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)

Iron (Fe) is an essential element for most organisms which must be obtained from the local environment. In the case of pathogenic bacteria, this fundamental element must be acquired from the fluids and tissues of the infected host. A variety of systems have evolved in bacteria for efficient acquisition of host-bound Fe. The gram-negative bacterium Bordetella avium, upon colonization of the avian upper respiratory tract, produces a disease in birds that has striking similarity to whooping cough, a disease caused by the obligate human pathogen Bordetella pertussis. We describe a B. avium Fe utilization locus comprised of bhuR and six accessory genes (rhuIR and bhuSTUV). Genetic manipulations of B. avium confirmed that bhuR, which encodes a putative outer membrane heme receptor, mediates efficient acquisition of Fe from hemin and hemoproteins (hemoglobin, myoglobin, and catalase). BhuR contains motifs which are common to bacterial heme receptors, including a consensus FRAP domain, an NPNL domain, and two TonB boxes. An N-terminal 32-amino-acid segment, putatively required for rhuIR-dependent regulated expression of bhuR, is present in BhuR but not in other bacterial heme receptors. Two forms of BhuR were observed in the outer membrane of B. avium: a 91-kDa polypeptide consistent in size with the predicted mature protein and a smaller 82-kDa polypeptide which lacks the 104 amino acids found at the N terminus of the 91-kDa form. A mutation in hemA was engineered in B. avium to demonstrate that the bacterium transports heme into the cytoplasm in a BhuR-dependent manner. The role of BhuR in virulence was established in turkey poults by use of a competitive-infection model.
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PMID:BhuR, a virulence-associated outer membrane protein of Bordetella avium, is required for the acquisition of iron from heme and hemoproteins. 1222 63

The Lady Dufferin Fund, founded in 1885 in India, had by 1940 established 400 hospitals to alleviate diseases and mortality related to childbirth. After independence 2328 community health centers and 21254 primary health centers were created in the country. During 1974-94 more than 131,000 subcenters were set up and about 620,000 auxiliary nurse midwives (ANMs) had been trained. The Ministry of Health introduced four health prevention schemes in 1969: 1) immunization of children against diphtheria, pertussis, and tetanus; 2) immunization of pregnant women against tetanus; 3) prophylaxis of mothers and children against nutritional anemia; and 4) prophylaxis of children against blindness caused by vitamin A deficiency. As a result, infant mortality declined from 146/1000 live births to 74/1000 in 1993; but maternal mortality still stayed around 4-5/1000. In 1993 an estimated 117,356 maternal deaths occurred out of a total of 26,057,000 births, equalling 4.5 deaths per 1000 live births. The main causes of maternal deaths are hemorrhage, anemia, abortion, toxemia, and puerperal sepsis. Only about 411 first referral units in community health centers are functioning properly. Prenatal care of mothers includes the administration of tetanus toxoid and iron-folic acid tablets. However, the prenatal coverage reached only about 50% of mothers; and the coverage was only 21.4% in Bihar, 23.8% in Nagaland, 29.3% in Rajasthan, and 29.6% in Uttar Pradesh. In these areas administrative inefficiency is widespread with nonavailability of essential drugs for malaria, infections, sepsis, dysentery, and colds. During 1992-93 the rate of hospital deliveries ranged from 6.1% in Nagaland to 88.4% in Kerala, with a national average of only 25.6%. 71% of deliveries in rural areas and 30% in urban areas were conducted by untrained assistants. Although there are 450 ANM training schools in the country, the level of training has deteriorated. The major causes of infant deaths are respiratory infections and diarrhea, responsible for 13.5% and 6.9% of mortality, respectively. Severe malnutrition and inadequate vaccination are other major causes of child deaths and morbidity.
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PMID:Maternal and child health in India: a critical review. 1229 Sep 61

