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PubMed1997

Molecular cloning, nucleotide sequence, and function of a site-specific recombinase encoded in the major 'pathogenicity island' of Salmonella typhi.

The genome of the typhoid fever bacterium, Salmonella typhi, contains at least three large insertions ('pathogenicity islands') relative to the chromosome of Salmonella typhimurium (which is normally non-invasive for humans) [Liu, S.-L., Sanderson, K.E., 1995. Rearrangements in the genome of the bacterium Salmonella typhi. Proc. Natl. Acad. Sci. USA 92, 1018-1022]. DNA encoding a site-specific recombinase (the rci gene) and an adjacent putative pilus-tip adhesin protein (the pilV gene) was located (near min 94) in the major 'pathogenicity island' of the S. typhi chromosome, cloned, and sequenced. It was shown that the Rci protein inverted a DNA segment of 490 bp, between two 19-bp inverted repeat elements, to place either of two possible C-termini on a constant N-terminal region of the PilV protein. Both possible PilV proteins were seen when the alternative pilV genes were transcribed from the T7 promoter and translated in vivo. Both the rci and the N-terminal region of the pilV gene show a high degree of homology to genes encoded by the IncI2 plasmid R721 and the IncI1 plasmid R64. One of the possible pilV C-termini (in the pilV1 gene) is highly homologous to shufflon C (one of the possible PilV C-termini) of R64; the other possible pilV C-terminus (in the pilV2 gene) shows no homology to any published shufflon. In the R64 plasmid, the PilV proteins are pilus-tip adhesins; different PilV proteins recognize different potential recipient bacterial strains as a prelude to mating in liquid culture [Komano, T., Kim, S.-R., Yoshida, T., Nisioka, T., 1994. DNA rearrangement of the shufflon determines recipient specificity in liquid mating of IncI1 plasmid R64. J. Mol. Biol. 243, 6-9]. It is likely that S. typhi encodes pili bearing two alternative PilV proteins as tip adhesins, one of which recognizes, specifically, a membrane component of Escherichia coli K-12, while the specificity of the other PilV protein is not known.

Amino Acid Sequence↗
PubMed2006

Dendritic cells in pathogen recognition and induction of immune responses: a functional genomics approach.

At the 38th Annual Meeting of the Society for Leukocyte Biology held in Oxford this year, the biology of dendritic cells (DCs) and macrophages was discussed. In particular, functional genomics approaches were presented to investigate transcriptional changes during microbe and phagocytes interactions. Here, we report functional genomics studies likely to be of interest to the Journal of Leukocyte Biology readers with a particular emphasis on DC biology. DCs are professional antigen-presenting cells, which are essential for the initiation and regulation of natural killer, T, and T regulatory cell responses. Immature DCs, resident in peripheral sites, are specialized in antigen capture and continually sample soluble and particulate antigens in their local environment. DCs express receptors for cytokines, chemokines, endogenous danger signals, and microbial structures. The interactions between DCs and microorganism are complex, but progress in the past few years has shed light on several aspects of these processes. Infectious disease is the result of an intimate relationship between pathogens and hosts. Thus, understanding the cross-talk between host and pathogen is essential to improve our knowledge of infectious disease. Functional genomics and proteomics applied to DCs and macrophage biology are now providing powerful tools to dissect, at the molecular level, host-pathogen interactions.

Animals↗
PubMed2001

Mitochondrial myopathies.

The first description of a patient with mitochondrial myopathy and deficient respiratory chain function was reported by Luft and coworkers almost 40 years ago. Subsequent studies in the 1970s and 1980s relied on a combination of morphological and biochemical methods to identify patients with mitochondrial disorders. However, the aetiology and pathogenesis remained largely unsolved and there was poor correlation between laboratory findings and clinical phenotypes. The fact that both mitochondrial DNA (mtDNA) and nuclear genes are necessary for the biogenesis of the respiratory chain, suggested that mutations of either genome might cause mitochondrial myopathy. This prediction has been verified during the last decade and pathogenic mutations of both genomes have been identified. This rapid accumulation of genetic information has lead to many good correlations between genotype and phenotype in mitochondrial disorders. The challenge for the future will be to elucidate molecular details of pathogenic processes and to develop effective treatments for patients with respiratory chain dysfunction.

