the biochemical and structural characteristics of these two AC toxins with host ACs reveal that they have diverse strategies of catalytic activation, yet use the same two-metal-ion catalytic mechanism.
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PMID:The adenylyl cyclase activity of anthrax edema factor. 1956 Apr 85

Type-IIA secreted phospholipase A(2) (sPLA(2)-IIA) has been proposed to play a role in the development of inflammatory diseases. It has been shown to release arachidonic acid, the precursor of proinflammatory eicosanoids, to hydrolyze phospholipids of pulmonary surfactant, and to bind to specific receptors located on cell surface membranes. However, the most established biological role of sPLA(2)-IIA is related to its potent bactericidal property in particular toward Gram-positive bacteria. This enzyme is present in animal and human biological fluids at concentrations sufficient to kill bacteria. Human recombinant sPLA(2)-IIA is able to kill Gram-positive bacteria at concentrations as low as 1.1 ng/ml. This remarkable property is due to the unique preference of sPLA(2)-IIA for anionic phospholipids such as phosphatidylglycerol, the main phospholipid component of bacterial membranes. Much higher concentrations of sPLA(2)-IIA are required for its action on host cell membranes and surfactant both of which are mainly composed by phosphatidylcholine, a poor substrate for sPLA(2)-IIA. Transgenic mice over-expressing human sPLA(2)-IIA are resistant to infection by Staphylococcus aureus, Escherichia coli, and Bacillus anthracis, the etiological agent of anthrax. Conversely, certain bacteria, such as B. anthracis, E. coli and Bordetella pertussis are able to inhibit sPLA(2)-IIA expression by host cells, thus highlighting a mechanism by which these bacteria can subvert the host immune system. Intranasal instillation of recombinant sPLA(2)-IIA protects mice from mortality caused by pulmonary anthrax. Interestingly, this protective effect was obtained even with B. anthracis strains that down-regulate the expression of endogenous sPLA(2)-IIA, indicating that instilled sPLA(2)-IIA can overcome the subversive action of B. anthracis. We conclude that sPLA(2)-IIA is an efficient endogenous antibiotic of the host and can play a role in host defense against pathogenic bacteria. It can be used as a therapeutic agent in adjunct with current therapy to treat bacteria resistant to multiple antibiotics.
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PMID:Type-IIA secreted phospholipase A2 is an endogenous antibiotic-like protein of the host. 2014 78

Matrix-assisted laser-desorption time-of-flight (MALDI-TOF) mass spectrometry (MS) is a valuable high-throughput tool for peptide analysis. Liquid chromatography electrospray ionization (LC-ESI) tandem-MS provides sensitive and specific quantification of small molecules and peptides. The high analytic power of MS coupled with high-specificity substrates is ideally suited for detection and quantification of bacterial enzymatic activities. As specific examples of the MS applications in disease diagnosis and select agent detection, we describe recent advances in the analyses of two high profile protein toxin groups, the Bacillus anthracis toxins and the Clostridium botulinum neurotoxins. The two binary toxins produced by B. anthracis consist of protective antigen (PA) which combines with lethal factor (LF) and edema factor (EF), forming lethal toxin and edema toxin respectively. LF is a zinc-dependent endoprotease which hydrolyzes specific proteins involved in inflammation and immunity. EF is an adenylyl cyclase which converts ATP to cyclic-AMP. Toxin-specific enzyme activity for a strategically designed substrate, amplifies reaction products which are detected by MALDI-TOF-MS and LC-ESI-MS/MS. Pre-concentration/purification with toxin specific monoclonal antibodies provides additional specificity. These combined technologies have achieved high specificity, ultrasensitive detection and quantification of the anthrax toxins. We also describe potential applications to diseases of high public health impact, including Clostridium difficile glucosylating toxins and the Bordetella pertussis adenylyl cyclase.
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PMID:Quantitative mass spectrometry for bacterial protein toxins--a sensitive, specific, high-throughput tool for detection and diagnosis. 2140 98


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