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PubMed2026

Whole genome of Lasiodiplodia theobromae, Lasiodiplodia euphorbiaceicola, and Lasiodiplodia brasiliensis isolates associated with Mango Dieback and stem-end rot in Côte d'Ivoire.

Mango productivity is threatened by dieback and fruit rot from Lasiodiplodia spp. (Botryosphaeriaceae fungal family). We report high-quality genomes of Lasiodiplodia theobromae, Lasiodiplodia euphorbiaceicola, and Lasiodiplodia brasiliensis from Côte d'Ivoire, enhancing genomic resources for comparative and pathogenicity studies of these fungal plant pathogens.

Lasiodiplodia spp.↗
PubMed2005

Bacterial genome adaptation to niches: divergence of the potential virulence genes in three Burkholderia species of different survival strategies.

BACKGROUND: Two closely related species Burkholderia mallei (Bm) and Burkholderia pseudomallei (Bp) are serious human health hazards and are potential bio-warfare agents, whereas another closely related species Burkholderia thailandensis (Bt) is a non-pathogenic saprophyte. To investigate the genomic factors resulting in such a dramatic difference, we first identified the Bm genes responsive to the mouse environment, and then examined the divergence of these genes in Bp and Bt. RESULTS: The genes down-expressed, which largely encode cell growth-related proteins, are conserved well in all three species, whereas those up-expressed, which include potential virulence genes, are less well conserved or absent notably in Bt. However, a substantial number of up-expressed genes is still conserved in Bt. Bm and Bp further diverged from each other in a small number of genes resulting from unit number changes in simple sequence repeats (ssr) in the homologs. CONCLUSION: Our data suggest that divergent evolution of a small set of genes, rather than acquisition or loss of pathogenic islands, is associated with the development of different life styles in these bacteria of similar genomic contents. Further divergence between Bm and Bp mediated by ssr changes may reflect different adaptive processes of Bm and Bp fine-tuning into their host environments.

Animals↗
PubMed2006

Comparative and functional genomic analyses of iron transport and regulation in Leptospira spp.

The spirochetes of the Leptospira genus contain saprophytic and pathogenic members, the latter being responsible for leptospirosis. Despite the recent sequencing of the genome of the pathogen L. interrogans, the slow growth of these bacteria, their virulence in humans, and a lack of genetic tools make it difficult to work with these pathogens. In contrast, the development of numerous genetic tools for the saprophyte L. biflexa enables its use as a model bacterium. Leptospira spp. require iron for growth. In this work, we show that Leptospira spp. can acquire iron from different sources, including siderophores. A comparative genome analysis of iron uptake systems and their regulation in the saprophyte L. biflexa and the pathogen L. interrogans is presented in this study. Our data indicated that, for instance, L. biflexa and L. interrogans contain 8 and 12 genes, respectively, whose products share homology with proteins that have been shown to be TonB-dependent receptors. We show that some genes involved in iron uptake were differentially expressed in response to iron. In addition, we were able to disrupt several putative genes involved in iron acquisition systems or iron regulation in L. biflexa. Comparative genomics, in combination with gene inactivation, gives us significant functional information on iron homeostasis in Leptospira spp.

Amino Acid Sequence↗
PubMed2000

Theileria parva genomics reveals an atypical apicomplexan genome.

The discipline of genomics is setting new paradigms in research approaches to resolving problems in human and animal health. We propose to determine the genome sequence of Theileria parva, a pathogen of cattle, using the random shotgun approach pioneered at The Institute for Genomic Research (TIGR). A number of features of the T. parva genome make it particularly suitable for this approach. The G+C content of genomic DNA is about 31%, non-coding repetitive DNA constitutes less than 1% of total DNA and a framework for the 10-12 Mbp genome is available in the form of a physical map for all four chromosomes. Minisatellite sequences are the only dispersed repetitive sequences identified so far, but they are limited in distribution to 13 of 33 SfiI fragments. Telomere and sub-telomeric non-coding sequences occupy less than 10 kbp at each chromosomal end and there are only two units encoding cytoplasmic rRNAs. Three sets of distinct multicopy sequences encoding ORFs have been identified but it is not known if these are associated with expression of parasite antigenic diversity. Protein coding genes exhibit a bias in codon usage and introns when present are unusually short. Like other apicomplexan organisms, T. parva contains two extrachromosomal DNAs, a mitochondrial DNA and a plastid DNA molecule. By annotating the genome sequence, in combination with the use of microarray technology and comparative genomics, we expect to gain significant insights into unique aspects of the biology of T. parva. We believe that the data will underpin future research to aid in the identification of targets of protective CD8+ cell mediated immune responses, and parasite molecules involved in inducing reversible host leukocyte transformation and tumour-like behaviour of transformed parasitised cells.

