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Heme sensing and detoxification by HatRT contributes to pathogenesis during Clostridium difficile infection.
Knippel RJ, Zackular JP, Moore JL, Celis AI, Weiss A, Washington MK, DuBois JL, Caprioli RM, Skaar EP
(2018) PLoS Pathog 14: e1007486
MeSH Terms: Animals, Bacterial Proteins, Clostridium Infections, Clostridium difficile, Genes, Bacterial, Heme, Male, Mice, Mice, Inbred C57BL, Operon, Virulence
Show Abstract · Added April 7, 2019
Clostridium difficile is a Gram-positive, spore-forming anaerobic bacterium that infects the colon, causing symptoms ranging from infectious diarrhea to fulminant colitis. In the last decade, the number of C. difficile infections has dramatically risen, making it the leading cause of reported hospital acquired infection in the United States. Bacterial toxins produced during C. difficile infection (CDI) damage host epithelial cells, releasing erythrocytes and heme into the gastrointestinal lumen. The reactive nature of heme can lead to toxicity through membrane disruption, membrane protein and lipid oxidation, and DNA damage. Here we demonstrate that C. difficile detoxifies excess heme to achieve full virulence within the gastrointestinal lumen during infection, and that this detoxification occurs through the heme-responsive expression of the heme activated transporter system (HatRT). Heme-dependent transcriptional activation of hatRT was discovered through an RNA-sequencing analysis of C. difficile grown in the presence of a sub-toxic concentration of heme. HatRT is comprised of a TetR family transcriptional regulator (hatR) and a major facilitator superfamily transporter (hatT). Strains inactivated for hatR or hatT are more sensitive to heme toxicity than wild-type. HatR binds heme, which relieves the repression of the hatRT operon, whereas HatT functions as a heme efflux pump. In a murine model of CDI, a strain inactivated for hatT displayed lower pathogenicity in a toxin-independent manner. Taken together, these data suggest that HatR senses intracellular heme concentrations leading to increased expression of the hatRT operon and subsequent heme efflux by HatT during infection. These results describe a mechanism employed by C. difficile to relieve heme toxicity within the host, and set the stage for the development of therapeutic interventions to target this bacterial-specific system.
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MeSH Terms
The Structure of the Bifunctional Everninomicin Biosynthetic Enzyme EvdMO1 Suggests Independent Activity of the Fused Methyltransferase-Oxidase Domains.
Starbird CA, Perry NA, Chen Q, Berndt S, Yamakawa I, Loukachevitch LV, Limbrick EM, Bachmann BO, Iverson TM, McCulloch KM
(2018) Biochemistry 57: 6827-6837
MeSH Terms: Amino Acid Sequence, Aminoglycosides, Bacterial Proteins, Biosynthetic Pathways, Catalytic Domain, Conserved Sequence, Crystallography, X-Ray, Gene Fusion, Genes, Bacterial, Methyltransferases, Micromonospora, Models, Molecular, Oxygenases, Protein Interaction Domains and Motifs, Sequence Homology, Amino Acid
Show Abstract · Added April 1, 2019
Members of the orthosomycin family of natural products are decorated polysaccharides with potent antibiotic activity and complex biosynthetic pathways. The defining feature of the orthosomycins is an orthoester linkage between carbohydrate moieties that is necessary for antibiotic activity and is likely formed by a family of conserved oxygenases. Everninomicins are octasaccharide orthosomycins produced by Micromonospora carbonacea that have two orthoester linkages and a methylenedioxy bridge, three features whose formation logically requires oxidative chemistry. Correspondingly, the evd gene cluster encoding everninomicin D encodes two monofunctional nonheme iron, α-ketoglutarate-dependent oxygenases and one bifunctional enzyme with an N-terminal methyltransferase domain and a C-terminal oxygenase domain. To investigate whether the activities of these domains are linked in the bifunctional enzyme EvdMO1, we determined the structure of the N-terminal methyltransferase domain to 1.1 Å and that of the full-length protein to 3.35 Å resolution. Both domains of EvdMO1 adopt the canonical folds of their respective superfamilies and are connected by a short linker. Each domain's active site is oriented such that it faces away from the other domain, and there is no evidence of a channel connecting the two. Our results support EvdMO1 working as a bifunctional enzyme with independent catalytic activities.
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15 MeSH Terms
Genetic signatures for Helicobacter pylori strains of West African origin.
