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At least 469 records · Page 26Linked to original sources
PubMed2004

Biotechnology and vaccines: application of functional genomics to Neisseria meningitidis and other bacterial pathogens.

Since its introduction, vaccinology has been very effective in preventing infectious diseases. However, in several cases, the conventional approach to identify protective antigens, based on biochemical, immunological and microbiological methods, has failed to deliver successful vaccine candidates against major bacterial pathogens. The recent development of powerful biotechnological tools applied to genome-based approaches has revolutionized vaccine development, biological research and clinical diagnostics. The availability of a genome provides an inclusive virtual catalogue of all the potential antigens from which it is possible to select the molecules that are likely to be more effective. Here, we describe the use of "reverse vaccinology", which has been successful in the identification of potential vaccines candidates against Neisseria meningitidis serogroup B and review the use of functional genomics approaches as DNA microarrays, proteomics and comparative genome analysis for the identification of virulence factors and novel vaccine candidates. In addition, we describe the potential of these powerful technologies in understanding the pathogenesis of various bacteria.

Bacterial Vaccines↗
PubMed2005

The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans.

Cryptococcus neoformans is a basidiomycetous yeast ubiquitous in the environment, a model for fungal pathogenesis, and an opportunistic human pathogen of global importance. We have sequenced its approximately 20-megabase genome, which contains approximately 6500 intron-rich gene structures and encodes a transcriptome abundant in alternatively spliced and antisense messages. The genome is rich in transposons, many of which cluster at candidate centromeric regions. The presence of these transposons may drive karyotype instability and phenotypic variation. C. neoformans encodes unique genes that may contribute to its unusual virulence properties, and comparison of two phenotypically distinct strains reveals variation in gene content in addition to sequence polymorphisms between the genomes.

Alternative Splicing↗
PubMed2006

The mitochondrial genome of Gyrodactylus salaris (Platyhelminthes: Monogenea), a pathogen of Atlantic salmon (Salmo salar).

In the present study, we describe the complete mitochondrial (mt) genome of the Atlantic salmon parasite Gyrodactylus salaris, the first for any monogenean species. The circular genome is 14,790 bp in size. All of the 35 genes recognized from other flatworm mitochondrial genomes were identified, and they are transcribed from the same strand. The protein-coding and ribosomal RNA (rRNA) genes share the same gene arrangement as those published previously for neodermatan mt genomes (representing cestodes and digeneans only), and the genome has an overall A+T content of 65%. Three transfer RNA (tRNA) genes overlap with other genes, whereas the secondary structure of 3 tRNA genes lack the DHU arm and 1 tRNA gene lacks the TphiC arm. Eighteen regions of non-coding DNA ranging from 4 to 112 bp in length, totalling 278 bp, were identified as well as 2 large non-coding regions (799 bp and 768 bp) that were almost identical to each other. The completion of the mt genome offers the opportunity of defining new molecular markers for studying evolutionary relationships within and among gyrodactylid species.

Animals↗
PubMed2001

Comparative whole-genome analyses reveal over 100 putative phase-variable genes in the pathogenic Neisseria spp.

Previously, a complete genome analysis of Neisseria meningitidis strain MC58 revealed the largest repertoire of putative phase-variable genes described in any species to date. Initial comparisons with two incomplete Neisseria spp. genome sequences available at that time revealed differences in the repeats associated with these genes in the form of polymorphisms, the absence of the potentially unstable elements in some alleles, and in the repertoire of the genes that were present. Analyses of the complete genomes of N. meningitidis strain Z2491 and Neisseria gonorrhoeae strain FA1090 have been performed and are combined with a comprehensive comparative analysis between the three available complete genome sequences. This has increased the sensitivity of these searches and provided additional contextual information that facilitates the interpretation of the functional consequences of repeat instability. This analysis identified: (i) 68 phase-variable gene candidates in N. meningitidis strain Z2491, rather than the 27 previously reported; (ii) 83 candidates in N. gonorrhoeae strain FA1090; and (iii) 82 candidates in N. meningitidis strain MC58, including an additional 19 identified through cross-comparisons with the other two strains. In addition to the 18 members of the opa gene family, a repertoire of 119 putative phase-variable genes is described, indicating a huge potential for diversification mediated by this mechanism of gene switching in these species that is central to their interactions with the host and environmental transitions. Eighty-two of these are either known (14) or strong (68) candidates for phase variation, which together with the opa genes make a total of 100 identified genes. The repertoires of the genes identified in this analysis diverge from the different species groupings, indicating horizontal exchange that significantly affects the species and strain complements of these genes.

