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PubMed2000

Will genomics revolutionize antimicrobial drug discovery?

Utilizing genome sequence data from bacterial and fungal pathogens for the discovery of new antimicrobial agents has received considerable attention, both practical and critical, from the pharmaceutical and biotechnological communities. Although no new drugs derived from genomics-based discovery have been reported to be in a development pipeline, the utilization of genomics has revolutionized many aspects of drug discovery. The application, utility, opportunity, and challenges afforded by many of these new approaches are discussed.

Drug Design↗
PubMed2004

The effect of stress on genome regulation and structure.

BACKGROUND: Stresses exert evolutionary pressures on all organisms, which have developed sophisticated responses to cope and survive. These responses involve cellular physiology, gene regulation and genome remodelling. SCOPE: In this review, the effects of stress on genomes and the connected responses are considered. Recent developments in our understanding of epigenetic genome regulation, including the role of RNA interference (RNAi), suggest a function for this in stress initiation and response. We review our knowledge of how different stresses, tissue culture, pathogen attack, abiotic stress, and hybridization, affect genomes. Using allopolyploid hybridization as an example, we examine mechanisms that may mediate genomic responses, focusing on RNAi-mediated perturbations. CONCLUSIONS: A common response to stresses may be the relaxation of epigenetic regulation, leading to activation of suppressed sequences and secondary effects as regulatory systems attempt to re-establish genomic order.

Climate↗
PubMed2001

[Organization of the Helicobacter pylori genome].

Helicobacter pylori is a Gram-negative, spiral-shaped pathogenic bacterium that was firstly isolated and cultured from biopsy specimens by Marshall and Warren in 1983. This organism is a human gastric pathogen associated with peptic ulcer disease as well as chronic gastritis. Recent epidemiological studies have demonstrated that H. pylori is a primary risk factor for the development of intestinal type gastric adenocarcinoma. H. pylori is the first bacterium for which the genomes of two unrelated strains (26695 and J99) have been sequenced. The genome of H. pylori is relatively low in size (1.6-1.73 Mb). In this review, we compare the organization of two sequenced H. pylori genomes. A special emphasis on genetic diversity of H. pylori including plasticity zone and cag pathogenicity island has been placed.

Antigens, Bacterial↗
PubMed2000

Simplified procedure for detection of enteric pathogenic viruses in shellfish by RT-PCR.

Epidemiological evidence linking the transmission of enteric viral disease to shellfish has been known for a long time. A variety of methods have been described for the detection of viral contaminants in shellfish using RT-PCR. However, these methods generally include numerous, often fastidious and time consuming steps for virus release from shellfish tissues and viral RNA isolation. A simplified procedure based on the enzymatic liquefaction of shellfish digestive tissues without any mechanical homogenisation step, followed by a simple clarification of the lysate using dichloromethane extraction, was developed. Viral RNA is isolated directly from the shellfish extract by a guanidium thiocyanate-silica extraction method, adapted for the use of a vacuum manifold system. Virus-specific RT-PCR assays were set up for detection of genomic sequences of the predominant viral pathogens, HAV, Astrovirus and Norwalk-like viruses (from genogoups I or II). The specificity of the amplicons is confirmed finally by hybridisation with DIG-labelled specific probes. The overall procedure applied to shellfish samples spiked with HAV particles allowed a detection of 20 pfu of HAV per g of hepatopancreas. In addition, up to 20 samples can be tested within 24 h.

Animals↗
PubMed2006

SseL is a salmonella-specific translocated effector integrated into the SsrB-controlled salmonella pathogenicity island 2 type III secretion system.

Bacterial pathogens use horizontal gene transfer to acquire virulence factors that influence host colonization, alter virulence traits, and ultimately shape the outcome of disease following infection. One hallmark of the host-pathogen interaction is the prokaryotic type III secretion system that translocates virulence factors into host cells during infection. Salmonella enterica possesses two type III secretion systems that are utilized during host colonization and intracellular replication. Salmonella pathogenicity island 2 (SPI2) is a genomic island containing approximately 30 contiguous genes required to assemble a functional secretion system including the two-component regulatory system called SsrA-SsrB that positively regulates transcription of the secretion apparatus. We used transcriptional profiling with DNA microarrays to search for genes that coregulate with the SPI2 type III secretion machinery in an SsrB-dependent manner. Here we report the identification of a Salmonella-specific translocated effector called SseL that is required for full virulence during murine typhoid-like disease. Analysis of infected macrophages using fluorescence-activated cell sorting revealed that sseL is induced inside cells and requires SsrB for expression. SseL is retained predominantly in the cytoplasm of infected cells following translocation by the type III system encoded in SPI2. Animal infection experiments with sseL mutant bacteria indicate that integration of SseL into the SsrB response regulatory system contributes to systemic virulence of this pathogen.

