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Volume 155,
Issue 9,
2009
Volume 155, Issue 9, 2009
- Review
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Interactions of Burkholderia cenocepacia and other Burkholderia cepacia complex bacteria with epithelial and phagocytic cells
More LessBurkholderia cenocepacia is a member of the B. cepacia complex (Bcc), a group of opportunistic bacteria that infect the airways of patients with cystic fibrosis (CF) and are extraordinarily resistant to almost all clinically useful antibiotics. Infections in CF patients with Bcc bacteria generally lead to a more rapid decline in lung function, and in some cases to the ‘cepacia syndrome’, a virtually deadly exacerbation of the lung infection with systemic manifestations. These characteristics of Bcc bacteria contribute to higher morbidity and mortality in infected CF patients. In the last 10 years considerable progress has been made in understanding the interactions between Bcc bacteria and mammalian host cells. Bcc isolates can survive either intracellularly within eukaryotic cells or extracellularly in host tissues. They survive within phagocytes and respiratory epithelial cells, and they have the ability to breach the respiratory epithelium layer. Survival and persistence of Bcc bacteria within host cells and tissues are believed to play a key role in pulmonary infection and to contribute to the persistent inflammation observed in patients with CF. This review summarizes recent findings concerning the interaction between Bcc bacteria and epithelial and phagocytic cells.
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- Cell And Molecular Biology Of Microbes
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The transcription factor DNR from Pseudomonas aeruginosa specifically requires nitric oxide and haem for the activation of a target promoter in Escherichia coli
More LessPseudomonas aeruginosa is a well-known pathogen in chronic respiratory diseases such as cystic fibrosis. Infectivity of P. aeruginosa is related to the ability to grow under oxygen-limited conditions using the anaerobic metabolism of denitrification, in which nitrate is reduced to dinitrogen via nitric oxide (NO). Denitrification is activated by a cascade of redox-sensitive transcription factors, among which is the DNR regulator, sensitive to nitrogen oxides. To gain further insight into the mechanism of NO-sensing by DNR, we have developed an Escherichia coli-based reporter system to investigate different aspects of DNR activity. In E. coli DNR responds to NO, as shown by its ability to transactivate the P. aeruginosa norCB promoter. The direct binding of DNR to the target DNA is required, since mutations in the helix–turn–helix domain of DNR and specific nucleotide substitutions in the consensus sequence of the norCB promoter abolish the transcriptional activity. Using an E. coli strain deficient in haem biosynthesis, we have also confirmed that haem is required in vivo for the NO-dependent DNR activity, in agreement with the property of DNR to bind haem in vitro. Finally, we have shown, we believe for the first time, that DNR is able to discriminate in vivo between different diatomic signal molecules, NO and CO, both ligands of the reduced haem iron in vitro, suggesting that DNR responds specifically to NO.
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Quorum sensing differentially regulates Pseudomonas aeruginosa type VI secretion locus I and homologous loci II and III, which are required for pathogenesis
B. Lesic, M. Starkey, J. He, R. Hazan and L. G. RahmePseudomonas aeruginosa harbours three type VI secretion (T6S) loci. Although HSI-I has been partially studied, limited knowledge is available on the homologous loci HSI-II and HSI-III. We show that quorum sensing (QS) differentially regulates the expression of genes at all three loci. HSI-I-associated gene expression is suppressed by both the homoserine lactone transcription factor LasR and the 4-hydroxy-2-alkylquinoline (HAQ) transcriptional regulator MvfR. Conversely, both HSI-II and HSI-III loci are positively controlled by LasR and MvfR. PqsE, a key component of the MvfR regulon, is required for the expression of part of HSI-III but not HSI-II, and previously identified inhibitors of HAQ biosynthesis significantly downregulate HSI-II and -III gene expression. Animal and plant infection studies reveal that both HSI-II and -III play important roles in pathogenesis. Furthermore, analysis of a double ΔHSI-II : : III mutant suggests that these loci functionally compensate for one another in virulence. This study illustrates the contribution of the QS systems to T6S gene regulation and reveals the importance of HSI-II and -III in mediating P. aeruginosa pathogenesis. Moreover, this work provides new insights into the design and development of selective compounds that may restrict human P. aeruginosa and possibly other clinical infections.