Bordetella pertussis and Bordetella bronchiseptica, gram-negative respiratory pathogens of mammals, possess a heme iron utilization system encoded by the bhuRSTUV genes. Preliminary evidence suggested that expression of the BhuR heme receptor was stimulated by the presence of heme under iron-limiting conditions. The hurIR (heme uptake regulator) genes were previously identified upstream of the bhuRSTUV gene cluster and are predicted to encode homologs of members of the iron starvation subfamily of extracytoplasmic function (ECF) regulators. In this study, B. pertussis and B. bronchiseptica DeltahurI mutants, predicted to lack an ECF sigma factor, were constructed and found to be deficient in the utilization of hemin and hemoglobin. Genetic complementation of DeltahurI strains with plasmid-borne hurI restored wild-type levels of heme utilization. B. bronchiseptica DeltahurI mutant BRM23 was defective in heme-responsive production of the BhuR heme receptor; hurI in trans restored heme-inducible BhuR expression to the mutant and resulted in BhuR overproduction. Transcriptional analyses with bhuR-lacZ fusion plasmids confirmed that bhuR transcription was activated in iron-starved cells in response to heme compounds. Heme-responsive bhuR transcription was not observed in mutant BRM23, indicating that hurI is required for positive regulation of bhu gene expression. Furthermore, bhuR was required for heme-inducible bhu gene activation, supporting the hypothesis that positive regulation of bhuRSTUV occurs by a surface signaling mechanism involving the heme-iron receptor BhuR.
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PMID:Heme-responsive transcriptional activation of Bordetella bhu genes. 1253 66

Bordetella pertussis undergoes phenotypic changes modulated by the bvgAS locus, which regulates the expression of many genes related to virulence and immunogenicity. We previously reported the N-terminal sequence of a 90 kDa bvg-regulated outer membrane protein (OMP) of B. pertussis (SWISS-PROT accession No. p81549), a novel potential virulence factor that we named Vir90. The open reading frames (ORFs) which potentially code for Vir90 in B. pertussis, B. parapertussis and B. bronchiseptica were identified by computer analysis of the genomic sequences available for the three Bordetella species. Nucleotide sequence analysis of the vir90 upstream region revealed the presence of a putative promoter, a BvgA binding site and a putative Fur binding site. The B. pertussis Vir90 protein showed significant homology with ferrisiderophore receptors from Gram-negative bacteria. An antiserum raised against Vir90His recombinant protein recognized the 90-kDa protein in immunoblots of OMPs from these three virulent Bordetella species. The accumulation of the Vir90 protein increased 4-fold under low iron growth conditions. Therefore, the vir90 gene is expressed in the tested species and its expression is regulated positively by the BvgAS system and negatively under high iron concentration, likely by Fur.
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PMID:Vir90, a virulence-activated gene coding for a Bordetella pertussis iron-regulated outer membrane protein. 1289 51

The effects of ferric-sorbitol-citrate and ferric-citrate on the severity of experimental arthritis, TNF-alpha secretion and the immune status were examined in mice. Arthritis was induced by footpad injection of methylated BSA and intraperitoneal injection of Bordetella pertussis. Joint and footpad swelling were measured weekly by a caliper. TNF-alpha serum levels were measured by ELISA. The immune status was determined by the response of mouse lymphocytes to ConA in vitro and by the antigen-presenting cell assay. Experimental arthritis was aggravated by ferric-citrate, whereas ferric-sorbitol-citrate did not promote it. If applied to normal (non-arthritic) mice three times a week for 4 weeks, ferric-sorbitol-citrate stimulated isolated splenocytes to increase production of TNF-alpha, the function of antigen-presenting cells and lymphocyte proliferation in response to ConA in vitro. TNF-alpha production by cultured splenocytes was also stimulated. In mice with antigen-induced arthritis, iron compounds did not additionally stimulate TNF-alpha production. Thus, we have shown that ferric-sorbitol-citrate stimulated TNF-alpha production, antigen-presenting cell activity and cellular immune response. Development of antigen-induced arthritis and TNF-alpha production in arthritic mice were not stimulated.
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PMID:Differing effects of two iron compounds on experimental arthritis, TNF-alpha levels and immune response in mice. 1463 25

