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PubMed1990

Sequence analysis and acute pathogenicity of molecularly cloned SIVSMM-PBj14.

The PBj14 isolate of simian immunodeficiency virus from sooty mangabey monkeys (SIVSMM-PBj14) is the most acutely pathogenic primate lentivirus so far described, always causing fatal disease in pig-tailed macaques (Macaca nemestrina) within 8 days of inoculation. As a first step in identifying viral genes and gene products that influence pathogenicity, the SIVSMM-PBj14 genome was amplified by the polymerase chain reaction as 5' and 3' genomic halves of 5.1 and 5.8 kilobases, respectively, and molecularly cloned. DNA sequence analysis revealed a high degree of conservation with other SIVs, except for a 22-base-pair duplication in the enhancer region of the viral long terminal repeat which included a second binding site for the transcription factor NF-kappa B. Of six genomic halves examined, four contributed to the formation of infectious virus that induced acute disease and death in pig-tailed macaques as early as 6 days post-inoculation, with pathology, disease syndromes and kinetics indistinguishable from those induced by the uncloned isolate. To our knowledge this is the first example of acute immunodeficiency disease induced by a molecularly defined lentivirus. Furthermore, the molecularly cloned SIVSMM-PBj14 viruses share with the uncloned virus cytopathicity for mangabey CD4+ cells, a property that may correlate with their observed pathogenicity in vivo.

Animals↗
PubMed2002

Genome size and the accumulation of simple sequence repeats: implications of new data from genome sequencing projects.

The relationship between the level of repetitiveness in genomic sequences and genome size has been re-investigated making use of the rapidly growing database of complete eubacterial and archaeal genome sequences combined with the fragmentary but now large amount of data from eukaryotic genomes. Relative simplicity factors (RSFs), which measure the repetitiveness of sequences, were calculated and significantly simple motifs (SSMs), which identify the kinds of sequences that are repeated, were identified. A previously reported correlation between genome size and repetitiveness was confirmed, but it was shown that the higher RSFs seen in eukaryotic genomes also reflect a generally higher level of repetitiveness independent of genome size differences. Differences in genome size are responsible for about 10% of the variance in RSF seen between species. The spectrum of SSMs seen within a genome differed markedly within the eubacteria but less so in eukaryotes and, particularly, in archaea. Species with SSM spectra that differ from the norm tend also to have high RSFs for their genome size and to be pathogens that make use of repetitive sequences to avoid host defence responses. Some of the variance in repetitiveness seen in other species may therefore also reflect the action of selection, although other forces such as variation in the effectiveness of mechanisms for regulating slippage errors of replication, may also be important.

Animals↗
PubMed2004

Biased distribution of DNA uptake sequences towards genome maintenance genes.

Repeated sequence signatures are characteristic features of all genomic DNA. We have made a rigorous search for repeat genomic sequences in the human pathogens Neisseria meningitidis, Neisseria gonorrhoeae and Haemophilus influenzae and found that by far the most frequent 9-10mers residing within coding regions are the DNA uptake sequences (DUS) required for natural genetic transformation. More importantly, we found a significantly higher density of DUS within genes involved in DNA repair, recombination, restriction-modification and replication than in any other annotated gene group in these organisms. Pasteurella multocida also displayed high frequencies of a putative DUS identical to that previously identified in H.influenzae and with a skewed distribution towards genome maintenance genes, indicating that this bacterium might be transformation competent under certain conditions. These results imply that the high frequency of DUS in genome maintenance genes is conserved among phylogenetically divergent species and thus are of significant biological importance. Increased DUS density is expected to enhance DNA uptake and the over-representation of DUS in genome maintenance genes might reflect facilitated recovery of genome preserving functions. For example, transient and beneficial increase in genome instability can be allowed during pathogenesis simply through loss of antimutator genes, since these DUS-containing sequences will be preferentially recovered. Furthermore, uptake of such genes could provide a mechanism for facilitated recovery from DNA damage after genotoxic stress.