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Expression of the Streptococcus mutans essential two-component regulatory system VicRK is pH and growth-phase dependent and controlled by the LiaFSR three-component regulatory system
More LessAs an inhabitant of the human oral cavity, Streptococcus mutans faces frequent environmental changes. Two-component regulatory systems (TCSs) play a critical role in responding to these changes. Recently, an essential TCS, VicRKX, has been identified. The objective of this study was to identify the environmental signal and bacterial factors regulating the expression of the vicRKX operon. The promoter of the vicRKX operon was fused to a promoterless lacZ reporter gene and introduced into S. mutans UA159. LacZ plate assay identified pH, vancomycin, ampicillin, penicillin G and polymyxin B, but not carbohydrates, as factors affecting expression. Using RNA dot-blotting, high levels of vicR transcript were observed in cells at the mid- and late-exponential phase of growth and in cells grown in media buffered at pH 7.8. Given that vicR expression was pH-dependent, the genes encoding a putative pH-sensing three-component regulatory system (LiaFSR) were deleted. The liaS mutant exhibited upregulation of vicR regardless of the growth condition. The role of VicK, VicX, and the competence-signal peptide (CSP) was also investigated; the results showed that vicR expression was not autoregulated and was downregulated by the CSP in a ComX-independent manner. In conclusion, the expression of vicRKX is influenced by culture pH, growth phase and antibiotic stress, and is regulated by LiaFRS.
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Identification and characterization of a family of toxin–antitoxin systems related to the Enterococcus faecalis plasmid pAD1 par addiction module
The par locus of the Enterococcus faecalis plasmid pAD1 is an RNA-regulated addiction module encoding the peptide toxin Fst. Homology searches revealed that Fst belongs to a family of at least nine related peptides encoded on the chromosomes and plasmids of six different Gram-positive bacterial species. Comparison of an alignment of these peptides with the results of a saturation mutagenesis analysis indicated regions of the peptides important for biological function. Examination of the genetic context of the fst genes revealed that all of these peptides are encoded within par-like loci with conserved features similar to pAD1 par. All four Ent. faecalis family members were demonstrated to produce the expected toxin-encoding and regulatory RNA products. The locus from the Ent. faecalis plasmid pAMS1 was demonstrated to function as an addiction module and Fst was shown to be toxic to Staphylococcus aureus, suggesting that a plasmid-encoded module in that species is performing the same function. Thus, the pAD1-encoded par locus appears to be the prototype of a family of related loci found in several Gram-positive species.
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Class II one-peptide bacteriocins target a phylogenetically defined subgroup of mannose phosphotransferase systems on sensitive cells
More LessMembrane-located proteins (IIC and IID) of the mannose-phosphotransferase system (man-PTS) have previously been shown to serve as target receptors for several bacteriocins. Although many bacteria contain at least one such man-PTS in their genome, most bacteriocins display a narrow inhibitory spectrum, targeting predominantly bacteria closely related to the producers. In the present study we have analysed the receptor spectrum of one-peptide bacteriocins of class II. A phylogenetic analysis of 86 man-PTSs from a wide range of bacterial genera grouped the man-PTSs into three main clusters (groups I–III). Fourteen man-PTSs distributed across the phylogenetic tree were selected for experimental analysis in a heterologous host. Only members of group I could serve as receptors for class IIa bacteriocins, and the receptor efficiencies varied in a pattern directly related to their phylogenetic position. A multiple sequence alignment of IIC and IID proteins revealed three sequence regions (two in IIC and one in IID) that distinguish members of the bacteriocin-susceptible group from those of the other groups, suggesting that these amino acid regions confer the specific bacteriocin receptor function. Moreover, we demonstrated that variation in sensitivity might also exist within the same species due to differential expression levels of the receptor, since three strains of Lactobacillus sakei harbouring identical man-PTSs were shown to display different expression levels of a man-PTS gene that corresponded to the variation in bacteriocin sensitivity. Together, the results of our study show that the level of bacteriocin susceptibility for a bacterial cell is primarily determined by differences in its man-PTS proteins, although the expression levels of the corresponding genes also play an important role.
