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PubMed2000

Fine-resolution physical mapping of genomic diversity in Candida albicans.

It has been suggested that Candida albicans, a diploid asexual fungus, achieves genetic diversity by genomic rearrangement. This important human pathogen may provide a system in which to analyze alternate routes to genomic diversity. C. albicans has a highly variable karyotype; its chromosomes contain a middle repeated DNA sequence called the Major Repeat Sequence (MRS), composed of subrepeats HOK, RPS, and RB2. RPS is tandemly repeated while the other subrepeats occur once in each MRS. Chromosome 7, the smallest of the eight chromosomes, has been previously mapped. The complete physical map of this chromosome was used to analyze chromosome 7 diversity in six strains, including two well-characterized laboratory strains (1006 and WO-1) and four clinical ones. We found four types of events to explain the genomic diversity: 1) Chromosome length polymorphism (CLP) results from expansion and contraction of the RPS; 2) reciprocal translocation occurs at the MRS loci; 3) chromosomal deletion; and (4) trisomy of individual chromosomes. These four phenomena play an important role in generating genomic diversity in C. albicans.

Aneuploidy↗

PubMed2006

Genomic analysis reveals that Pseudomonas aeruginosa virulence is combinatorial.

BACKGROUND: Pseudomonas aeruginosa is a ubiquitous environmental bacterium and an important opportunistic human pathogen. Generally, the acquisition of genes in the form of pathogenicity islands distinguishes pathogenic isolates from nonpathogens. We therefore sequenced a highly virulent strain of P. aeruginosa, PA14, and compared it with a previously sequenced (and less pathogenic) strain, PAO1, to identify novel virulence genes. RESULTS: The PA14 and PAO1 genomes are remarkably similar, although PA14 has a slightly larger genome (6.5 megabses [Mb]) than does PAO1 (6.3 Mb). We identified 58 PA14 gene clusters that are absent in PAO1 to determine which of these genes, if any, contribute to its enhanced virulence in a Caenorhabditis elegans pathogenicity model. First, we tested 18 additional diverse strains in the C. elegans model and observed a wide range of pathogenic potential; however, genotyping these strains using a custom microarray showed that the presence of PA14 genes that are absent in PAO1 did not correlate with the virulence of these strains. Second, we utilized a full-genome nonredundant mutant library of PA14 to identify five genes (absent in PAO1) required for C. elegans killing. Surprisingly, although these five genes are present in many other P. aeruginosa strains, they do not correlate with virulence in C. elegans. CONCLUSION: Genes required for pathogenicity in one strain of P. aeruginosa are neither required for nor predictive of virulence in other strains. We therefore propose that virulence in this organism is both multifactorial and combinatorial, the result of a pool of pathogenicity-related genes that interact in various combinations in different genetic backgrounds.

Base Sequence↗

PubMed2001

Ralstonia solanacearum needs motility for invasive virulence on tomato.

Ralstonia solanacearum, a widely distributed and economically important plant pathogen, invades the roots of diverse plant hosts from the soil and aggressively colonizes the xylem vessels, causing a lethal wilting known as bacterial wilt disease. By examining bacteria from the xylem vessels of infected plants, we found that R. solanacearum is essentially nonmotile in planta, although it can be highly motile in culture. To determine the role of pathogen motility in this disease, we cloned, characterized, and mutated two genes in the R. solanacearum flagellar biosynthetic pathway. The genes for flagellin, the subunit of the flagellar filament (fliC), and for the flagellar motor switch protein (fliM) were isolated based on their resemblance to these proteins in other bacteria. As is typical for flagellins, the predicted FliC protein had well-conserved N- and C-terminal regions, separated by a divergent central domain. The predicted R. solanacearum FliM closely resembled motor switch proteins from other proteobacteria. Chromosomal mutants lacking fliC or fliM were created by replacing the genes with marked interrupted constructs. Since fliM is embedded in the fliLMNOPQR operon, the aphA cassette was used to make a nonpolar fliM mutation. Both mutants were completely nonmotile on soft agar plates, in minimal broth, and in tomato plants. The fliC mutant lacked flagella altogether; moreover, sheared-cell protein preparations from the fliC mutant lacked a 30-kDa band corresponding to flagellin. The fliM mutant was usually aflagellate, but about 10% of cells had abnormal truncated flagella. In a biologically representative soil-soak inoculation virulence assay, both nonmotile mutants were significantly reduced in the ability to cause disease on tomato plants. However, the fliC mutant had wild-type virulence when it was inoculated directly onto cut tomato petioles, an inoculation method that did not require bacteria to enter the intact host from the soil. These results suggest that swimming motility makes its most important contribution to bacterial wilt virulence in the early stages of host plant invasion and colonization.