Bacterial Proteins↗
PubMed2006

Role of pathogenicity island-associated integrases in the genome plasticity of uropathogenic Escherichia coli strain 536.

The genome of uropathogenic Escherichia coli isolate 536 contains five well-characterized pathogenicity islands (PAIs) encoding key virulence factors of this strain. Except PAI IV(536), the four other PAIs of strain 536 are flanked by direct repeats (DRs), carry intact integrase genes and are able to excise site-specifically from the chromosome. Genome screening of strain 536 identified a sixth putative asnW-associated PAI. Despite the presence of DRs and an intact integrase gene, excision of this island was not detected. To investigate the role of PAI-encoded integrases for the recombination process the int genes of each unstable island of strain 536 were inactivated. For PAI I(536) and PAI II(536), their respective P4-like integrase was required for their excision. PAI III(536) carries two integrase genes, intA, encoding an SfX-like integrase, and intB, coding for an integrase with weak similarity to P4-like integrases. Only intB was required for site-specific excision of this island. For PAI V(536), excision could not be abolished after deleting its P4-like integrase gene but additional deletion of the PAI II(536)-specific integrase gene was required. Therefore, although all mediated by P4-like integrases, the activity of the PAI excision machinery is most often restricted to its cognate island. This work also demonstrates for the first time the existence of a cross-talk between integrases of different PAIs and shows that this cross-talk is unidirectional.

Amino Acid Sequence↗
PubMed1997

A Candida albicans genome project: cosmid contigs, physical mapping, and gene isolation.

A new project to map the genome of the pathogenic fungus, Candida albicans, has been started. The entire genome was cloned as 5088 cosmids, stored in individual microtiter plate wells. DNA was prepared and fingerprinted using restriction digestion, fluorescent labeling, and analysis on an ABI sequencer. These data are being used to construct contigs of the genome. Simultaneously, a DNA pooling system has been set up, suitable for PCR-based isolation of cosmids containing any known gene. Ultimately, these approaches will lead to the creation of a physically based map of the C. albicans genome, providing the means to localize precisely all the genes, act as a substrate for genome sequencing projects, and provide probes for future studies of genome rearrangement and comparative genomics.

Candida albicans↗
PubMed2002

Salmonella effectors within a single pathogenicity island are differentially expressed and translocated by separate type III secretion systems.

Pathogenicity islands (PAIs) are large DNA segments in the genomes of bacterial pathogens that encode virulence factors. Five PAIs have been identified in the Gram-negative bacterium Salmonella enterica. Two of these PAIs, Salmonella pathogenicity island (SPI)-1 and SPI-2, encode type III secretion systems (TTSS), which are essential virulence determinants. These 'molecular syringes' inject effectors directly into the host cell, whereupon they manipulate host cell functions. These effectors are either encoded with their respective TTSS or scattered elsewhere on the Salmonella chromosome. Importantly, SPI-1 and SPI-2 are expressed under distinct environmental conditions: SPI-1 is induced upon initial contact with the host cell, whereas SPI-2 is induced intracellularly. Here, we demonstrate that a single PAI, in this case SPI-5, can encode effectors that are induced by distinct regulatory cues and targeted to different TTSS. SPI-5 encodes the SPI-1 TTSS translocated effector, SigD/SopB. In contrast, we report that the adjacently encoded effector PipB is part of the SPI-2 regulon. PipB is translocated by the SPI-2 TTSS to the Salmonella-containing vacuole and Salmonella-induced filaments. We also show that regions of SPI-5 are not conserved in all Salmonella spp. Although sigD/sopB is present in all Salmonella spp., pipB is not found in Salmonella bongori, which also lacks a functional SPI-2 TTSS. Thus, we demonstrate a functional and regulatory cross-talk between three chromosomal PAIs, SPI-1, SPI-2 and SPI-5, which has significant implications for the evolution and role of PAIs in bacterial pathogenesis.

Animals↗
PubMed1996

The Leishmania genome comprises 36 chromosomes conserved across widely divergent human pathogenic species.