DNA, Mitochondrial↗
PubMed2002

Complete genome sequence and comparative analysis of the metabolically versatile Pseudomonas putida KT2440.

Pseudomonas putida is a metabolically versatile saprophytic soil bacterium that has been certified as a biosafety host for the cloning of foreign genes. The bacterium also has considerable potential for biotechnological applications. Sequence analysis of the 6.18 Mb genome of strain KT2440 reveals diverse transport and metabolic systems. Although there is a high level of genome conservation with the pathogenic Pseudomonad Pseudomonas aeruginosa (85% of the predicted coding regions are shared), key virulence factors including exotoxin A and type III secretion systems are absent. Analysis of the genome gives insight into the non-pathogenic nature of P. putida and points to potential new applications in agriculture, biocatalysis, bioremediation and bioplastic production.

Bacterial Proteins↗
PubMed2005

The genome of Salmonella enterica serovar gallinarum: distinct insertions/deletions and rare rearrangements.

Salmonella enterica serovar Gallinarum is a fowl-adapted pathogen, causing typhoid fever in chickens. It has the same antigenic formula (1,9,12:--:--) as S. enterica serovar Pullorum, which is also adapted to fowl but causes pullorum disease (diarrhea). The close relatedness but distinct pathogeneses make this pair of fowl pathogens good models for studies of bacterial genomic evolution and the way these organisms acquired pathogenicity. To locate and characterize the genomic differences between serovar Gallinarum and other salmonellae, we constructed a physical map of serovar Gallinarum strain SARB21 by using I-CeuI, XbaI, and AvrII with pulsed-field gel electrophoresis techniques. In the 4,740-kb genome, we located two insertions and six deletions relative to the genome of S. enterica serovar Typhimurium LT2, which we used as a reference Salmonella genome. Four of the genomic regions with reduced lengths corresponded to the four prophages in the genome of serovar Typhimurium LT2, and the others contained several smaller deletions relative to serovar Typhimurium LT2, including regions containing srfJ, std, and stj and gene clusters encoding a type I restriction system in serovar Typhimurium LT2. The map also revealed some rare rearrangements, including two inversions and several translocations. Further characterization of these insertions, deletions, and rearrangements will provide new insights into the molecular basis for the specific host-pathogen interactions and mechanisms of genomic evolution to create a new pathogen.

Bacterial Proteins↗
PubMed2006

A new member of the aldo-keto reductase family from the plant pathogen Xylella fastidiosa.

The Xylella fastidiosa genome program generated a large number of gene sequences that belong to pathogenicity, virulence and adaptation categories from this important plant pathogen. One of these genes (XF1729) encodes a protein similar to a superfamily of aldo-keto reductase together with a number of structurally and functionally related NADPH-dependent oxidoreductases. In this work, the similar sequence XF1729 from X. fastidiosa was cloned onto the pET32Xa/LIC vector in order to overexpress a recombinant His-tag fusion protein in Escherichia coli BL21(DE3). The expressed protein in the soluble fraction was purified by immobilized metal affinity chromatography (agarose-IDA-Ni resin). Secondary structure contents were verified by circular dichroism spectroscopy. Small angle X-ray scattering (SAXS) measurements furnish general structural parameters and provide a strong indication that the protein has a monomeric form in solution. Also, ab initio calculations show that the protein has some similarities with a previously crystallized aldo-keto reductase protein. The recombinant XF1729 purified to homogeneity catalyzed the reduction of dl-glyceraldehyde (K(cat) 2.26s(-1), Km 8.20+/-0.98 mM) and 2-nitrobenzaldehyde (K(cat) 11.74 s(-1), Km 0.14+/-0.04 mM) in the presence of NADPH. The amino acid sequence deduced from XF1729 showed the highest identity (40% or higher) with several functional unknown proteins. Among the identified AKRs, we found approximately 29% of identity with YakC (AKR13), 30 and 28% with AKR11A and AKR11B, respectively. The results establish XF1729 as the new member of AKR family, AKR13B1. Finally, the first characterization by gel filtration chromatography assays indicates that the protein has an elongated shape, which generates an apparent higher molecular weight. The study of this protein is an effort to fight X. fastidiosa, which causes tremendous losses in many economically important plants.