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Illumination stimulates cAMP receptor protein-dependent transcriptional activation from regulatory regions containing class I and class II promoter elements in Synechocystis sp. PCC 6803
The cAMP receptor protein (Crp) is a global transcriptional regulator that binds sequence-specific promoter elements when associated with cAMP. In the motile cyanobacterium Synechocystis sp. strain PCC 6803, intracellular cAMP increases when dark-adapted cells are illuminated. Previous work has established that Crp binds proposed Crp target sites upstream of slr1351 (murF), sll1874 (chlAII ), sll1708 (narL), slr0442 and sll1268 in vitro, and that slr0442 is downregulated in a crp mutant during photoautotrophic growth. To identify additional Crp target genes in Synechocystis, 11 different Crp binding sites proposed during a previous computational survey were tested for in vitro sequence-specific binding and crp-dependent transcription. The results indicate that murF, chlAII and slr0442 can be added as ‘target genes of Sycrp1’ in Synechocystis. Promoter mapping of the targets revealed the same close association of RNA polymerase and Crp as that found in Escherichia coli class I and class II Crp-regulated promoters, thereby strongly suggesting similar mechanisms of transcriptional activation.
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DNA polymerase X from Deinococcus radiodurans implicated in bacterial tolerance to DNA damage is characterized as a short patch base excision repair polymerase
More LessThe Deinococcus radiodurans R1 genome encodes an X-family DNA repair polymerase homologous to eukaryotic DNA polymerase β. The recombinant deinococcal polymerase X (PolX) purified from transgenic Escherichia coli showed deoxynucleotidyltransferase activity. Unlike the Klenow fragment of E. coli, this enzyme showed short patch DNA synthesis activity on heteropolymeric DNA substrate. The recombinant enzyme showed 5′-deoxyribose phosphate (5′-dRP) lyase activity and base excision repair function in vitro, with the help of externally supplied glycosylase and AP endonuclease functions. A polX disruption mutant of D. radiodurans expressing 5′-dRP lyase and a truncated polymerase domain was comparatively less sensitive to γ-radiation than a polX deletion mutant. Both mutants showed higher sensitivity to hydrogen peroxide. Excision repair mutants of E. coli expressing this polymerase showed functional complementation of UV sensitivity. These results suggest the involvement of deinococcal polymerase X in DNA-damage tolerance of D. radiodurans, possibly by contributing to DNA double-strand break repair and base excision repair.
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Identification and characterization of target genes of the GinI/GinR quorum-sensing system in Gluconacetobacter intermedius
More LessThe GinI/GinR quorum-sensing system represses oxidative fermentation, including acetic acid and gluconic acid fermentation, as well as antifoam activity in Gluconacetobacter intermedius NCI1051. An 89 aa protein, GinA, whose production is induced by the quorum-sensing system, represses both oxidative fermentation and antifoam activity via a still unknown mechanism, although an OmpA family protein, GmpA, as a target of the GinI/GinR quorum-sensing system via GinA, has been found to repress oxidative fermentation. In this study, four novel GinA-inducible genes (gltA, pdeA, pdeB and nagA) were identified and their involvement in oxidative fermentation and antifoam activity was examined by gene disruption. Disruption of nagA (which encodes a putative N-acetylglucosamine-6-phosphate deacetylase) decreased the growth rate in the exponential growth phase, indicating that nagA was required for the rapid growth of the strain. This unexpected finding revealed a new aspect of the GinI/GinR quorum-sensing system: it accelerates exponential growth by induction of nagA. In contrast, gltA (a putative glycosyltransferase) and pdeA (a putative cyclic-di-GMP phosphodiesterase) were shown to repress oxidative fermentation, including acetic acid and gluconic acid fermentation. gltA was also shown to repress antifoam activity. Disruption of pdeB (a putative phosphodiesterase/diguanylate cyclase) caused no phenotypic changes. Taking our previous results into consideration, these results showed an apparently complex mechanism for repressing oxidative fermentation by the quorum-sensing system; at least three GinA-inducible genes, gltA, pdeA and gmpA, were involved in the repression of oxidative fermentation by the GinI/GinR quorum-sensing system, the most characteristic feature of the acetic acid bacteria.