Bullock KK, Shaffer CL, Brooks AW, Secka O, Forsyth MH, McClain MS, Cover TL
(2017) PLoS One 12: e0188804
MeSH Terms: Africa, Western, Amino Acid Sequence, Bacterial Proteins, Genes, Bacterial, Helicobacter pylori, Sequence Homology, Amino Acid
Show Abstract · Added March 21, 2018
Helicobacter pylori is a genetically diverse bacterial species that colonizes the stomach in about half of the human population. Most persons colonized by H. pylori remain asymptomatic, but the presence of this organism is a risk factor for gastric cancer. Multiple populations and subpopulations of H. pylori with distinct geographic distributions are recognized. Genetic differences among these populations might be a factor underlying geographic variation in gastric cancer incidence. Relatively little is known about the genomic features of African H. pylori strains compared to other populations of strains. In this study, we first analyzed the genomes of H. pylori strains from seven globally distributed populations or subpopulations and identified encoded proteins that exhibited the highest levels of sequence divergence. These included secreted proteins, an LPS glycosyltransferase, fucosyltransferases, proteins involved in molybdopterin biosynthesis, and Clp protease adaptor (ClpS). Among proteins encoded by the cag pathogenicity island, CagA and CagQ exhibited the highest levels of sequence diversity. We then identified proteins in strains of Western African origin (classified as hspWAfrica by MLST analysis) with sequences that were highly divergent compared to those in other populations of strains. These included ATP-dependent Clp protease, ClpS, and proteins of unknown function. Three of the divergent proteins sequences identified in West African strains were characterized by distinct insertions or deletions up to 8 amino acids in length. These polymorphisms in rapidly evolving proteins represent robust genetic signatures for H. pylori strains of West African origin.
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6 MeSH Terms
The Response of Acinetobacter baumannii to Zinc Starvation.
Nairn BL, Lonergan ZR, Wang J, Braymer JJ, Zhang Y, Calcutt MW, Lisher JP, Gilston BA, Chazin WJ, de Crécy-Lagard V, Giedroc DP, Skaar EP
(2016) Cell Host Microbe 19: 826-36
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Bacterial Proteins, Chlorides, GTP Phosphohydrolases, Gene Expression Regulation, Bacterial, Genes, Bacterial, Histidine, Histidine Ammonia-Lyase, Metallochaperones, Mice, Mice, Inbred C57BL, Mutation, Zinc, Zinc Compounds
Show Abstract · Added April 8, 2017
Zinc (Zn) is an essential metal that vertebrates sequester from pathogens to protect against infection. Investigating the opportunistic pathogen Acinetobacter baumannii's response to Zn starvation, we identified a putative Zn metallochaperone, ZigA, which binds Zn and is required for bacterial growth under Zn-limiting conditions and for disseminated infection in mice. ZigA is encoded adjacent to the histidine (His) utilization (Hut) system. The His ammonia-lyase HutH binds Zn very tightly only in the presence of high His and makes Zn bioavailable through His catabolism. The released Zn enables A. baumannii to combat host-imposed Zn starvation. These results demonstrate that A. baumannii employs several mechanisms to ensure bioavailability of Zn during infection, with ZigA functioning predominately during Zn starvation, but HutH operating in both Zn-deplete and -replete conditions to mobilize a labile His-Zn pool.
Copyright © 2016 Elsevier Inc. All rights reserved.
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16 MeSH Terms
The capability of Pseudomonas aeruginosa to recruit zinc under conditions of limited metal availability is affected by inactivation of the ZnuABC transporter.
D'Orazio M, Mastropasqua MC, Cerasi M, Pacello F, Consalvo A, Chirullo B, Mortensen B, Skaar EP, Ciavardelli D, Pasquali P, Battistoni A
(2015) Metallomics 7: 1023-35
MeSH Terms: Alginates, Animals, Bacterial Proteins, Female, Genes, Bacterial, Glucuronic Acid, Hexuronic Acids, Membrane Transport Proteins, Mice, Inbred C57BL, Mutation, Peptide Hydrolases, Pseudomonas Infections, Pseudomonas aeruginosa, Zinc
Show Abstract · Added February 8, 2016
The ability of a large number of bacterial pathogens to multiply in the infected host and cause disease is dependent on their ability to express high affinity zinc importers. In many bacteria, ZnuABC, a transporter of the ABC family, plays a central role in the process of zinc uptake in zinc poor environments, including the tissues of the infected host. To initiate an investigation into the relevance of the zinc uptake apparatus for Pseudomonas aeruginosa pathogenicity, we have generated a znuA mutant in the PA14 strain. We have found that this mutant strain displays a limited growth defect in zinc depleted media. The znuA mutant strain is more sensitive than the wild type strain to calprotectin-mediated growth inhibition, but both the strains are highly resistant to this zinc sequestering antimicrobial protein. Moreover, intracellular zinc content is not evidently affected by inactivation of the ZnuABC transporter. These findings suggest that P. aeruginosa is equipped with redundant mechanisms for the acquisition of zinc that might favor P. aeruginosa colonization of environments containing low levels of this metal. Nonetheless, deletion of znuA affects alginate production, reduces the activity of extracellular zinc-containing proteases, including LasA, LasB and protease IV, and decreases the ability of P. aeruginosa to disseminate during systemic infections. These results indicate that efficient zinc acquisition is critical for the expression of various virulence features typical of P. aeruginosa and that ZnuABC also plays an important role in zinc homeostasis in this microorganism.