Bacterial Proteins↗
PubMed1999

Cloning of an ORF with homology to Mycobacterium echA1, encoding the enoyl-CoA hydratase, in Rhodococcus fascians.

An open reading frame encoding a polypeptide of significant homology (55.7% identity) with the enoyl-CoA hydratase encoded by the gene echA1 from Mycobacterium tuberculosis has been found in the genome of the plant-pathogen bacteria Rhodococcus fascians strain NRRL-B-15096. Sequence alignments showed that it possesses several conserved blocks common to E. coli, M. tuberculosis and human mitochondria. One of such blocks includes a glutamate residue located at position 149, corresponding to the glutamate 139 of Escherichia coli. This glutamate was previously shown to be the catalytic residue of enoyl-CoA hydratase in the multienzyme complex of fatty acid oxidation from E. coli. Our results provide additional information on the conserved domains of this enzyme. Significant homologies in other genome regions between R. fascians and M. tuberculosis confirm their phylogenetic relationship.

Amino Acid Sequence↗
PubMed2006

Targeting mechanisms of Pseudomonas aeruginosa pathogenesis.

Pseudomonas aeruginosa is an opportunistic pathogen responsible for ventilator-acquired pneumonia, acute lower respiratory tract infections in immunocompromised patients and chronic respiratory infections in cystic fibrosis patients. High incidence, infection severity and increasing resistance characterize P. aeruginosa infections, highlighting the need for new therapeutic options. One such option is to target the many pathogenic mechanisms conferred to P. aeruginosa by its large genome encoding many different virulence factors. This article reviews the pathogenic mechanisms and potential therapies targeting these mechanisms in P. aeruginosa respiratory infections.

Fimbriae, Bacterial↗
PubMed2004

An historical and genomic view of schistosome conjugal biology with emphasis on sex-specific gene expression.

The genetic programmes associated with the sexual biology of dioecious schistosomes remain a critically important but significantly understudied area of parasitology. Throughout the last four decades, progress has been slow in describing the gross antigenic and proteomic differences linked to sexually mature schistosomes and in characterizing some of the sex-associated transcripts and regulatory mechanisms induced during developmental maturation. These investigations have been severely hindered by the lack of complete EST/genomic information, as well as corresponding post- and functional-genomic tools for studying these pathogenic parasites. As near complete transcriptomes for Schistosoma japonicum and S. mansoni have recently been reported, and both DNA microarrays and post-transcriptional gene silencing have been applied to schistosomes, the tools and techniques for the high-throughput identification and characterization of transcripts involved in conjugal biology are now readily available. Here, an historical review is presented that summarizes some of the most significant findings associated with schistosome sex and sexual maturation during the last several decades. Following this discussion is a current overview of some modern day genomic approaches used to study schistosomes, which illustrates how major advances in the field of conjugal biology will be achieved.

Animals↗
PubMed1990

A physical map of the genome of Haemophilus influenzae type b.

Contour-clamped homogeneous electric field pulsed-field gel electrophoresis (PFGE) was used in combination with Southern hybridization to construct a genomic restriction map for the pathogen Haemophilus influenzae serotype b, strain Eagan. Sites for four restriction endonucleases, EagI, NaeI, RsrII and SmaI, were located on the 2100 kbp circular chromosome. Twelve potential virulence loci have been placed on the map together with certain loci essential for growth of the bacteria (e.g. ribosomal RNA operons). PFGE also provided a valuable tool for characterizing ten capsulated, type b isolates (other than Eagan) known to be genetically heterogeneous and two laboratory-derived variants (transformants) derived through complex recombinational events involving random uptake of high-molecular-mass donor genomic DNA.

Base Sequence↗
PubMed2005

Genome-wide RNAi screen for host factors required for intracellular bacterial infection.