All the physical linkage groups constituting the genome of Leishmania infantum have been identified for the first time by hybridization of specific DNA probes to pulsed field gradient-separated chromosomes. The numerous co-migrating chromosomes were individualised using the distinctive size polymorphisms which occur among strains of the L. infantum/L. donovani complex as a tool. A total of 244 probes, consisting of 41 known genes, 66 expressed sequence tags (ESTs) and 137 anonymous DNA sequences, were assigned to a specific linkage group. We show that this genome comprises 36 chromosomes ranging in size from 0.35 to -3 Mb. This information enabled us to compare the genome structure of L. infantum with those of the three other main Leishmania species that infect man in the Old World, L. major, L. tropica and L. aethiopica. The linkage groups were consistently conserved in all species examined. This result is in striking contrast to the large genetic distances that separate these species and suggests that conservation of the chromosome structure may be critical for this human pathogen. Finally, the high density of markers obtained during the present study (with a mean of 1 marker/130 kb) will speed up the construction of a detailed physical map that would facilitate the genetic analysis of this parasite, for which no classical genetics is available.

Animals↗
PubMed2002

Comparative mycobacterial genomics as a tool for drug target and antigen discovery.

Genomics and the associated downstream technologies are generating vast data sets that provide new opportunities for understanding and combating both infectious and genetic diseases in humans. The genomic approach has been applied to tuberculosis, a major cause of transmissible morbidity and mortality, with notable success. Complete genome sequences are now available for three members of the Mycobacterium tuberculosis complex and the related intracellular pathogen M. leprae. Many of the predictions generated in silico by genomics have been validated through functional analysis, including studies of the transcriptome and proteome, and led to the identification of essential genes. Knowledge of the latter defines potential targets for new and existing drugs and their specificity can be assessed by comparative genomics with the host or other pathogens. Genomics is also furthering tuberculosis vaccine development by pinpointing potentially antigenic proteins as well as providing better diagnostic tools to detect infection.

Antigens↗
PubMed2001

Comparative genomics reveals close genetic relationships between phages from dairy bacteria and pathogenic Streptococci: evolutionary implications for prophage-host interactions.

The genome of the highly pathogenic M1 serotype Streptococcus pyogenes isolate SF370 contains eight prophage elements. Only prophage SF370.1 could be induced by mitomycin C treatment. Prophage SF370.3 showed a 33.5-kb-long genome that closely resembled the genome organization of the cos-site temperate Siphovirus r1t infecting the dairy bacterium Lactococcus lactis. The two-phage genomes shared between 60 and 70% nucleotide sequence identity over the DNA packaging, head and tail genes. Analysis of the SF370.3 genome revealed mutations in the replisome organizer gene that may prevent the induction of the prophage. The mutated phage replication gene was closely related to a virulence marker identified in recently emerged M3 serotype S. pyogenes strains in Japan. This observation suggests that prophage genes confer selective advantage to the lysogenic host. SF370.3 encodes a hyaluronidase and a DNase that may facilitate the spreading of S. pyogenes through tissue planes of its human host. Prophage SF370.2 showed a 43-kb-long genome that closely resembled the genome organization of pac-site temperate Siphoviridae infecting the dairy bacteria S. thermophilus and L. lactis. Over part of the structural genes, the similarity between SF370.2 and S. thermophilus phage O1205 extended to the nucleotide sequence level. SF370.2 showed two probable inactivating mutations: one in the replisome organizer gene and another in the gene encoding the portal protein. Prophage SF370.2 also encodes a hyaluronidase and in addition two very likely virulence factors: prophage-encoded toxins acting as superantigens that may contribute to the immune deregulation observed during invasive streptococcal infections. The superantigens are encoded between the phage lysin and the right attachment site of the prophage genome. The genes were nearly sequence identical with a DNA segment in S. equi, suggesting horizontal gene transfer. The trend for prophage genome inactivation was even more evident for the remaining five prophage sequences that showed massive losses of prophage DNA. In these prophage remnants only 13-0.3 kb of putative prophage DNA was detected. We discuss the genomics data from S. pyogenes strain SF370 within the framework of Darwinian coevolution of prophages and lysogenic bacteria and suggest elements of genetic cooperation and elements of an arms race in this host-parasite relationship.

Bacteriophages↗
PubMed2026

Clinical and Genomic Insights into the Allodiploid Hybrid Pathogen Aspergillus latus: A Retrospective Case Series.