Alcohol Oxidoreductases↗
PubMed2025

GRUMB: a genome-resolved metagenomic framework for monitoring urban microbiomes and diagnosing pathogen risk.

SUMMARY: Urban infrastructure hosts dynamic microbial communities that complicate biosurveillance and AMR monitoring. Existing tools rarely combine genome-resolved reconstruction with ecological modeling and batch-aware analytics tailored to infrastructure-scale studies. We present GRUMB (Genome-Resolved Urban Microbiome Biosurveillance), an open-source, SLURM-compatible pipeline that reconstructs high-quality metagenome-assembled genomes (MAGs) from shotgun sequencing reads and integrates taxonomic/functional annotation (CARD, VFDB), batch-aware normalization, ecological diagnostics and machine learning classification of environment types with uncertainty and risk scoring. GRUMB accepts either SRA project accessions or paired-end FASTQ files with metadata, and produces assemblies, MAGs, taxonomic and functional profiles, ecological outputs and risk-informed classification. Its modular design enables reproducible, infrastructure-scale biosurveillance across diverse environments. AVAILABILITY AND IMPLEMENTATION: GRUMB is freely available under the MIT License at: https://github.com/SuleimanAminu/genome-resolved-urban-microbiome-biosurveillance; Zenodo DOI: https://doi.org/10.5281/zenodo.15505402. Requirements: Linux (Ubuntu 20.04+), Python 3.11, R 4.2+, SLURM. Issues and feature requests are tracked on GitHub.

Microbiota↗
PubMed2006

ShiBASE: an integrated database for comparative genomics of Shigella.

Among the major enteric bacterial pathogens, Shigella is found to display extreme genome diversity and dynamics, which imposes a challenge in comparative genomic studies. To facilitate further studies in this area, we have constructed an integrated online database, ShiBASE (http://www.mgc.ac.cn/ShiBASE/),which contains Shigella genomic sequences of four species and additional comparative genomic hybridization (CGH) data of 43 serotypes. ShiBASE offers online comparative analysis on DNA sequences, gene orders, metabolic pathways and virulence factors. In addition, ShiBASE has a newly developed online comparative visualization service, Shi-align, which enables the alignment of any query sequence with the reference genome sequences.

Databases, Nucleic Acid↗
PubMedDate not supplied

The minimal cellular genome of mycoplasma.

