Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genes involved in iron (Fe) acquisition often are regulated in response to the local availability of Fe. In many bacteria, Fe-dependent responsiveness is mediated by Fur, a global Fe-dependent transcriptional repressor. Tighter regulatory control of Fur-responsive genes is afforded by incorporating additional regulators into Fur-dependent regulatory cascades. RhuI, a Fur-dependent extracytoplasmic function sigma factor of Bordetella avium, in response to the dual stimulation of Fe starvation and the presence of heme (or hemoproteins), regulates P(bhuR), a heme-responsive promoter which directs expression of the bhuRSTUV heme utilization operon. While BhuR, the outer membrane heme receptor, and RhuI have been shown to be indispensable for heme-dependent activation of P(bhuR), collateral components of the regulatory cascade have not been described. In this investigation, RhuR, an integral cytoplasmic membrane protein with homology to anti-sigma factors, is shown to be an essential activator of P(bhuR) expression. The functional domain of RhuR required for heme-dependent activation of P(bhuR) expression was mapped to the N-terminal 97 amino acids of the protein by use of a chimeric RhuR-BlaM fusion. Expression of the chimera in a rhuR mutant rendered P(bhuR) constitutive, thereby decoupling the promoter from heme dependency. Growth studies confirmed that B. avium requires RhuR for optimal utilization of hemoglobin, but not hemin, as a sole source of nutrient Fe. These data imply that B. avium expresses, in addition to the BhuR heme/hemoprotein utilization system, an alternative RhuR-independent heme utilization mechanism. A model is proposed in which RhuR is the functional bridge between BhuR and RhuI in a heme-dependent regulatory cascade.
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PMID:RhuR, an extracytoplasmic function sigma factor activator, is essential for heme-dependent expression of the outer membrane heme and hemoprotein receptor of Bordetella avium. 1474 34

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

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

Bordetella pertussis, Bordetella parapertussis, and Bordetella bronchiseptica are pathogens with a complex iron starvation stress response important for adaptation to nutrient limitation and flux in the mammalian host environment. The iron starvation stress response is globally regulated by the Fur repressor using ferrous iron as the co-repressor. Expression of iron transport system genes of Bordetella is coordinated by priority regulation mechanisms that involve iron source sensing. Iron source sensing is mediated by distinct transcriptional activators that are responsive to the cognate iron source acting as the inducer.
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PMID:Bordetella iron transport and virulence. 1729 50

Regulation of gene expression in response to local iron concentration is commonly observed in bacterial pathogens that face this nutrient limitation during host infection. In this study, a proteomic approach was used to analyze the differential protein expression of Bordetella pertussis under iron limitation. Whole cell lysates (WCL) and outer membrane fractions of bacteria grown either under iron-starvation or iron-excess conditions were analyzed by two-dimensional (2-D) gel electrophoresis. Statistical analysis revealed 36 proteins displaying differential expression, 9 with higher expression under iron-excess and 27 with increased expression under iron-starvation. These proteins were subjected to tryptic digestion and MALDI-TOF MS. Apart from those previously reported, we identified new low-iron-induced proteins that might help to explain the increased virulence of this phenotype. Additionally, we found evidence that at least one of the identified proteins, solely expressed under iron starvation, is highly immunogenic in infected individuals.
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PMID:Profiling the Bordetella pertussis proteome during iron starvation. 1752 12

Bordetella pertussis, the causative agent of human whooping cough, or pertussis, is an obligate human pathogen with diverse high-affinity transport systems for the assimilation of iron, a biometal that is essential for growth. Under iron starvation stress conditions, B. pertussis produces the siderophore alcaligin. The alcaligin siderophore gene cluster, consisting of the alcABCDERS and fauA genes, encodes activities required for alcaligin biosynthesis, the export of the siderophore from the cell, the uptake of the ferric alcaligin complex across the outer membrane, and the transcriptional activation of alcaligin system genes by an autogenous mechanism involving alcaligin sensing. The fauA gene encodes a 79-kDa TonB-dependent outer membrane receptor protein required for the uptake and utilization of ferric alcaligin as an iron source. In this study, using mixed-infection competition experiments in a mouse respiratory model, inactivation of the B. pertussis ferric alcaligin receptor protein was found to have a profound impact on in vivo growth and survival of a fauA mutant compared with a coinfecting wild-type strain. The attenuating effect of fauA inactivation was evident early in the course of the infection, suggesting that the contribution of ferric alcaligin transport to the ecological fitness of B. pertussis may be important for adaptation to iron-restricted host conditions that exist at the initial stages of infection. Alcaligin-mediated iron acquisition by B. pertussis may be critical for successful host colonization and establishment of infection.
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PMID:Impact of alcaligin siderophore utilization on in vivo growth of Bordetella pertussis. 1772 74