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Rhizobium leguminosarum biovar viciae 3841, deficient in 27-hydroxyoctacosanoate-modified lipopolysaccharide, is impaired in desiccation tolerance, biofilm formation and motility
The lipopolysaccharide (LPS) of the Gram-negative legume symbiont Rhizobium leguminosarum biovar viciae 3841 contains several unique modifications, including the addition of a 27-hydroxyoctacosanoic acid (27OHC28 : 0), also termed the very long chain fatty acid (VLCFA), attached at the 2′ position of lipid A. A transposon mutant that lacks expression of two putative 3-oxo-acyl [acyl-carrier protein] synthase II genes, fabF1 and fabF2, from the VLCFA biosynthetic cluster, was isolated and characterized. MS indicated that the lipid A of the mutant lacked the VLCFA modification, and sodium deoxycholate (DOC)-PAGE of the LPS indicated further structural alterations. The mutant was characteristically sensitive to several stresses that would be experienced in the soil environment, such as desiccation and osmotic stresses. An increase in the excretion of neutral surface polysaccharides was observed in the mutant. This mutant was also altered in its attachment to solid surfaces, and was non-motile, with most of the mutant cells lacking flagella. Despite the pleiotropic effects of the mutation, these mutants were still able to nodulate legumes and fix atmospheric nitrogen. This report emphasizes that a structurally intact VLCFA-containing lipid A is critical to cellular traits that are important for survival in the rhizosphere.
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Effects of oriC relocation on control of replication initiation in Bacillus subtilis
In bacteria, DNA replication initiation is tightly regulated in order to coordinate chromosome replication with cell growth. In Escherichia coli, positive factors and negative regulatory mechanisms playing important roles in the strict control of DNA replication initiation have been reported. However, it remains unclear how bacterial cells recognize the right time for replication initiation during the cell cycle. In the Gram-positive bacterium Bacillus subtilis, much less is known about the regulation of replication initiation, specifically, regarding negative control mechanisms which ensure replication initiation only once per cell cycle. Here we report that replication initiation was greatly enhanced in strains that had the origin of replication (oriC) relocated to various loci on the chromosome. When oriC was relocated to new loci further than 250 kb counterclockwise from the native locus, replication initiation became asynchronous and earlier than in the wild-type cells. In two oriC-relocated strains (oriC at argG or pnbA, 25 ° or 30 ° on the 36 ° chromosome map, respectively), DnaA levels were higher than in the wild-type but not enough to cause earlier initiation of replication. Our results suggest that the initiation capacity of replication is accumulated well before the actual time of initiation, and its release may be suppressed by a unique DNA structure formed near the native oriC locus.
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Low pH regulates the production of deoxynivalenol by Fusarium graminearum
More LessFusarium graminearum, which causes the globally important head blight disease of wheat, is responsible for the production of the harmful mycotoxin deoxynivalenol (DON) in infected grain. The production of DON by F. graminearum occurs at much higher levels during infection than during axenic growth, and it is therefore important to understand how DON production is regulated in the fungus. Recently, we have identified amines as potent inducers of in vitro DON production in F. graminearum. Although amines strongly induced expression of the key DON biosynthesis gene TRI5 and DON production to levels equivalent to those observed during infection, the timing of this induction suggested that other factors are also likely to be important for the regulation of DON biosynthesis. Here we demonstrate that low extracellular pH both promotes and is required for DON production in F. graminearum. A combination of low pH and amines results in significantly enhanced expression of the TRI5 gene and increased DON production during axenic growth. A better understanding of DON production in F. graminearum would have implications in developing future toxin management strategies.