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14 MeSH Terms
Low prevalence of Clostridium septicum fecal carriage in an adult population.
Kopliku FA, Schubert AM, Mogle J, Schloss PD, Young VB, Aronoff DM
(2015) Anaerobe 32: 34-36
MeSH Terms: Adult, Carrier State, Clostridium Infections, Clostridium septicum, DNA, Bacterial, Feces, Gas Gangrene, Genes, Bacterial, Humans, Polymerase Chain Reaction, Prevalence
Show Abstract · Added June 2, 2017
Clostridium septicum is an uncommon cause of severe infection. Real-time PCR against the C. septicum-specific alpha-toxin gene (csa) was used to estimate the prevalence of this microbe in human stool from 161 asymptomatic community-dwelling adults and 192 hospitalized patients with diarrhea. All samples were negative, suggesting a low prevalence.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Antibacterial gene transfer across the tree of life.
Metcalf JA, Funkhouser-Jones LJ, Brileya K, Reysenbach AL, Bordenstein SR
(2014) Elife 3:
MeSH Terms: Amino Acid Sequence, Anti-Bacterial Agents, Archaea, Bacteria, Coculture Techniques, Escherichia coli, Gene Transfer, Horizontal, Genes, Bacterial, Microbial Viability, Models, Molecular, Molecular Sequence Data, Muramidase, Phylogeny, RNA, Ribosomal
Show Abstract · Added October 8, 2015
Though horizontal gene transfer (HGT) is widespread, genes and taxa experience biased rates of transferability. Curiously, independent transmission of homologous DNA to archaea, bacteria, eukaryotes, and viruses is extremely rare and often defies ecological and functional explanations. Here, we demonstrate that a bacterial lysozyme family integrated independently in all domains of life across diverse environments, generating the only glycosyl hydrolase 25 muramidases in plants and archaea. During coculture of a hydrothermal vent archaeon with a bacterial competitor, muramidase transcription is upregulated. Moreover, recombinant lysozyme exhibits broad-spectrum antibacterial action in a dose-dependent manner. Similar to bacterial transfer of antibiotic resistance genes, transfer of a potent antibacterial gene across the universal tree seemingly bestows a niche-transcending adaptation that trumps the barriers against parallel HGT to all domains. The discoveries also comprise the first characterization of an antibacterial gene in archaea and support the pursuit of antibiotics in this underexplored group.
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14 MeSH Terms
Genes required for assembly of pili associated with the Helicobacter pylori cag type IV secretion system.
Johnson EM, Gaddy JA, Voss BJ, Hennig EE, Cover TL
(2014) Infect Immun 82: 3457-70
MeSH Terms: Bacterial Proteins, Bacterial Secretion Systems, Cell Line, Epithelial Cells, Fimbriae, Bacterial, Gene Knockout Techniques, Genes, Bacterial, Genetic Complementation Test, Genomic Islands, Helicobacter pylori, Humans, Multiprotein Complexes, Protein Multimerization
Show Abstract · Added July 2, 2014
Helicobacter pylori causes numerous alterations in gastric epithelial cells through processes that are dependent on activity of the cag type IV secretion system (T4SS). Filamentous structures termed "pili" have been visualized at the interface between H. pylori and gastric epithelial cells, and previous studies suggested that pilus formation is dependent on the presence of the cag pathogenicity island (PAI). Thus far, there has been relatively little effort to identify specific genes that are required for pilus formation, and the role of pili in T4SS function is unclear. In this study, we selected 7 genes in the cag PAI that are known to be required for T4SS function and investigated whether these genes were required for pilus formation. cagT, cagX, cagV, cagM, and cag3 mutants were defective in both T4SS function and pilus formation; complemented mutants regained T4SS function and the capacity for pilus formation. cagY and cagC mutants were defective in T4SS function but retained the capacity for pilus formation. These results define a set of cag PAI genes that are required for both pilus biogenesis and T4SS function and reveal that these processes can be uncoupled in specific mutant strains.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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13 MeSH Terms
Expression of Streptococcus pneumoniae Virulence-Related Genes in the Nasopharynx of Healthy Children.