Animals↗
PubMed2006

Pathogenicity island integrase cross-talk: a potential new tool for virulence modulation.

Instability and excision of pathogenicity islands (PAIs) have already been described in Escherichia coli 536. In this edition of Molecular Microbiology, Bianca Hochhut and colleagues from the University of Würzburg in Germany have shown that the instability of four of the E. coli 536 PAIs is mediated by a P4-type integrase encoded within the specific PAI by a site-specific recombination mechanism. The integrase encoded on PAI II(536) is able to mediate excision and integration of both PAI II(536), and also PAI V(536). The att sites of both these PAIs have a region of sequence similarity, which is also found in several other PAIs and in tRNA genes in several bacterial species. The cross-PAI activity of this integrase (Int(PAI II)) suggests that it plays an important role in both genome evolution and horizontal transfer of pathogenicity elements, possibly even across species barriers. Deletion of PAIs that carry genes for adhesins and other traits might lead to a phase variation-like phenomenon. Differential regulation of integrase activity or production might add a further level of fine-tuning during bacterial infection.

Biological Evolution↗
PubMed2003

Single-nucleotide polymorphisms and genome diversity in Plasmodium vivax.

The study of genetic variation in malaria parasites has practical significance for developing strategies to control the disease. Vaccines based on highly polymorphic antigens may be confounded by allelic restriction of the host immune response. In response to drug pressure, a highly plastic genome may generate resistant mutants more easily than a monomorphic one. Additionally, the study of the distribution of genomic polymorphisms may provide information leading to the identification of genes associated with traits such as parasite development and drug resistance. Indeed, the age and diversity of the human malaria parasite Plasmodium falciparum has been the subject of recent debate, because an ancient parasite with a complex genome is expected to present greater challenges for drug and vaccine development. The genome diversity of the important human pathogen Plasmodium vivax, however, remains essentially unknown. Here we analyze an approximately 100-kb contiguous chromosome segment from five isolates, revealing 191 single-nucleotide polymorphisms (SNPs) and 44 size polymorphisms. The SNPs are not evenly distributed across the segment with blocks of high and low diversity. Whereas the majority (approximately 63%) of the SNPs are in intergenic regions, introns contain significantly less SNPs than intergenic sequences. Polymorphic tandem repeats are abundant and are more uniformly distributed at a frequency of about one polymorphic tandem repeat per 3 kb. These data show that P. vivax has a highly diverse genome, and provide useful information for further understanding the genome diversity of the parasite.

Animals↗
PubMed2025

Pathogenic Variants in MPDZ are Associated with a Syndromic Neurodevelopmental Disorder: A Case Report and Review of the Literature.

Pathogenic variants in MPDZ are typically associated with congenital hydrocephalus. We report on siblings who present with more complex central nervous system malformations and defects in cardiovascular, ocular, and respiratory systems. Phenotyping of the proband revealed aortic coarctation, bicuspid aortic valve, partial anomalous pulmonary venous return, ventricular septal defect, Dandy-Walker malformation, along with subependymal gray matter heterotopia, megalocornea, and chorioretinal punctate lesions. Prenatal phenotyping of the proband's now deceased brother noted left-sided diaphragmatic hernia, a single cardiac ventricle of right ventricular morphology, aortic and mitral valve hypoplasia with aortic coarctation, ventriculomegaly, and mega cisterna magna. Whole genome sequencing identified a homozygous likely pathogenic canonical splice site variant in MPDZ, c.2650-1G>A in both siblings. These siblings present with features suggesting that MPDZ pathogenicity may be associated with a more complex syndromic neurodevelopmental phenotype with both central nervous system and non-central nervous system features. We speculate that MPDZ influences common morphogenetic pathways underlying these relationships.

Humans↗
PubMed2005

Codon and amino acid usage in two major human pathogens of genus Bartonella--optimization between replicational-transcriptional selection, translational control and cost minimization.

Intra-genomic variation in synonymous codon and amino acid usage in two human pathogens Bartonella henselae and B. quintana has been carried out through multivariate analysis. Asymmetric mutational bias, coupled with replicational-transcriptional selection, has been identified as the prime selection force behind synonymous codon selection--a characteristic of the genus Bartonella, not exhibited by any other alpha-proteobacterial genome. Distinct codon usage patterns and low synonymous divergence values between orthologous sequences of highly expressed genes from the two Bartonella species indicate that there exists a residual intra-strand synonymous codon bias in the highly expressed genes, possibly operating at the level of translation. In the case of amino acid usage, the mean hydropathy level and aromaticity are the major sources of variation, both having nearly equal impact, while strand-specific mutational pressure and gene expressivity strongly influence the inter-strand variations. In both species under study, the highly expressed gene products tend not to contain heavy and/or aromatic residues, following the cost-minimization hypothesis in spite of their intracellular lifestyle. The codon and amino acid usage in these two human pathogens are, therefore, consequences of a complex balance between replicational-transcriptional selection, translational control, protein hydropathy and cost minimization.