The Bordetella pertussis heme utilization gene cluster hurIR bhuRSTUV encodes regulatory and transport functions required for assimilation of iron from heme and hemoproteins. Expression of the bhu genes is iron regulated and heme inducible. The putative extracytoplasmic function (ECF) sigma factor, HurI, is required for heme-responsive bhu gene expression. In this study, transcriptional activation of B. pertussis bhu genes in response to heme compounds was shown to be dose dependent and specific for heme; protoporphyrin IX and other heme structural analogs did not activate bhu gene expression. Two promoters controlling expression of the heme utilization genes were mapped by primer extension analysis. The hurI promoter showed similarity to sigma(70)-like promoters, and its transcriptional activity was iron regulated and heme independent. A second promoter identified upstream of bhuR exhibited little similarity to previously characterized ECF sigma factor-dependent promoters. Expression of bhuR was iron regulated, heme responsive, and hurI dependent in B. pertussis, as shown in a previous study with Bordetella bronchiseptica. Further analyses showed that transcription originating at a distal upstream site and reading through the hurR-bhuR intergenic region contributes to bhuR expression under iron starvation conditions in the absence of heme inducer. The pattern of regulation of the readthrough transcript was consistent with transcription from the hurI promoter. The positions and regulation of the two promoters within the hur-bhu gene cluster influence the production of heme transport machinery so that maximal expression of the bhu genes occurs under iron starvation conditions only in the presence of heme iron sources.
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PMID:Integration of environmental signals controls expression of Bordetella heme utilization genes. 1476 88

We have previously reported that, depending on the dose, nitric oxide (NO)-generating agents exert a dual facilitatory and inhibitory action on glutamatergic transmission on the rostral ventrolateral medulla (RVLM) neurons. The molecular mechanisms underlying the NO-mediated synaptic inhibition have not yet been defined. Here we show that the amplitude of excitatory postsynaptic currents (EPSCs) was reversibly reduced by the NO donors 3-morpholinylsydnoneimine (SIN-1) (1 mM) and spermine NONOate (1 mM). This effect was antagonized by an active peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride, G(i/o)-coupled receptor blockers, N-ethylmaleimide and pertussis toxin, A(1) adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, or adenosine deaminase. However, NO-sensitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), or cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) had no effect on the inhibitory action of SIN-1 on EPSCs. Perfusion of adenosine mimicked and subsequently occluded the action of SIN-1. Inhibition of EPSC amplitude by SIN-1 was associated with an increase in the paired-pulse ratio of EPSCs. Furthermore, SIN reduced the frequency of spontaneous EPSCs without altering their amplitude of distribution. Pretreatment with N-type Ca(2+)-channel blocker omega-conotoxin GVIA selectively blocked SIN-1-induced inhibition of EPSCs. These results suggest that a higher dose of SIN-1 acts presynaptically to elicit a synaptic depression on the RVLM neurons through an inhibition of presynaptic N-type Ca(2+)-channel activity, leading to reduced glutamate release. The presynaptic action of SIN-1 is mediated by the formation of peroxynitrite, which subsequently acts to release adenosine to activate A(1) adenosine receptors.
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PMID:3-Morpholinylsydnonimine inhibits glutamatergic transmission in rat rostral ventrolateral medulla via peroxynitrite formation and adenosine release. 1532 40

Utilization of the enterobactin siderophore by the respiratory pathogens Bordetella pertussis and Bordetella bronchiseptica is dependent on the BfeA outer membrane receptor. This study determined that production of BfeA was increased significantly in iron-starved bacteria upon supplementation of cultures with enterobactin. A 1.01-kb open reading frame, designated bfeR, encoding a predicted positive transcriptional regulator of the AraC family was identified upstream and divergently oriented from bfeA. In iron-depleted cultures containing enterobactin, a Bordetella bfeR mutant exhibited markedly decreased BfeA receptor production compared to that of the wild-type strain. Additionally, B. pertussis and B. bronchiseptica bfeR mutants exhibited impaired growth with ferric enterobactin as the sole source of iron, demonstrating that effective enterobactin utilization is bfeR dependent. Transcriptional analysis using bfeA-lacZ reporter fusions in wild-type strains demonstrated that bfeA transcription was stimulated in iron-depleted conditions in the presence of enterobactin, compared to modest expression levels in cultures lacking enterobactin. In contrast, bfeA transcription in B. pertussis and B. bronchiseptica bfeR mutants was completely unresponsive to the enterobactin inducer. bfeA transcriptional analyses of a bfeA mutant demonstrated that induction by enterobactin did not require BfeA receptor-mediated uptake of the siderophore. These studies establish that bfeR encodes an enterobactin-dependent positive regulator of bfeA transcription in these Bordetella species.
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PMID:The BfeR regulator mediates enterobactin-inducible expression of Bordetella enterobactin utilization genes. 1548 42