Sakai F, Talekar SJ, Lanata CF, Grijalva CG, Klugman KP, Vidal JE, RESPIRA PERU Group, Investigators Group
(2013) PLoS One 8: e67147
MeSH Terms: Child, Genes, Bacterial, Humans, Nasopharynx, Polymerase Chain Reaction, Streptococcus pneumoniae, Virulence
Show Abstract · Added July 27, 2018
Colonization and persistence in the human nasopharynx are prerequisites for Streptococcus pneumoniae disease and carriage acquisition, which normally occurs during early childhood. Animal models and in vitro studies (i.e. cell adhesion and cell cytotoxicity assays) have revealed a number of colonization and virulence factors, as well as regulators, implicated in nasopharyngeal colonization and pathogenesis. Expression of genes encoding these factors has never been studied in the human nasopharynx. Therefore, this study analyzed expression of S. pneumoniae virulence-related genes in human nasopharyngeal samples. Our experiments first demonstrate that a density of ≥10(4) CFU/ml of S. pneumoniae cells in the nasopharynx provides enough DNA and RNA to amplify the lytA gene by conventional PCR and to detect the lytA message, respectively. A panel of 21 primers that amplified S. pneumoniae sequences was designed, and their specificity for S. pneumoniae sequences was analyzed in silico and validated against 20 related strains inhabitants of the human upper respiratory tract. These primers were utilized in molecular reactions to find out that all samples contained the genes ply, pavA, lytC, lytA, comD, codY, and mgrA, whereas nanA, nanB, pspA, and rrgB were present in ∼91-98% of the samples. Gene expression studies of these 11 targets revealed that lytC, lytA, pavA and comD were the most highly expressed pneumococcal genes in the nasopharynx whereas the rest showed a moderate to low level of expression. This is the first study to evaluate expression of virulence- and, colonization-related genes in the nasopharynx of healthy children and establishes the foundation for future gene expression studies during human pneumococcal disease.
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Phylogeographic origin of Helicobacter pylori determines host-adaptive responses upon coculture with gastric epithelial cells.
Sheh A, Chaturvedi R, Merrell DS, Correa P, Wilson KT, Fox JG
(2013) Infect Immun 81: 2468-77
MeSH Terms: Adaptation, Physiological, Antigens, Bacterial, Apoptosis, Bacterial Proteins, Cell Line, Tumor, Cluster Analysis, Coculture Techniques, Epithelial Cells, Gastric Mucosa, Gene Expression Regulation, Bacterial, Genes, Bacterial, Helicobacter Infections, Helicobacter pylori, Host-Pathogen Interactions, Humans, Interleukin-8, Middle Aged, Movement, Phylogeography, Transcriptome
Show Abstract · Added September 3, 2013
While Helicobacter pylori infects over 50% of the world's population, the mechanisms involved in the development of gastric disease are not fully understood. Bacterial, host, and environmental factors play a role in disease outcome. To investigate the role of bacterial factors in H. pylori pathogenesis, global gene expression of six H. pylori isolates was analyzed during coculture with gastric epithelial cells. Clustering analysis of six Colombian clinical isolates from a region with low gastric cancer risk and a region with high gastric cancer risk segregated strains based on their phylogeographic origin. One hundred forty-six genes had increased expression in European strains, while 350 genes had increased expression in African strains. Differential expression was observed in genes associated with motility, pathogenicity, and other adaptations to the host environment. European strains had greater expression of the virulence factors cagA, vacA, and babB and were associated with increased gastric histologic lesions in patients. In AGS cells, European strains promoted significantly higher interleukin-8 (IL-8) expression than did African strains. African strains significantly induced apoptosis, whereas only one European strain significantly induced apoptosis. Our data suggest that gene expression profiles of clinical isolates can discriminate strains by phylogeographic origin and that these profiles are associated with changes in expression of the proinflammatory and protumorigenic cytokine IL-8 and levels of apoptosis in host epithelial cells. These findings support the hypothesis that bacterial factors determined by the phylogeographic origin of H. pylori strains may promote increased gastric disease.
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20 MeSH Terms