Amino Acids↗
PubMed2004

Lessons learned from the genome analysis of ralstonia solanacearum.

Ralstonia solanacearum is a devastating plant pathogen with a global distribution and an unusually wide host range. This bacterium can also be free-living as a saprophyte in water or in the soil in the absence of host plants. The availability of the complete genome sequence from strain GMI1000 provided the basis for an integrative analysis of the molecular traits determining the adaptation of the bacterium to various environmental niches and pathogenicity toward plants. This review summarizes current knowledge and speculates on some key bacterial functions, including metabolic versatility, resistance to metals, complex and extensive systems for motility and attachment to external surfaces, and multiple protein secretion systems. Genome sequence analysis provides clues about the evolution of essential virulence genes such as those encoding the Type III secretion system and related pathogenicity effectors. It also provided insights into possible mechanisms contributing to the rapid adaptation of the bacterium to its environment in general and to its interaction with plants in particular.

Amino Acid Sequence↗
PubMed2003

Rapid and efficient construction of recombinant bovine herpesvirus 1 genomes.

Bovine herpesvirus 1 (BoHV-1) is an important pathogen of cattle. Recombinant bovine herpesvirus 1 viruses (rBoHV) have been studied extensively as potential vaccines for BoHV-1 associated diseases. A method is described which advances protocols used currently for constructing rBoHV by producing recombinant viruses free of parent virus. The method, restriction endonuclease mediated recombination (REMR), utilises a unique NsiI site in the BoHV-1 genome. Following NsiI digestion the two genomic fragments are prevented from recombining by dephosphorylation. However, when the genomic fragments are co-transfected into a susceptible cell-line with a third DNA fragment (DNA bridge), which encodes DNA homologous to the digested viral termini, the three DNA molecules are able to undergo homologous recombination and produce infectious BoHV-1. During the recombination process foreign DNA within the DNA bridge is incorporated into the BoHV-1 genome, producing rBoHV. In the absence of the DNA bridge virus reconstitution does not occur thus eliminating contamination by the nonrecombinant parent virus. As REMR used an NsiI site occurring naturally in the BoHV-1 genome it can be used for the insertion of foreign DNA into the genome without any prior modifications. REMR could also be applied to any herpesvirus for which the genome sequence is known.

Animals↗
PubMed1985

Molecular cloning and characterization of the genome of wound tumor virus: a tumor-inducing plant reovirus.

The double-stranded RNA genome of the tumor-inducing plant pathogen, wound tumor virus, was converted to double-stranded DNA and cloned into plasmid pBR322. Multiple apparent full-length copies of 9 of the 12 wound tumor virus genome segments were identified. The entire sequence of cloned genome segment S12, the smallest of the genome segments, was determined. This genome segment was found to be 851 nucleotides in length and to possess a single long open reading frame that extends 178 codons from the first AUG triplet (residues 35-37): information sufficient to encode a protein of the size estimated for the smallest of the previously identified wound tumor virus primary gene products, Pns 12. Sequence data obtained from analysis of cloned cDNA copies of several genome segments and from direct analysis of the 3' termini of the double-stranded genome RNAs revealed that each wound tumor virus genome segment possesses the common terminal sequences: (+) 5'GGUAUU ... UGAU 3' (-) 3'CCAUAA ... ACUA 5'.

Base Sequence↗
PubMed2005

A preliminary analysis of the process of protein secretion and the diversity of putative secreted hydrolases encoded in Aspergillus fumigatus: insights from the genome.

The genome sequence of Aspergillus fumigatus has enabled the annotation of genes likely to encode secreted enzymes that may be important in underpinning the natural lifestyle of the fungus and its pathogenicity. We summarize the data from the genome sequence relevant to both the process of protein secretion and the predicted hydrolase enzymes secreted by A. fumigatus.

Animals↗
PubMed2006

Genomic organization and molecular characterization of Clostridium difficile bacteriophage PhiCD119.