Bordetella pertussis and Bordetella bronchiseptica, which are respiratory mucosal pathogens of mammals, produce and utilize the siderophore alcaligin to acquire iron in response to iron starvation. A predicted permease of the major facilitator superfamily class of membrane efflux pumps, AlcS (synonyms, OrfX and Bcr), was reported to be encoded within the alcaligin gene cluster. In this study, alcS null mutants were found to be defective in growth under iron starvation conditions, in iron source utilization, and in alcaligin export. trans complementation using cloned alcS genes of B. pertussis or B. bronchiseptica restored the wild-type phenotype to the alcS mutants. Although the levels of extracellular alcaligin measured in alcS strain culture fluids were severely reduced compared with the wild-type levels, alcS mutants had elevated levels of cell-associated alcaligin, implicating AlcS in alcaligin export. Interestingly, a deltaalcA mutation that eliminated alcaligin production suppressed the growth defects of alcS mutants. This suppression and the alcaligin production defect were reversed by trans complementation of the deltaalcA mutation in the double-mutant strain, confirming that the growth-defective phenotype of alcS mutants is associated with alcaligin production. In an alcA::mini-Tn5 lacZ1 operon fusion strain background, an alcS null mutation resulted in enhanced AlcR-dependent transcriptional responsiveness to alcaligin inducer; conversely, AlcS overproduction blunted the transcriptional response to alcaligin. These transcription studies indicate that the alcaligin exporter activity of AlcS is required to maintain appropriate intracellular alcaligin levels for normal inducer sensing and responsiveness necessary for positive regulation of alcaligin system gene expression.
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PMID:Bordetella AlcS transporter functions in alcaligin siderophore export and is central to inducer sensing in positive regulation of alcaligin system gene expression. 1590 87

Bordetella pertussis, the causative agent of whooping cough or pertussis, is an obligate human pathogen with multiple high-affinity iron transport systems. Maximal expression of the dedicated heme utilization functions encoded by the hurIR bhuRSTUV genes requires an iron starvation signal to relieve Fur repression at the hurIR promoter-operator and an inducing signal supplied by heme for HurI-mediated transcriptional activation at the bhuRSTUV promoter. The BhuR outer membrane receptor protein is required for heme uptake and for heme sensing for induction of bhuRSTUV transcription. It was hypothesized that heme utilization contributed to the success of B. pertussis as a pathogen. In this study, virulence attenuation resulting from inactivation of the B. pertussis heme system was assessed using mixed infection competition experiments in a mouse model. As a measure of in vivo fitness, the ability of a B. pertussis heme utilization mutant to colonize and persist was determined relative to that of an isogenic coinfecting wild-type strain. Relative fitness of the mutant strain declined significantly after 7 days postinfection and continued to decline throughout the remainder of the 28-day infection time course. In parallel infections using inocula supplemented with an inducing 2 microM concentration of hemin chloride, hemin coadministration augmented the competitive advantage of the wild-type strain over the mutant. The results confirm that heme utilization contributes to the pathogenesis of B. pertussis in the mouse infection model and indicate that heme utilization may be most important for adaptation to host conditions existing during the later stages of infection.
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PMID:Heme transport contributes to in vivo fitness of Bordetella pertussis during primary infection in mice. 1649 46


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