The mycoplasmas are the smallest and simplest self-replicating organisms, being built of a plasma membrane, ribosomes, and a circular double-stranded DNA molecule-the typical prokaryotic genome. The idea of using mycoplasmas as models for defining in molecular terms the entire machinery of a living cell was raised by Morowitz in 1984. The goal has been to prove the dogma of the completeness of molecular biology, that is, that the logic of life is finite, relatively simple and subject to full exploration. The recent complete sequencing of the genome of the human pathogen Mycoplasma genitalium brings us much closer to achieving this goal. The M. genitalium genome is only 580 kb long and contains only 470 predicted coding sequences(genes), as compared with 1727 in Haemophilus influenzae and about 4000 in E. coli. Thus, M. genitalium is apparently the simplest organism capable of independent life with a minimal set of genes. The drastic economization in genetic information must be associated with the parasitic mode of life of the mycoplasmas. Mycoplasmas evolved by reductive evolution from Gram-positive bacteria with low G + C genomes. During evolution the mycoplasmas have lost the cell wall and many biosynthetic systems involved in synthesis of macromolecule building blocks provided by their host. Thus, the M. genitalium genome carries only one gene involved in amino acid biosynthesis, and very few genes for vitamin and nucleic acid precursors; the lack of genes involved in fatty acid biosynthesis, leads to dependence on exogenous fatty acids, enabling the introduction of controlled variations in membrane acyl chains and the use of mycoplasmas as models in studying membrane fluidity. Moreover, the dependence of mycoplasmas on exogenous cholesterol for growth was exploited to show the role of cholesterol as a buffer of membrane fluidity. The mycoplasma genome carries the minimal set of energy metabolism genes, being content with a restricted supply of ATP needed for their parasitic mode of life. Being limited by a single permeability barrier enabled the saving of a considerable number of transport system genes. Nevertheless, these minimal organisms were shown to carry all the essential genes needed for DNA replication, transcription and translation, but even here gene saving is expressed in a minimal number of rRNA and tRNA genes. A genomic price had been paid to maintain parasitism, so that a significant number of mycoplasmal genes is devoted to adhesins, attachment organelles and variable membrane surface antigens directed towards evasion of the host immune system.

Genome, Bacterial↗
PubMed2006

Serine threonine protein kinases of mycobacterial genus: phylogeny to function.

Serine/threonine protein kinases (STPKs) are known to act as sensors of environmental signals that thereby regulate developmental changes and host pathogen interactions. In this study, we carried out comparative genome analysis of six completely sequenced pathogenic and nonpathogenic mycobacterial species to systematically characterize the STPK complement of mycobacterium. Our analysis revealed that while Mycobacterium tuberculosis strains have 11 conserved kinases, this number varies from 4 to 24 in other mycobacterial species. pknA, an essential STPK encoding gene, was found to be truncated in the initial analysis of M. avium subsp. paratuberculosis (Map) and M. tuberculosis C genomes. However, resequencing of pknA gene in Map confirmed that the truncation was due to a sequencing error. The conservation of division and cell wall gene cluster involved in cell envelope biosynthesis and cell division, in the vicinity of pknL locus, implicates a possible role of PknL in cell division and envelop biosynthesis. We identified a cyclophilin domain as part of a mycobacterial kinase in Map that suggests a plausible regulation of cyclophilins by phosphorylation. The co-inheritance of pknA, pknB, pknG, and pknL loci across genomes and some unique repertoire of pathogen-specific kinases such as pknI and pknJ of Mtb complex suggest similitude and divergence between pathogenic and nonpathogenic signaling. This study would add another dimension toward identification of physiological substrates and thereby function, while resolving the existing complexities in signaling network between the two domains of life, pathogen and nonpathogen.

Bacterial Proteins↗
PubMed2005

Genome-wide screens to identify genes of human pathogenic Yersinia species that are expressed during host infection.

An obvious goal in the study of bacteria that cause human disease is to identify the bacterial genes required for growth within the host. Historically, this has presented a significant technological challenge. However, with this goal in mind, the in vivo expression technology (IVET) and signature-tagged mutagenesis (STM) techniques were developed during the 1990s. These techniques have been used to identify virulence genes in the three human pathogenic Yersinia species, Y. enterocolitica, Y. pseudotuberculosis and Y. pestis, using variations of their mouse models of infection. In this review, each of these studies is described individually, including the pertinent details of how each was done, and a brief discussion of the genes identified. In addition, the results of these IVET and STM screens are compared, and the striking lack of overlap between the genes identified is discussed. Most of these studies were only recently published, which means that there have been few follow-up studies on some of the novel virulence genes identified. However, the Y. enterocolitica hreP, rscR and psp genes have become the subject of further studies, which are also summarized here. Finally, I briefly describe the use of the genome-wide (but not in vivo) technology, subtractive hybridization, to identify Yersinia virulence genes.

Animals↗
PubMed2003

Gene content and organization of an 85-kb DNA segment from the genome of the phytopathogenic mollicute Spiroplasma kunkelii.