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- Environmental And Evolutionary Microbiology
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Rhizobium etli HrpW is a pectin-degrading enzyme and differs from phytopathogenic homologues in enzymically crucial tryptophan and glycine residues
While establishing a nitrogen-fixing symbiosis with leguminous plants, rhizobia are faced with the problem of penetrating the plant cell wall at several stages of the infection process. One of the major components of this barrier is pectin, a heteropolysaccharide composed mainly of galacturonic acid subunits. So far, no enzymes capable of degrading pectin have been isolated from rhizobia. Here, we make an inventory of rhizobial candidate pectinolytic enzymes based on available genome sequence data and present an initial biochemical and functional characterization of a protein selected from this list. Rhizobium etli hrpW is associated with genes encoding a type III secretion system, a macromolecular structure that allows bacteria to directly inject so-called effector proteins into a eukaryotic host's cell cytosol and an essential virulence determinant of many Gram-negative pathogenic bacteria. In contrast to harpin HrpW from phytopathogens, R. etli HrpW possesses pectate lyase activity and is most active on highly methylated substrates. Through comparative sequence analysis, three amino acid residues crucial for the observed enzymic activity were identified: Trp192, Gly212 and Gly213. Their importance was confirmed by site-directed mutagenesis and biochemical characterization of the resulting proteins, with the tryptophan mutant showing no detectable pectate lyase activity and the double-glycine mutant's activity reduced by about 80 %. Surprisingly, despite hrpW expression being induced specifically on the plant root surface, a knockout mutation of the gene does not appear to affect symbiosis with the common bean Phaseolus vulgaris.
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Biodegradation of phenanthrene by Pseudomonas sp. strain PPD: purification and characterization of 1-hydroxy-2-naphthoic acid dioxygenase
More LessPseudomonas sp. strain PPD can metabolize phenanthrene as the sole source of carbon and energy via the ‘phthalic acid’ route. The key enzyme, 1-hydroxy-2-naphthoic acid dioxygenase (1-HNDO, EC 1.13.11.38), was purified to homogeneity using a 3-hydroxy-2-naphthoic acid (3-H2NA)-affinity matrix. The enzyme was a homotetramer with a native molecular mass of 160 kDa and subunit molecular mass of ∼39 kDa. It required Fe(II) as the cofactor and was specific for 1-hydroxy-2-naphthoic acid (1-H2NA), with K m 13.5 μM and V max 114 μmol min−1 mg−1. 1-HNDO failed to show activity with gentisic acid, salicylic acid and other hydroxynaphthoic acids tested. Interestingly, the enzyme showed substrate inhibition with a K i of 116 μM. 1-HNDO was found to be competitively inhibited by 3-H2NA with a K i of 24 μM. Based on the pH-dependent spectral changes, the enzyme reaction product was identified as 2-carboxybenzalpyruvic acid. Under anaerobic conditions, the enzyme failed to convert 1-H2NA to 2-carboxybenzalpyruvic acid. Stoichiometric studies showed the incorporation of 1 mol O2 into the substrate to yield 1 mol product. These results suggest that 1-HNDO from Pseudomonas sp. strain PPD is an extradiol-type ring-cleaving dioxygenase.