Most studies of host-pathogen interactions have focused on pathogen-specific virulence determinants. Here, we report a genome-wide RNA interference screen to identify host factors required for intracellular bacterial pathogenesis. Using Drosophila cells and the cytosolic pathogen Listeria monocytogenes, we identified 305 double-stranded RNAs targeting a wide range of cellular functions that altered L. monocytogenes infection. Comparison to a similar screen with Mycobacterium fortuitum, a vacuolar pathogen, identified host factors that may play a general role in intracellular pathogenesis and factors that specifically affect access to the cytosol by L. monocytogenes.

Animals↗
PubMed2005

Transcriptome profiling of bacterial responses to root exudates identifies genes involved in microbe-plant interactions.

Molecules exuded by plant roots are thought to act as signals to influence the ability of microbial strains to colonize the roots and to survive in the rhizosphere. Differential bacterial responses to signals from different plant species may mediate the selection of specific rhizosphere populations. Very little, however, is known about the effects of plant exudates on patterns of bacterial gene expression. Here, we have tested the concept that plant root exudates modulate expression of bacterial genes involved in establishing microbe-plant interactions. We have examined the influence on the Pseudomonas aeruginosa PA01 transcriptome of exudates from two varieties of sugarbeet that select for genetically distinct pseudomonad populations in the rhizosphere. The response to the two exudates showed only a partial overlap; the majority of those genes with altered expression was regulated in response to only one of the two exudates. Genes with altered expression included those with functions previously implicated in microbe-plant interactions, such as aspects of metabolism, chemotaxis and type III secretion, and a subset with putative or unknown function. Use of a panel of mutants with targeted disruptions allowed us to identify previously uncharacterized genes with roles in the competitive ability of P. aeruginosa in the rhizosphere within this subset. No genes with host-specific effects were identified. Homologues of the genes identified occur in the genomes of both beneficial and pathogenic root-associated bacteria, suggesting that this strategy may help to elucidate molecular interactions that are important for biocontrol, plant growth promotion, and plant pathogenesis.

Beta vulgaris↗
PubMed2004

PCR-mediated whole genome amplification of phytoplasmas.

A method was developed for genome analysis of phytoplasmas, bacterial plant pathogens that cannot be cultivated in vitro in cell-free media. The procedure includes a CsCl-bisbenzimide gradient buoyant centrifugation followed by polymerase chain reaction (PCR)-mediated whole genome amplification. The latter step involves digestion of the DNA by a restriction enzyme with an A/T-rich recognition sequence. Due to the different A/T content in the DNA of the pathogen and its plant host, the fragments originating from phytoplasma are shorter and are preferentially amplified in the PCR reaction. Products obtained were cloned and screened by dot-blot hybridization. Results showed that about 90% of recombinant clones appeared to harbor phytoplasma specific DNA inserts. Sequencing of randomly selected clones was carried out and comparison with the NCBI database confirmed the bacterial origin for the sequences, which have been assigned a putative function. The origin of the recombinant clones was further confirmed by the generation of specific amplicons from the phytoplasma-infected plant and not from the healthy control, using PCR primers devised from the sequences of the recombinant clones. This method could be used for genome-wide comparisons between phytoplasmas.

AT Rich Sequence↗
PubMed2001

Lettuce mosaic virus pathogenicity determinants in susceptible and tolerant lettuce cultivars map to different regions of the viral genome.

Full-length infectious cDNA clones were constructed for two isolates (LMV-0 and LMV-E) of Lettuce mosaic virus (LMV), a member of the genus Potyvirus. These two isolates differ in pathogenicity in susceptible and tolerant-resistant lettuce cultivars. In susceptible plants, LMV-0 induces mild mosaic symptoms, whereas LMV-E induces severe stunting, leaf deformation, and a necrotic mosaic. In plants carrying either of the two probably allelic recessive resistance genes mol1 or mol2, LMV-0 is restricted partially to the inoculated leaves. When a systemic invasion does occur, however, symptoms fail to develop. LMV-E overcomes the protection afforded by the resistance genes, resulting in systemic mosaic symptoms. Analysis of the behavior of recombinants constructed between the two virus isolates determined that the HC-Pro protein of LMV-E causes the severe stunting and necrotic mosaic induced by this isolate in susceptible cultivars. In contrast, the ability to overcome mol resistance and induce symptoms in the resistant-tolerant cultivars was mapped to the 3' half of the LMV-E genome. These results indicate that the ability to induce severe symptoms and to overcome the protection afforded by the recessive genes mol1 or mol2 are independent phenomena.