Serological studies of patients with pertussis and the identification of antigenic Bordetella pertussis proteins support the hypothesis that B. pertussis perceives an iron starvation cue and expresses multiple iron source utilization systems in its natural human host environment. Furthermore, previous studies using a murine respiratory tract infection model showed that several of these B. pertussis iron systems are required for colonization and persistence and are differentially expressed over the course of infection. The present study examined genome-wide changes in B. pertussis gene transcript abundance in response to iron starvation in vitro. In addition to known iron source utilization genes, we identified a previously uncharacterized iron-repressed cytoplasmic membrane transporter system, fbpABC, that is required for the utilization of multiple structurally distinct siderophores including alcaligin, enterobactin, ferrichrome, and desferrioxamine B. Expression of type III secretion system genes was also found to be upregulated during iron starvation in both B. pertussis strain Tohama I and Bordetella bronchiseptica strain RB50. In a survey of type III secretion system protein production by an assortment of B. pertussis laboratory-adapted and low-passage clinical isolate strains, iron limitation increased the production and secretion of the type III secretion system-specific translocation apparatus tip protein Bsp22 in all Bvg-proficient strains. These results indicate that iron starvation in the infected host is an important environmental cue influencing not only Bordetella iron transport gene expression but also the expression of other important virulence-associated genes.
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PMID:Transcriptional profiling of the iron starvation response in Bordetella pertussis provides new insights into siderophore utilization and virulence gene expression. 2174 63

Antigenic proteins whose expression is induced under iron starvation, an environmental condition that bacterial pathogens have to face during colonization, might be potential candidates for improved vaccine. By mean of immune proteomics we identified novel antigens of Bordetella pertussis maximally expressed under iron limitation. Among them, Bp1152 (named as IRP1-3) showed a particularly strong reaction with human IgG purified from pooled sera of pertussis-infected individuals. Computer analysis showed IRP1-3 as a dimeric membrane protein potentially involved in iron uptake. Experimental data revealed the surface-exposure of this protein and showed its increase under iron starvation to be independent of bacterial virulence phase. Immunization of mice with the recombinant IRP1-3 resulted in a strong antibody response. These antibodies not only recognized the native protein on bacterial surface but also promote effective bacterial phagocytosis by human PMN, a key protecting activity against this pathogen. Accordingly, IRP1-3 proved protective against B. pertussis infection in mouse model. Expression of IRP1-3 was found conserved among clinical isolates of B. pertussis and positively regulated by iron starvation in these strains. Taken together these results suggest that this protein might be an interesting novel vaccine candidate.
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PMID:Identification of a new protective antigen of Bordetella pertussis. 2188 46

The type III secretion system (T3SS) plays a key role in the exertion of full virulence by Bordetella bronchiseptica. However, little is known about the environmental stimuli that induce expression of T3SS genes. Here, it is reported that iron starvation is a signal for T3SS gene expression in B. bronchiseptica. It was found that, when B. bronchiseptica is cultured under iron-depleted conditions, secretion of type III secreted proteins is greater than that in bacteria grown under iron-replete conditions. Furthermore, it was confirmed that induction of T3SS-dependent host cell cytotoxicity and hemolytic activity is greatly enhanced by infection with iron-depleted Bordetella. In contrast, production of filamentous hemagglutinin is reduced in iron-depleted Bordetella. Thus, B. bronchiseptica controls the expression of virulence genes in response to iron starvation.
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PMID:Iron starvation regulates the type III secretion system in Bordetella bronchiseptica. 2237 89


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