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Mode of vegetative reproduction of the bipolar budding yeast species Wickerhamomyces pijperi and related strains
More LessTo clarify the budding pattern of Wickerhamomyces pijperi, the vegetative cells were observed by scanning electron microscopy. The cells grew by bipolar budding, but cells that budded from the shoulder of a mother cell were occasionally observed. We examined the cell morphology and phylogeny of five strains of Wickerhamomyces sp. isolated in Thailand as well as seven W. pijperi and three Wickerhamomyces sp. strains that were preserved in culture collections. Phylogenetic analysis based on three different nucleotide sequences (D1/D2 domain of 26S rDNA, the actin gene ACT1 and the elongation factor 2 gene EF2) indicated that all the strains belonged to the genus Wickerhamomyces and were neighbours of the type strain W. pijperi NBRC 1290T. The strains fell into two groups in this analysis. The budding patterns of the strains were carefully observed by staining the bud scars, and these patterns were categorized into three groups: types I–III. Type I included cells that grew by bipolar budding and formed multiple scars, type III included cells that grew by multilateral budding and formed a single scar, and type II included cells that exhibited a mixture of type I and type III patterns. Among the 15 strains, 12 strains, including W. pijperi NBRC 1290T, mainly exhibited type I or type II budding patterns; these strains belonged to group 1 of the phylogenetic analysis. The remaining three strains, which belonged to group 2, exhibited either type II or type III patterns. Thus the phylogenetic relationship and budding patterns are related. Moreover, some cells also exhibited budding characteristics that were intermediate between bipolar and multilateral budding.
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- Genes And Genomes
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Subinhibitory concentrations of the cationic antimicrobial peptide colistin induce the pseudomonas quinolone signal in Pseudomonas aeruginosa
More LessColistin is an important cationic antimicrobial peptide (CAMP) in the fight against Pseudomonas aeruginosa infection in cystic fibrosis (CF) lungs. The effects of subinhibitory concentrations of colistin on gene expression in P. aeruginosa were investigated by transcriptome and functional genomic approaches. Analysis revealed altered expression of 30 genes representing a variety of pathways associated with virulence and bacterial colonization in chronic infection. These included response to osmotic stress, motility, and biofilm formation, as well as genes associated with LPS modification and quorum sensing (QS). Most striking was the upregulation of Pseudomonas quinolone signal (PQS) biosynthesis genes, including pqsH, pqsB and pqsE, and the phenazine biosynthesis operon. Induction of this central component of the QS network following exposure to subinhibitory concentrations of colistin may represent a switch to a more robust population, with increased fitness in the competitive environment of the CF lung.
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Mycobacteriophages BPs, Angel and Halo: comparative genomics reveals a novel class of ultra-small mobile genetic elements
Mycobacteriophages BPs, Angel and Halo are closely related viruses isolated from Mycobacterium smegmatis, and possess the smallest known mycobacteriophage genomes, 41 901 bp, 42 289 bp and 41 441 bp, respectively. Comparative genome analysis reveals a novel class of ultra-small mobile genetic elements; BPs and Halo each contain an insertion of the proposed mobile elements MPME1 and MPME2, respectively, at different locations, while Angel contains neither. The close similarity of the genomes provides a comparison of the pre- and post-integration sequences, revealing an unusual 6 bp insertion at one end of the element and no target duplication. Nine additional copies of these mobile elements are identified in a variety of different contexts in other mycobacteriophage genomes. In addition, BPs, Angel and Halo have an unusual lysogeny module in which the repressor and integrase genes are closely linked. The attP site is located within the repressor-coding region, such that prophage formation results in expression of a C-terminally truncated, but active, form of the repressor.
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Transcriptional analysis of the response of Neurospora crassa to phytosphingosine reveals links to mitochondrial function
More LessTreatment of Neurospora crassa cells with phytosphingosine (PHS) induces programmed cell death (PCD) by an unknown mechanism. To determine the relationship between PHS treatment and PCD, we determined changes in global gene expression levels in N. crassa during a time-course of PHS treatment. Most genes having differential expression levels compared to untreated samples showed an increase in relative expression level upon PHS exposure. However, genes encoding mitochondrial proteins were highly enriched among ∼100 genes that showed a relative decrease in expression levels after PHS treatment, suggesting that repression of these genes might be related to the death-inducing effects of PHS. Since mutants in respiratory chain complex I are more resistant to both PHS and hydrogen peroxide (H2O2) than the wild-type strain, possibly related to the production of reactive oxygen species, we also compared gene expression profiles of a complex I mutant (nuo14) and wild-type in response to H2O2. Genes with higher expression levels in the mutant, in the presence of H2O2, are also significantly enriched in genes encoding mitochondrial proteins. These data suggest that complex I mutants cope better with drug-induced decrease in expression of genes encoding mitochondrial proteins and may explain their increased resistance to both PHS and H2O2. As a way of identifying new components required for PHS-induced death, we analysed the PHS sensitivity of 24 strains carrying deletions in genes that showed a significant alteration in expression pattern when the wild-type was exposed to the sphingolipid. Two additional mutants showing increased resistance to PHS were identified and both encode predicted mitochondrial proteins, further supporting the role of the mitochondria in PHS-induced PCD.