Animals↗
PubMed2003

The impact of "ancient pathogen" studies on the practice of public health.

A new field of "ancient pathogens" is making an impact on our concepts of the evolution of infectious diseases, and it will eventually alter the practice of public health in their control. It has begun to answer important questions regarding past epidemics of influenza and tuberculosis by recovering the genetic sequences of the ancient causative agents. Vaccination strategics will have to study these microbial variants in order to develop tomorrow's vaccines. It may also be possible to examine the role of past and present reservoirs in the dynamics of emerging diseases. In unraveling the evolution of pathogens, insights into the mechanisms of drug and antibiotic resistance are possible. As "genome projects" of more and more pathogens are being completed. Targets for chemotherapy are being revealed which are totally different from the metabolic processes of the mammalian host. Signal molecules are being identified which alter the virulence of the microbe. Focussing on these mechanisms without attempting to kill the pathogen may in some cases drive it into a benign state. These and other aspects of the evolution of pathogens are discussed which may lead to innovative approaches to the control of infectious diseases.

Biological Evolution↗
PubMedDate not supplied

Detection and expression of corticosteroid binding protein gene in human pathogenic fungi.

Participation of steroid hormones in the growth of several fungal species has been widely reported. The aim of the present study was to detect the presence and expression of the corticosteroid binding protein (CBP) gene in different pathogenic fungal isolates from human clinical specimens. Genomic DNA and total RNA were obtained from six different pathogenic fungal species and submitted to Southern blot and Reverse Transcription-Polymerase Chain Reaction respectively. The results indicated that all the fungi studied presented and expressed CBP gene. The sequence of a PCR product of CBP gene fragment corresponding to the carboxyl terminal region in Trichophyton mentagrophytes, which presented the highest CBP expression, showed an identity of 98% as compared to the previously reported gene sequence from Candida albicans. The overall results indicate that CBP is a highly conserved gene in fungi and suggest that steroid hormones should play an important physiological role in these eukaryotic organisms.

Adrenal Cortex Hormones↗
PubMed2003

Consequences of reductive evolution for gene expression in an obligate endosymbiont.

The smallest cellular genomes are found in obligate symbiotic and pathogenic bacteria living within eukaryotic hosts. In comparison with large genomes of free-living relatives, these reduced genomes are rearranged and have lost most regulatory elements. To test whether reduced bacterial genomes incur reduced regulatory capacities, we used full-genome microarrays to evaluate transcriptional response to environmental stress in Buchnera aphidicola, the obligate endosymbiont of aphids. The 580 genes of the B. aphidicola genome represent a subset of the 4500 genes known from the related organism, Escherichia coli. Although over 20 orthologues of E. coli heat stress (HS) genes are retained by B. aphidicola, only five were differentially expressed after near-lethal heat stress treatments, and only modest shifts were observed. Analyses of upstream regulatory regions revealed loss or degradation of most HS (sigma32) promoters. Genomic rearrangements downstream of an intact HS promoter yielded upregulation of a functionally unrelated and an inactivated gene. Reanalyses of comparable experimental array data for E. coli and Bacillus subtilis revealed that genome-wide differential expression was significantly lower in B. aphidicola. Our demonstration of a diminished stress response validates reports of temperature sensitivity in B. aphidicola and suggests that this reduced bacterial genome exhibits transcriptional inflexibility.

Amino Acid Sequence↗
PubMed2006

Simple sequence proteins in prokaryotic proteomes.