In this study, we have isolated a temperate phage (PhiCD119) from a pathogenic Clostridium difficile strain and sequenced and annotated its genome. This virus has an icosahedral capsid and a contractile tail covered by a sheath and contains a double-stranded DNA genome. It belongs to the Myoviridae family of the tailed phages and the order Caudovirales. The genome was circularly permuted, with no physical ends detected by sequencing or restriction enzyme digestion analysis, and lacked a cos site. The DNA sequence of this phage consists of 53,325 bp, which carries 79 putative open reading frames (ORFs). A function could be assigned to 23 putative gene products, based upon bioinformatic analyses. The PhiCD119 genome is organized in a modular format, which includes modules for lysogeny, DNA replication, DNA packaging, structural proteins, and host cell lysis. The PhiCD119 attachment site attP lies in a noncoding region close to the putative integrase (int) gene. We have identified the phage integration site on the C. difficile chromosome (attB) located in a noncoding region just upstream of gene gltP, which encodes a carrier protein for glutamate and aspartate. This genetic analysis represents the first complete DNA sequence and annotation of a C. difficile phage.

Bacteriophages↗
PubMed2000

Restriction enzyme-mediated integration used to produce pathogenicity mutants of Colletotrichum graminicola.

We have developed a restriction enzyme-mediated insertional mutagenesis (REMI) system for the maize pathogen Colletotrichum graminicola. In this report, we demonstrate the utility of a REMI-based mutagenesis approach to identify novel pathogenicity genes. Use of REMI increased transformation efficiency by as much as 27-fold over transformations with linearized plasmid alone. Ninety-nine transformants were examined by Southern analysis, and 51% contained simple integrations consisting of one copy of the vector integrated at a single site in the genome. All appeared to have a plasmid integration at a unique site. Sequencing across the integration sites of six transformants demonstrated that in all cases the plasmid integration occurred at the corresponding restriction enzyme-recognition site. We used an in vitro bioassay to identify two pathogenicity mutants among 660 transformants. Genomic DNA flanking the plasmid integration sites was used to identify corresponding cosmids in a wild-type genomic library. The pathogenicity of one of the mutants was restored when it was transformed with the cosmids.

Blotting, Southern↗
PubMed2007

Gastric cancers in young and elderly patients show different genomic profiles.

Although most gastric cancers occur in elderly patients, a substantial number of cases of this common disease occur in young patients. Gastric cancer is a heterogeneous disease at the genomic level and different patterns of DNA copy number alterations are associated with different clinical behaviour. The aim of the present study was to explore differences in DNA copy number alterations in relation to age of onset of gastric cancer. DNA isolated from 46 paraffin-embedded gastric cancer tissue samples from 17 patients less than 50 years of age [median 43 (21-49) years] and 29 patients greater than or equal to 70 years of age [median 75 (70-83) years] was analysed by genome-wide microarray comparative genomic hybridization (array CGH) using an array of 5000 BAC clones. Patterns of DNA copy number aberrations were analysed by hierarchical cluster analysis of the mode-normalized and smoothed log(2) ratios of tumour to normal reference fluorescence signal intensities using TMEV software, after which cluster membership was correlated with age group. In addition, supervised analysis was performed using CGH Multi-array. Hierarchical cluster analysis of the array CGH data revealed three clusters with different genomic profiles that correlated significantly with age (p = 0.006). Cluster 1 mainly contained young patients, while elderly patients were divided over clusters 2 and 3. Chromosome regions 11q23.3 and 19p13.3 contributed most to age-related differences in tumour profiles. Gastric cancers of young and old patients belong to groups with different genomic profiles, which likely reflect different pathogenic mechanisms of the disease.

Adult↗
PubMed2003

Application of DNA microarrays to study the evolutionary genomics of Yersinia pestis and Yersinia pseudotuberculosis.

Yersinia pestis, the causative agent of plague, diverged from Yersinia pseudotuberculosis, an enteric pathogen, an estimated 1500-20,000 years ago. Genetic characterization of these closely related organisms represents a useful model to study the rapid emergence of bacterial pathogens that threaten mankind. To this end, we undertook genome-wide DNA microarray analysis of 22 strains of Y. pestis and 10 strains of Y. pseudotuberculosis of diverse origin. Eleven Y. pestis DNA loci were deemed absent or highly divergent in all strains of Y. pseudotuberculosis. Four were regions of phage origin, whereas the other seven included genes encoding a vitamin B12 receptor and the insect toxin sepC. Sixteen differences were identified between Y. pestis strains, with biovar Antiqua and Mediaevalis strains showing most divergence from the arrayed CO92 Orientalis strain. Fifty-eight Y. pestis regions were specific to a limited number of Y. pseudotuberculosis strains, including the high pathogenicity island, three putative autotransporters, and several possible insecticidal toxins and hemolysins. The O-antigen gene cluster and one of two possible flagellar operons had high levels of divergence between Y. pseudotuberculosis strains. This study reports chromosomal differences between species, biovars, serotypes, and strains of Y. pestis and Y. pseudotuberculosis that may relate to the evolution of these species in their respective niches.

Adaptation, Physiological↗