Aspergillus latus is an emerging cryptic allodiploid hybrid pathogen within Aspergillus section Nidulantes that closely resembles related species and therefore prone to misidentification by routine diagnostic methods. Therefore, its true clinical burden is likely underestimated. In this study, we retrospectively characterized five patients with A. latus infections identified by metagenomic next-generation sequencing (mNGS) at a tertiary hospital in China. Clinical manifestations varied according to host immune status, ranging from a subclinical pulmonary lesion in an immunocompetent individual to aggressive disease in highly immunocompromised patients. Conventional microbiological methods showed limited sensitivity and consistently misidentified the isolates as A. nidulans, whereas mNGS enabled accurate detection of A. latus together with complex co-infections. Three viable clinical isolates were recovered for morphological characterization, antifungal susceptibility testing, and whole-genome sequencing (WGS). All tested isolates demonstrated reduced susceptibility to echinocandins but remained susceptible to mold-active triazoles and amphotericin B. Furthermore, WGS and macrosynteny analyses confirmed their allodiploid hybrid nature, revealing a mosaic genome derived from A. spinulosporus and an A. quadrilineatus-related lineage. Collectively, these findings highlight that A. latus may be missed by routine diagnostic methods and may exhibit a distinct antifungal susceptibility profile. Molecular approaches such as mNGS and WGS may therefore help achieve accurate species-level identification and support targeted antifungal therapy. Given this small retrospective case series, larger prospective and multicenter studies are needed to validate these observations and better define the epidemiology, clinical spectrum, and therapeutic implications of this emerging allodiploid hybrid pathogen.

Retrospective Studies↗
PubMed2005

A genome sequence survey shows that the pathogenic yeast Candida parapsilosis has a defective MTLa1 allele at its mating type locus.

Candida parapsilosis is responsible for ca. 15% of Candida infections and is of particular concern in neonates and surgical intensive care patients. The related species Candida albicans has recently been shown to possess a functional mating pathway. To analyze the analogous pathway in C. parapsilosis, we carried out a genome sequence survey of the type strain. We identified ca. 3,900 genes, with an average amino acid identity of 59% with C. albicans. Of these, 23 are predicted to be predominantly involved in mating. We identified a genomic locus homologous to the MTLa mating type locus of C. albicans, but the C. parapsilosis type strain has at least two internal stop codons in the MTLa1 open reading frame, and two predicted introns are not spliced. These stop codons were present in MTLa1 of all eight C. parapsilosis isolates tested. Furthermore, we found that all isolates of C. parapsilosis tested appear to contain only the MTLa idiomorph at the presumptive mating locus, unlike C. albicans and C. dubliniensis. MTLalpha sequences are present but at a different chromosomal location. It is therefore likely that all (or at least the majority) of C. parapsilosis isolates have a mating pathway that is either defective or substantially different from that of C. albicans.

Alleles↗
PubMed2003

Genome sequence of Vibrio parahaemolyticus: a pathogenic mechanism distinct from that of V cholerae.

BACKGROUND: Vibrio parahaemolyticus, a gram-negative marine bacterium, is a worldwide cause of food-borne gastroenteritis. V parahaemolyticus strains of a few specific serotypes, probably derived from a common clonal ancestor, have lately caused a pandemic of gastroenteritis. The organism is phylogenetically close to V cholerae, the causative agent of cholera. METHODS: The whole genome sequence of a clinical V parahaemolyticus strain RIMD2210633 was established by shotgun sequencing. The coding sequences were identified by use of Gambler and Glimmer programs. Comparative analysis with the V cholerae genome was undertaken with MUMmer. FINDINGS: The genome consisted of two circular chromosomes of 3288558 bp and 1877212 bp; it contained 4832 genes. Comparison of the V parahaemolyticus genome with that of V cholerae showed many rearrangements within and between the two chromosomes. Genes for the type III secretion system (TTSS) were identified in the genome of V parahaemolyticus; V cholerae does not have these genes. INTERPRETATION: The TTSS is a central virulence factor of diarrhoea-causing bacteria such as shigella, salmonella, and enteropathogenic Escherichia coli, which cause gastroenteritis by invading or intimately interacting with intestinal epithelial cells. Our results suggest that V parahaemolyticus and V cholerae use distinct mechanisms to establish infection. This finding explains clinical features of V parahaemolyticus infections, which commonly include inflammatory diarrhoea and in some cases systemic manifestations such as septicaemia, distinct from those of V cholerae infections, which are generally associated with non-inflammatory diarrhoea.