Spiroplasma kunkelii, the causative agent of corn stunt disease in maize (Zea maysL.), is a helical, cell wall-less prokaryote assigned to the class Mollicutes. As part of a project to sequence the entire S. kunkelii genome, we analyzed an 85-kb DNA segment from the pathogenic strain CR2-3x. This genome segment contains 101 ORFs and two tRNA genes. The majority of the ORFs code for predicted proteins that can be assigned to respective clusters of orthologous groups (COGs). These COGs cover diverse functional categories including genetic information storage and processing, cellular processes, and metabolism. The most notable gene cluster in this genome segment is a super-operon capable of encoding 24 ribosomal proteins. The organization of genes in this operon reflects the unique evolutionary position of the spiroplasma. Gene duplications, domain rearrangements, and frameshift mutations in the segment are interpreted as indicators of phase variation in the spiroplasma. To our knowledge, this is the first analysis of a large genome segment from a plant pathogenic spiroplasma.

Base Sequence↗
PubMed2000

Structural and functional complexity of the genomic region controlling AK-toxin biosynthesis and pathogenicity in the Japanese pear pathotype of Alternaria alternata.

The Japanese pear pathotype of Alternaria alternata produces host-specific AK-toxin and causes black spot of Japanese pear. Previously, a cosmid clone, pcAKT-1, was isolated that contains two genes, AKT1 and AKT2, within a 5.0-kb region required for AK-toxin biosynthesis. The wild-type strain has multiple, nonfunctional copies of these genes. In the present study, two additional genes, AKTR-1 and AKT3-1, downstream of AKT2 were identified. Transformation of the wild type with AKTR-1- and AKT3-1-targeting vectors produced toxin-deficient (Tox-), nonpathogenic mutants. DNA gel blot analysis, however, demonstrated that the fragments targeted in Tox- mutants were different from those containing AKTR-1 and AKT3-1 on the transforming vectors. A cosmid clone, pcAKT-2, containing the targeted DNA was isolated and shown to carry two genes, AKTR-2 and AKT3-2, with high similarity to AKTR-1 and AKT3-1, respectively. Transcripts from not only AKTR-2 and AKT3-2 but also AKTR-1 and AKT3-1 were found in the wild type. DNA gel blot analysis with pulsed-field gel electrophoresis showed that AKT1, AKT2, AKT3, and AKTR and their homologues are on a single chromosome. These results indicate the structural and functional complexity of the genomic region controlling AK-toxin biosynthesis.

Alternaria↗
PubMed2001

Genomics of Mycobacterium bovis.

The imminent completion of the genome sequence of Mycobacterium bovis will reveal the genetic blueprint for this most successful pathogen. Comparative analysis with the genome sequences of M. tuberculosis and M. bovis BCG promises to expose the genetic basis for the phenotypic differences between the tubercle bacilli, offering unparalleled insight into the virulence factors of the M. tuberculosis complex. Initial analysis of the sequence data has already revealed a novel deletion from M. bovis, as well as identifying variation in members of the PPE family of proteins. As the study of bacterial pathogenicity enters the postgenomic phase, the genome sequence of M. bovis promises to serve as a cornerstone of mycobacterial genetics.

BCG Vaccine↗
PubMed2001

cDNA-AFLP analysis unravels a genome-wide hrpG-regulon in the plant pathogen Xanthomonas campestris pv. vesicatoria.