Cloning, Molecular↗
PubMed2001

Surface attachment and pre-penetration stage development by plant pathogenic fungi.

Fungal pathogens cause many of the most serious crop diseases. One of the principal reasons for the success of this group is their ability to locate and perceive appropriate host surfaces and then to elaborate specialized infection structures. Here we review the processes implicated in surface attachment, germ tube elongation, and development of appressoria. The involvement of surface-acting proteins such as fungal hydrophobins and integrins in these processes is evaluated, along with a description of studies that have revealed the existence of conserved signaling pathways that regulate appressorium formation. Finally, we anticipate the prospect of genome-level analysis of fungal pathogens and the key research questions that will need to be addressed.

Fungal Proteins↗
PubMed2002

Comparative genome sequencing for discovery of novel polymorphisms in Bacillus anthracis.

Comparison of the whole-genome sequence of Bacillus anthracis isolated from a victim of a recent bioterrorist anthrax attack with a reference reveals 60 new markers that include single nucleotide polymorphisms (SNPs), inserted or deleted sequences, and tandem repeats. Genome comparison detected four high-quality SNPs between the two sequenced B. anthracis chromosomes and seven differences among different preparations of the reference genome. These markers have been tested on a collection of anthrax isolates and were found to divide these samples into distinct families. These results demonstrate that genome-based analysis of microbial pathogens will provide a powerful new tool for investigation of infectious disease outbreaks.

Animals↗
PubMed2001

Whole genome sequencing of meticillin-resistant Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is one of the major causes of community-acquired and hospital-acquired infections. It produces numerous toxins including superantigens that cause unique disease entities such as toxic-shock syndrome and staphylococcal scarlet fever, and has acquired resistance to practically all antibiotics. Whole genome analysis is a necessary step towards future development of countermeasures against this organism. METHODS: Whole genome sequences of two related S aureus strains (N315 and Mu50) were determined by shot-gun random sequencing. N315 is a meticillin-resistant S aureus (MRSA) strain isolated in 1982, and Mu50 is an MRSA strain with vancomycin resistance isolated in 1997. The open reading frames were identified by use of GAMBLER and GLIMMER programs, and annotation of each was done with a BLAST homology search, motif analysis, and protein localisation prediction. FINDINGS: The Staphylococcus genome was composed of a complex mixture of genes, many of which seem to have been acquired by lateral gene transfer. Most of the antibiotic resistance genes were carried either by plasmids or by mobile genetic elements including a unique resistance island. Three classes of new pathogenicity islands were identified in the genome: a toxic-shock-syndrome toxin island family, exotoxin islands, and enterotoxin islands. In the latter two pathogenicity islands, clusters of exotoxin and enterotoxin genes were found closely linked with other gene clusters encoding putative pathogenic factors. The analysis also identified 70 candidates for new virulence factors. INTERPRETATION: The remarkable ability of S aureus to acquire useful genes from various organisms was revealed through the observation of genome complexity and evidence of lateral gene transfer. Repeated duplication of genes encoding superantigens explains why S aureus is capable of infecting humans of diverse genetic backgrounds, eliciting severe immune reactions. Investigation of many newly identified gene products, including the 70 putative virulence factors, will greatly improve our understanding of the biology of staphylococci and the processes of infectious diseases caused by S aureus.

Animals↗
PubMed2000

The evolution of human pathogens: examples and clinical implications.