BACKGROUND: The structural and functional features associated with Simple Sequence Proteins (SSPs) are non-globularity, disease states, signaling and post-translational modification. SSPs are also an important source of genetic and possibly phenotypic variation. Analysis of 249 prokaryotic proteomes offers a new opportunity to examine the genomic properties of SSPs. RESULTS: SSPs are a minority but they grow with proteome size. This relationship is exhibited across species varying in genomic GC, mutational bias, life style, and pathogenicity. Their proportion in each proteome is strongly influenced by genomic base compositional bias. In most species simple duplications is favoured, but in a few cases such as Mycobacteria, large families of duplications occur. Amino acid preference in SSPs exhibits a trend towards low cost of biosynthesis. In SSPs and in non-SSPs, Alanine, Glycine, Leucine, and Valine are abundant in species widely varying in genomic GC whereas Isoleucine and Lysine are rich only in organisms with low genomic GC. Arginine is abundant in SSPs of two species and in the non-SSPs of Xanthomonas oryzae. Asparagine is abundant only in SSPs of low GC species. Aspartic acid is abundant only in the non-SSPs of Halobacterium sp NRC1. The abundance of Serine in SSPs of 62 species extends over a broader range compared to that of non-SSPs. Threonine(T) is abundant only in SSPs of a couple of species. SSPs exhibit preferential association with Cell surface, Cell membrane and Transport functions and a negative association with Metabolism. Mesophiles and Thermophiles display similar ranges in the content of SSPs. CONCLUSION: Although SSPs are a minority, the genomic forces of base compositional bias and duplications influence their growth and pattern in each species. The preferences and abundance of amino acids are governed by low biosynthetic cost, evolutionary age and base composition of codons. Abundance of charged amino acids Arginine and Aspartic acid is severely restricted. SSPs preferentially associate with cell surface and interface functions as opposed to metabolism, wherein proteins of high sequence complexity with globular structures are preferred. Mesophiles and Thermophiles are similar with respect to the content of SSPs. Our analysis serves to expand the commonly held views on SSPs.

Amino Acid Sequence↗
PubMed2003

Utilization of genomic sequence information to develop malaria vaccines.

Recent advances in the fields of genomics, proteomics and molecular immunology offer tremendous opportunities for the development of novel interventions against public health threats, including malaria. However, there is currently no algorithm that can effectively identify the targets of protective T cell or antibody responses from genomic data. Furthermore, the identification of antigens that will stimulate the most effective immunity against the target pathogen is problematic, particularly if the genome is large. Malaria is an attractive model for the development and validation of approaches to translate genomic information to vaccine development because of the critical need for effective anti-malarial interventions and because the Plasmodium parasite is a complex multistage pathogen targeted by multiple immune responses. Sterile protective immunity can be achieved by immunization with radiation-attenuated sporozoites, and anti-disease immunity can be induced in residents in malaria-endemic areas. However, the 23 Mb Plasmodium falciparum genome encodes more than 5,300 proteins, each of which is a potential target of protective immune responses. The current generation of subunit vaccines is based on a single or few antigens and therefore might elicit too narrow a breadth of response. We are working towards the development of a new generation vaccine based on the presumption that duplicating the protection induced by the whole organism may require a vaccine nearly as complex as the organism itself. Here, we present our strategy to exploit the genomic sequence of P. falciparum for malaria vaccine development.

Animals↗
PubMed1997

Bias in the genomic distribution of CAG and CTG trinucleotide repeats.

We investigated the hypothesis that the trinucleotide repeat CAG is disproportionately located in exons in genomic DNA by analyzing unbiased genomic sequences with the Gene Recognition and Analysis Internet Link program (http@avalon.epm.ornl.gov/). Forty percent of CAG/CTG repeats were predicted to lie within exons. This is significantly greater than would be expected by chance, and is also greater than we have observed for ATT/AAT repeats. Therefore, our data support the hypothesis. Furthermore, the data support the utility of a recently reported CAG/CTG PCR genomic screening set for identifying pathogenic expanded CAG/CTG repeats.

Computer Communication Networks↗
PubMed2004

Psi-Phi: exploring the outer limits of bacterial pseudogenes.