Cholera↗
PubMed2005

A simple and economic preservation method for genomic bacterial DNA from clinically significant pathogens.

Bacterial culture was allowed to dry to completeness on Columbia agar base with defibrinated horse blood. Following 6 months storage at room temperature, microbial DNA was extracted and successfully amplified by PCR. This storage technique has the advantage over other methods of not requiring (i) a DNA extraction protocol prior to storage and (ii) refrigeration and/or freezing. This technique maybe useful in the transportation of bacterial genomic DNA in nonviable cells as well as reliable method for the storage of DNA in underdeveloped countries.

Base Sequence↗
PubMed2005

Insights in the pathogenic potential of Propionibacterium acnes from its complete genome.

One of the long-lasting open questions in understanding acne is the role of the skin bacterium Propionibacterium acnes. Opinions within the scientific community diverge regarding the importance of this Gram-positive bacterium not only in acne but also in other P. acnes-associated diseases. The recently decoded genome gives us some clues with respect to its pathogenic potential and its strategies to survive in the harsh environment of human skin. This review focuses on the major findings of the genome sequence. Special attention has been drawn to the cell surface composition of P. acnes, its antigenic potential, and to enzymes that are potentially involved in degrading skin-derived substances.

Acne Vulgaris↗
PubMed2026

Primer design through submodular function estimation.

MOTIVATION: Multiplex PCR-based enrichment is widely used in viral genome sequencing and pathogen surveillance. However, designing large sets of primers that maximize genome coverage while minimizing primer-primer interactions remains a major computational challenge. Existing methods such as SADDLE and Olivar use heuristics to optimize a Badness score for primer dimers but lack theoretical guarantees on solution quality. RESULTS: We introduce PRISM, a new framework that formulates multiplex primer design as a constrained submodular maximization problem. Our method defines an objective that balances genome coverage and dimer risk, and applies a local search algorithm with a constant-factor approximation guarantee. Evaluations on viral genome datasets demonstrate that PRISM consistently achieves lower Badness scores compared to PrimalScheme, Olivar, and primerJinn. These results highlight the scalability and theoretical rigor of submodular optimization in primer design. AVAILABILITY: PRISM is open-source and available at https://github.com/yhhan19/PRISM-new. The experimental data, scripts, and results used in this paper are archived on Figshare at https://doi.org/10.6084/m9.figshare.32806499.

Algorithms↗
PubMed1990

Analysis of three different repeated DNA elements present in the P1 operon of Mycoplasma pneumoniae: size, number and distribution on the genome.

Mycoplasma pneumoniae, a bacterium pathogenic for humans, has a relatively small genome size of 840 kbp. Even though, several repeated DNA elements have been identified in the genome of this prokaryote, particularly within the P1 gene which codes for a major adhesin protein of M. pneumoniae. These elements were characterized in detail with respect to size, number and distribution on the genome, represented by an ordered cloned library covering the complete chromosome. Three different repetitive elements were detected in and around the P1 gene designated as RepMP2/3, RepMP4 and RepMP5. The length of these elements varies between 1.1-1.5 kbp (RepMP4), 1.8 kbp (RepMP2/3) and 1.9-2.2 kpb (RepMP5). They occur at least 8 to 10 times on the chromosome. Possible functions are discussed and a uniform nomenclature for these repeats is proposed.

Blotting, Southern↗
PubMed2006

Comparative genomics reveals what makes an enterobacterial plant pathogen.

The bacterial family Enterobacteriaceae contains some of the most devastating human and animal pathogens, including Escherichia coli, Salmonella enterica and species of Yersinia and Shigella. These are among the best-studied of any organisms, yet there is much to be learned about the nature and evolution of interactions with their hosts and with the wider environment. Comparative and functional genomics have fundamentally improved our understanding of their modes of adaptation to different ecological niches and the genes that determine their pathogenicity. In addition to animal pathogens, Enterobacteriaceae include important plant pathogens, such as Erwinia carotovora subsp. atroseptica (Eca), the first plant-pathogenic enterobacterium to be sequenced. This review focuses on genomic comparisons between Eca and other enterobacteria, with particular emphasis on the differences that exemplify or explain the plant-associated lifestyle(s) of Eca. Horizontal gene transfer in Eca may directly have led to the acquisition of a number of determinants that mediate its interactions, pathogenic or otherwise, with plants, offering a glimpse into its evolutionary divergence from animal-pathogenic enterobacteria.

Enterobacteriaceae↗