Recent advances in sequencing of complete bacterial genomes, molecular typing of micro-organisms, and research on microbial pathogenicity factors changed our view on the evolution of human bacterial pathogens. We review current evolutionary concepts on plague and meningococcal disease to illustrate the interplay of molecular phylogeny, epidemiology, and pathogenicity research. Furthermore, examples of the tremendous velocity of bacterial evolution under changing environmental conditions will be discussed.

Adaptation, Physiological↗
PubMed2005

Array-based binary analysis for bacterial typing.

An allele-specific oligonucleotide microarray was developed for rapid typing of pathogens based on analysis of genomic variations. Using a panel of Escherichia coli strains as a model system, selected loci were sequenced to uncover differences, such as single- or multiple-nucleotide polymorphisms as well as insertion/deletions (indels). While typical genomic profiling experiments employ specific sequences targeted to genomic DNA unique to a single strain or virulent gene, the present array is designed to type bacteria based on a patterned signature response across multiple loci. In the signature concept, all strains are interrogated by hybridizing their amplified DNA to an array containing multiple probe sequences. Allele-specific oligonucleotide probe sequences targeting each of these variable regions were synthesized and included in a custom fiber-optic array. For each locus, a set of specific probe sequences is selected, such that hybridization gives a binary signal/no signal response to each of the probes. Using this strategy for multiple loci, many pathogens or microorganisms could be classified using a limited number of probes. Because of the advantages of the fiber-optic array platform over other array formats, including sensitivity and speed, the platform described in this paper is capable of supporting a high-throughput diagnostic strategy.

Bacterial Typing Techniques↗
PubMed2006

Construction of a Vibrio splendidus mutant lacking the metalloprotease gene vsm by use of a novel counterselectable suicide vector.

Vibrio splendidus is a dominant culturable Vibrio in seawater, and strains related to this species are also associated with mortality in a variety of marine animals. The determinants encoding the pathogenic properties of these strains are still poorly understood; however, the recent sequencing of the genome of V. splendidus LGP32, an oyster pathogen, provides an opportunity to decipher the basis of the virulence properties by disruption of candidate genes. We developed a novel suicide vector based on the pir-dependent R6K replicative origin, which potentially can be transferred by RP4-based conjugation to any Vibrio strain and which also carries the plasmid F toxin ccdB gene under control of the PBAD promoter. We demonstrated that this genetic system allows efficient counterselection of integrated plasmids in the presence of arabinose in both V. splendidus and Vibrio cholerae and thus permits efficient markerless allelic replacement in these species. We used this technique to construct several mutants of V. splendidus LGP32, including a derivative with a secreted metalloprotease gene, vsm, deleted. We found that this gene is essential for LGP32 extracellular product toxicity when the extracellular products are injected into oysters but is not necessary for virulence of bacteria in the oyster infection model when bacteria are injected.

Animals↗
PubMed2002

Sequencing the Aspergillus fumigatus genome.

Aspergillus fumigatus is the most common mould pathogen of human beings and unusually causes both invasive disease in immunocompromised patients and allergic disease in patients with atopic immune systems. 4% of patients dying in modern European teaching hospitals have invasive aspergillosis and it is the leading infectious cause of death in leukaemia and bone marrow transplant patients. Until 2001, only two licensed antifungal drugs were available to treat aspergillosis-amphotericin B and itraconazole. Its 28-30Mb genome is being sequenced in an international collaboration, with the Wellcome Trust Sanger Institute (UK) and The Institute for Genomic Research (TIGR, USA) as the two main centres. A whole-genome shotgun approach was adopted and initiated in 2001 with an expected completion date in 2003. The complete sequence will permit identification of pathways specific to pathogenic Aspergillus species, help identify new targets for antifungal drugs, and enable investigations into the basic biology of fungi. Numerous secondary metabolic pathways with biotechnological applications and pharmacological properties are found in the Aspergilli and the genome sequence will facilitate research in this area.

Amphotericin B↗