Because bacterial chromosomes are tightly packed with genes and were traditionally viewed as being optimized for size and replication speed, it was not surprising that the early annotations of sequenced bacterial genomes reported few, if any, pseudogenes. But because pseudogenes are generally recognized by comparisons with their functional counterparts, as more genome sequences accumulated, many bacterial pathogens were found to harbor large numbers of truncated, inactivated, and degraded genes. Because the mutational events that inactivate genes occur continuously in all genomes, we investigated whether the rarity of pseudogenes in some bacteria was attributable to properties inherent to the organism or to the failure to recognize pseudogenes. By developing a program suite (called Psi-Phi, for Psi-gene Finder) that applies a comparative method to identify pseudogenes (attributable both to misannotation and to nonrecognition), we analyzed the pseudogene inventories in the sequenced members of the Escherichia coli/Shigella clade. This approach recovered hundreds of previously unrecognized pseudogenes and showed that pseudogenes are a regular feature of bacterial genomes, even in those whose original annotations registered no truncated or otherwise inactivated genes. In Shigella flexneri 2a, large proportions of pseudogenes are generated by nonsense mutations and IS element insertions, events that seldom produce the pseudogenes present in the other genomes examined. Almost all (>95%) pseudogenes are restricted to only one of the genomes and are of relatively recent origin, suggesting that these bacteria possess active mechanisms to eliminate nonfunctional genes.

Codon, Nonsense↗
PubMed2005

Mapping of essential replication functions of the linear plasmid lp17 of B. burgdorferi by targeted deletion walking.

The genome of the Lyme disease pathogen Borrelia burgdorferi strain B31 MI includes one linear chromosome, 10 circular and 12 linear plasmids. Members of four paralogous gene families, revealed by genome sequencing, have been suggested as replication/partition functions for both the linear and circular plasmids. Some of these genes have been experimentally shown to be essential for the replication of the B. burgdorferi replicons that encode them. In this study, we located the region essential for replication of lp17, the second smallest linear plasmid in B. burgdorferi. We used a novel in vivo method, targeted deletion walking, to systematically delete DNA from either the left or right end of lp17. We report that the region essential for replication of lp17 is 1.8 kb (bp 7946-9766) and contains only one intact open reading frame (BBD14). Expression of BBD14 is required for the replication, suggesting that it is the replication initiator for lp17. The BBD14 protein is a member of paralogous family (PF) 62 and we present the first experimental evidence for the role of a PF 62 member. Adjacent non-coding sequences are also required, suggesting that the origin lies at least partially outside the coding region. Surprisingly, deletion of BBD21, the ParA orthologue (PF 32), had little effect upon plasmid stability or incompatibility. Finally, data are presented suggesting that lp17 replication occurs preferentially on a linear rather than a circular DNA molecule.

Bacterial Proteins↗
PubMed1999

Strategies for isolation of in vivo expressed genes from bacteria.

The discovery and characterization of genes specifically induced in vivo upon infection and/or at a specific stage of the infection will be the next phase in studying bacterial virulence at the molecular level. Genes isolated are most likely to encode virulence-associated factors or products essential for survival, bacterial cell division and multiplication in situ. Identification of these genes is expected to provide new means to prevent infection, new targets for, antimicrobial therapy, as well as new insights into the infection process. Analysis of genes and their sequences initially discovered as in vivo induced may now be revealed by functional and comparative genomics. The new field of virulence genomics and their clustering as pathogenicity islands makes feasible their in-depth analysis. Application of new technologies such as in vivo expression technologies, signature-tagged mutagenesis, differential fluorescence induction, differential display using polymerase chain reaction coupled to bacterial genomics is expected to provide a strong basis for studying in vivo induced genes, and a better understanding of bacterial pathogenicity in vivo. This review presents technologies for characterization of genes expressed in vivo.

Cloning, Molecular↗
PubMed1995

Cloning of genes required for hypersensitivity and pathogenicity in Pseudomonas syringae pv. aptata.

A genomic library of Pseudomonas syringae pv. aptata strain NCPPB 2664, which causes bacterial blight of sugar beet, lettuce and other plants, was constructed in the cosmid vector pCPP31. The 13.4 kb EcoRI fragment of the cosmid pHIR11, containing the hrp (hypersensitive response and pathogenicity) gene cluster of the closely related bacterium Pseudomonas syringae pv. syringae strain 61, was used as a probe to identify a homologous hrp gene cluster in P. syringae pv. aptata. Thirty of 2500 cosmid clones, screened by colony hybridization, gave a strong hybridization signal with the probe, but none of these conferred to the non-pathogenic bacterium, Pseudomonas fluorescens, the ability to elicit the hypersensitive response (HR) in tobacco. Southern blot analysis of EcoRI-digested genomic DNA of P. syringae pv. aptata showed hybridizing bands of 12 kb and 4.4 kb. Only a 12 kb fragment hybridized in digests of the cosmids. Cosmid clone pCPP1069 was mutagenized with Tn10-minitet and marker-exchanged into the genome of P. syringae pv. aptata. Three resulting prototrophic mutant strains failed to elicit the HR in tobacco and to cause disease in lettuce. The DNA flanking the Tn10-minitet insertions from mutated derivatives of pCPP1069 hybridized with the 10.6 kb Bg/II fragment of pHIR11. These results indicate that P. syringae pv. aptata harbours hrp genes that are similar to, but arranged differently from, homologous hrp genes of P. syringae pv. syringae.