The Hrp type III protein secretion system is essential for pathogenicity of the Gram-negative plant pathogen Xanthomonas campestris pv. vesicatoria. Expression of the hrp gene cluster is controlled by HrpG, a two-component response regulator, and HrpX, an AraC-type transcriptional activator. Using the cDNA-AFLP technique, 30 hrpG-induced (hgi) and five hrpG-repressed (hgr) cDNA fragments were identified, defining a large hrpG-regulon in X. campestris pv. vesicatoria. Expression of most genes in the hrpG-regulon was dependent on hrpX. Seven cDNA fragments map to the known hrp gene cluster and flanking regions. All other genes appear to be scattered over the chromosome and endogenous plasmids. Sequence analysis identified genes encoding putative extracellular proteases, a putative transcriptional regulator and XopJ and XopB (Xanthomonas outer proteins), homologues of YopJ from Yersinia spp. and the avirulence protein AvrPphD of Pseudomonas syringae respectively. XopB is secreted by the Hrp type III secretion system. Analysis of deletion mutants in several hgi genes revealed a new virulence locus. This study demonstrates that cDNA-AFLP is a powerful tool to study prokaryotic transcriptomes and to identify genes contributing to Xanthomonas virulence and putative effector proteins.

Bacterial Proteins↗
PubMed1997

Ancient mtDNA sequences in the human nuclear genome: a potential source of errors in identifying pathogenic mutations.

Nuclear-localized mtDNA pseudogenes might explain a recent report describing a heteroplasmic mtDNA molecule containing five linked missense mutations dispersed over the contiguous mtDNA CO1 and CO2 genes in Alzheimer's disease (AD) patients. To test this hypothesis, we have used the PCR primers utilized in the original report to amplify CO1 and CO2 sequences from two independent rho degrees (mtDNA-less) cell lines. CO1 and CO2 sequences amplified from both of the rho degrees cells, demonstrating that these sequences are also present in the human nuclear DNA. The nuclear pseudogene CO1 and CO2 sequences were then tested for each of the five "AD" missense mutations by restriction endonuclease site variant assays. All five mutations were found in the nuclear CO1 and CO2 PCR products from rho degrees cells, but none were found in the PCR products obtained from cells with normal mtDNA. Moreover, when the overlapping nuclear CO1 and CO2 PCR products were cloned and sequenced, all five missense mutations were found, as well as a linked synonymous mutation. Unlike the findings in the original report, an additional 32 base substitutions were found, including two in adjacent tRNAs and a two base pair deletion in the CO2 gene. Phylogenetic analysis of the nuclear CO1 and CO2 sequences revealed that they diverged from modern human mtDNAs early in hominid evolution about 770,000 years before present. These data would be consistent with the interpretation that the missense mutations proposed to cause AD may be the product of ancient mtDNA variants preserved as nuclear pseudogenes.

Alzheimer Disease↗
PubMed2005

DNA sequence and comparative genomics of pAPEC-O2-R, an avian pathogenic Escherichia coli transmissible R plasmid.

In this study, a 101-kb IncF plasmid from an avian pathogenic Escherichia coli (APEC) strain (APEC O2) was sequenced and analyzed, providing the first completed APEC plasmid sequence. This plasmid, pAPEC-O2-R, has functional transfer and antimicrobial resistance-encoding regions. The resistance-encoding region encodes resistance to eight groups of antimicrobial agents, including silver and other heavy metals, quaternary ammonium compounds, tetracycline, sulfonamides, aminoglycosides, trimethoprim, and beta-lactam antimicrobial agents. This region of the plasmid is unique among previously described IncF plasmids in that it possesses a class 1 integron that harbors three gene cassettes and a heavy metal resistance operon. This region spans 33 kb and is flanked by the RepFII plasmid replicon and an assortment of plasmid maintenance genes. pAPEC-O2-R also contains a 32-kb transfer region that is nearly identical to that found in the E. coli F plasmid, rendering it transferable by conjugation to plasmid-less strains of bacteria, including an APEC strain, a fecal E. coli strain from an apparently healthy bird, a Salmonella enterica serovar Typhimurium strain, and a uropathogenic E. coli strain from humans. Differences in the G+C contents of individual open reading frames suggest that various regions of pAPEC-O2-R had dissimilar origins. The presence of pAPEC-O2-R-like plasmids that encode resistance to multiple antimicrobial agents and that are readily transmissible from APEC to other bacteria suggests the possibility that such plasmids may serve as a reservoir of resistance genes for other bacteria of animal and human health significance.

Animals↗