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- Microbial Pathogenicity
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Burkholderia cenocepacia zinc metalloproteases influence resistance to antimicrobial peptides
More LessBurkholderia cenocepacia secretes two zinc-dependent metalloproteases, designated ZmpA and ZmpB. Previously, ZmpA and ZmpB have been shown to cleave several proteins important in host defence. In this study, the ability of ZmpA and ZmpB to digest and inactivate antimicrobial peptides involved in innate immunity was examined. ZmpB but not ZmpA cleaved β-defensin-1. ZmpA but not ZmpB cleaved the cathelicidin LL-37. Both enzymes cleaved elafin and secretory leukocyte inhibitor, which are antimicrobial peptides as well as neutrophil elastase inhibitors. Both ZmpA and ZmpB cleaved protamine, a fish antimicrobial peptide, and a zmpA zmpB mutant was more sensitive to protamine killing than the parental strain. ZmpA or ZmpB cleavage of elafin inactivated its anti-protease activity. The effect of ZmpA and ZmpB on the neutrophil proteases elastase and cathepsin G was also examined but neither enzyme was active against these host proteases. These studies suggest that ZmpA and ZmpB may influence the resistance of B. cenocepacia to host antimicrobial peptides as well as alter the host protease/anti-protease balance in chronic respiratory infections.
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The modular architecture of meningococcal factor H-binding protein
More LessMeningococcal factor H binding protein (fHbp) is a promising vaccine antigen that binds the human complement downregulatory molecule factor H (fH), and this binding enhances the survival of the organism in serum. Based on sequence variability of the entire protein, fHbp has been divided into three variant groups or two subfamilies. Here, we present evidence based on phylogenetic analysis of 70 unique fHbp amino acid sequences that the molecular architecture is modular. From sequences of natural chimeras we identified blocks of two to five invariant residues that flanked five modular variable segments. Although overall, 46 % of the fHbp amino acids were invariant, based on a crystal structure, the invariant blocks that flanked the modular variable segments clustered on the membrane surface containing the amino-terminal lipid anchor, while the remaining invariant residues were located throughout the protein. Each of the five modular variable segments could be classified into one of two types, designated α or β, based on homology with segments encoded by variant 1 or 3 fHbp genes, respectively. Forty of the fHbps (57 %) comprised only α (n=33) or β (n=7) type segments. The remaining 30 proteins (43 %) were chimeras and could be classified into one of four modular groups. These included all 15 proteins assigned to the previously described variant 2 in subfamily A. The modular segments of one chimeric modular group had 96 % amino acid identity with those of fHbp orthologs in Neisseria gonorrhoeae. Collectively, the data suggest that recombination between Neisseria meningitidis and N. gonorrhoeae progenitors generated a family of modular, antigenically diverse meningococcal fHbps.
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Volume 24 (1961)
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Volume 23 (1960)
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Volume 22 (1960)
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Volume 21 (1959)
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Volume 20 (1959)
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Volume 19 (1958)
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Volume 18 (1958)
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Volume 17 (1957)
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Volume 16 (1957)
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Volume 15 (1956)
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Volume 14 (1956)
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Volume 13 (1955)
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Volume 12 (1955)
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Volume 11 (1954)
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Volume 10 (1954)
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Volume 9 (1953)
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Volume 8 (1953)
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Volume 7 (1952)
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Volume 6 (1952)
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Volume 5 (1951)
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Volume 4 (1950)
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Volume 3 (1949)
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Volume 2 (1948)
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Volume 1 (1947)
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