Blotting, Southern↗
PubMed2006

Truncated hemoglobin GlbO from Mycobacterium leprae alleviates nitric oxide toxicity.

As a consequence of reductive genome evolution, the obligate intracellular pathogen Mycobacterium leprae has minimized the repertoire of genes implicated in defense against reactive oxygen and nitrogen species. Genes for multiple hemoglobin types coexist in mycobacterial genomes, but M. leprae has retained only glbO, encoding a group-II truncated hemoglobin. Mycobacterium tuberculosis GlbO has been involved in oxygen transfer and respiration during hypoxia, but a role in protection from nitric oxide (NO) has not been documented yet. Here, we report that the in vitro reaction of oxygenated recombinant M. leprae GlbO with NO results in an immediate stoichiometric formation of nitrate, concomitant with heme-protein oxidation. Overexpression of GlbO alleviates the growth inhibition of Escherichia colihmp (flavohemoglobin gene) mutants in the presence of NO-donors, partly complementing the defect in Hmp synthesis. A promoter element upstream of glbO was predicted in silico, and confirmed by using a glbO::lacZ transcriptional fusion in the heterologous Mycobacterium smegmatis system. The glbO::lacZ fusion was expressed through the whole growth cycle of M. smegmatis, and moderately induced by NO. We propose that M. leprae, by retaining the unique truncated hemoglobin GlbO, may have coupled O2 delivery to the terminal oxidase with a defensive mechanism to scavenge NO from respiratory enzymes. These activities would help to sustain the obligate aerobic metabolism required for intracellular survival of leprosy bacilli.

Base Sequence↗
PubMed2006

Functional and structural characterization of Spl proteases from Staphylococcus aureus.

Staphylococcus aureus is the major cause of nosocomial infections world-wide, with increasing prevalence of community-acquired diseases. The recent dramatic increase in multi-antibiotic resistance, including resistance to the last-resort drug, vancomycin, together with the lack of an effective vaccine highlight the need for better understanding of S.aureus pathogenicity. Comparative analysis of available bacterial genomes allows for the identification of previously uncharacterized S.aureus genes with potential roles in pathogenicity. A good example is a cluster of six serine protease-like (spl) genes encompassed in one operon, which encode for putative proteases with similarity to staphylococcal glutamylendopeptidase (V8 protease). Here, we describe an efficient expression system for the production of recombinant SplB and SplC proteases in Escherichia coli, together with structural and functional characterization of the purified enzymes. A unique mechanism of cytoplasm protection against activity of misdirected SplB was uncovered. Apparently, the co-translated signal peptide maintains protease latency until it is cleaved by the signal peptidase during protein secretion. Furthermore, the crystal structure of the SplC protease revealed a fold resembling that of the V8 protease and epidermolytic toxins. Arrangement of the active site cleft and substrate-binding pocket of SplC explains the mechanism of enzyme latency and suggests that some Spl proteases possess restricted substrate specificity similar to that of the V8 protease and epidermolytic toxins.

Amino Acid Sequence↗
PubMed2004

Germs, genomes and genealogies.

Genetic diversity in pathogen species contains information about evolutionary and epidemiological processes, including the origins and history of disease, the nature of the selective forces acting on pathogen genes and the role of recombination in generating genetic novelty. Here, we review recent developments in these fields and compare the use of population genetic, or population-model based, approaches to phylogenetic, or population-model free, methodologies. We show how simple epidemiological models can be related to the ancestral, or coalescent, process underlying samples from pathogen species, enabling detailed inference about pathogen biology from patterns of molecular variation.

Journal Article↗