Bacterial Proteins↗

PubMed2001

[Aspects of ecological occurrences Trichosporon cutaneum (de Beurman Gougerot et Vaucher, 1909 ota, 1915) in waters north-east Polands].

The aim of work was settlement of occurrence of pathogenic fungus Trichosporon cutaneum in diverse ecological environments. Object to investigations former river Wegorapa, Supraśl, lakes of complex Mamry and Sejny group, of cultivation ponds in Popielewo and in Poryte Jabłoń a few springs of city Białystok. In investigations one used method of baits to isolated water fungus. Quality of waters determined by physico-chemistry methods. One fixed, that pathogenic fungus Trichosporon cutaneum stepped out in waters north-east evn Poland on all investigated sites. It was developed in both strong poluted water of lakes and ponds also in good oxygened waters and springs it was too.

Ecosystem↗

PubMed2005

Pathogen adaptation to seasonal forcing and climate change.

Many diverse infectious diseases exhibit seasonal dynamics. Seasonality in disease incidence has been attributed to seasonal changes in pathogen transmission rates, resulting from fluctuations in extrinsic climate factors. Multi-strain infectious diseases with strain-specific seasonal signatures, such as cholera, indicate that a range of seasonal patterns in transmission rates is possible in identical environments. We therefore consider pathogens capable of evolving their 'seasonal phenotype', a trait that determines the sensitivity of their transmission rates to environmental variability. We introduce a theoretical framework, based on adaptive dynamics, for predicting the evolution of disease dynamics in seasonal environments. Changes in the seasonality of environmental factors are one important avenue for the effects of climate change on disease. This model also provides a framework for examining these effects on pathogen evolution and associated disease dynamics. An application of this approach gives an explanation for the recent cholera strain replacement in Bangladesh, based on changes in monsoon rainfall patterns.

Adaptation, Physiological↗

PubMed1999

Population study of allelic diversity in the human MHC class I-related MIC-A gene.

The polymorphism of major histocompatibility complex (MHC) class I HLA-A, -B, and -C molecules may have evolved through pathogen-driven selection of alleles with diverse peptide-binding specificities. Two MHC-encoded molecules that are distantly related to class I, MIC-A and MIC-B, do not function in the presentation of pathogen-derived peptides to T cells with alphabeta T-cell receptors (TCRs), but are broadly recognized by intraepithelial T cells with gammadelta TCRs. However, both MIC-A and MIC-B are polymorphic, displaying an unusual distribution of a number of variant amino acids in their extracellular alpha1, alpha2, and alpha3 domains. In order to further define the polymorphism of MIC-A, we examined its alleles among 275 individuals with common and rare HLA genotypes. Of 16 previously defined alleles, 12 were confirmed and 5 new alleles were identified. A two-by-two analysis of MIC-A and HLA-B alleles uncovered a number of statistically significant associations. These results confirm and extend previous knowledge on the polymorphism of MIC-A. The strong positive linkage of certain MIC-A and HLA-B alleles may have implications for studies related to MHC-associated diseases and transplantation.

Alleles↗

PubMed2005

Proteome analysis of serovars Typhimurium and Pullorum of Salmonella enterica subspecies I.

BACKGROUND: Salmonella enterica subspecies I includes several closely related serovars which differ in host ranges and ability to cause disease. The basis for the diversity in host range and pathogenic potential of the serovars is not well understood, and it is not known how host-restricted variants appeared and what factors were lost or acquired during adaptations to a specific environment. Differences apparent from the genomic data do not necessarily correspond to functional proteins and more importantly differential regulation of otherwise identical gene content may play a role in the diverse phenotypes of the serovars of Salmonella. RESULTS: In this study a comparative analysis of the cytosolic proteins of serovars Typhimurium and Pullorum was performed using two-dimensional gel electrophoresis and the proteins of interest were identified using mass spectrometry. An annotated reference map was created for serovar Typhimurium containing 233 entries, which included many metabolic enzymes, ribosomal proteins, chaperones and many other proteins characteristic for the growing cell. The comparative analysis of the two serovars revealed a high degree of variation amongst isolates obtained from different sources and, in some cases, the variation was greater between isolates of the same serovar than between isolates with different sero-specificity. However, several serovar-specific proteins, including intermediates in sulphate utilisation and cysteine synthesis, were also found despite the fact that the genes encoding those proteins are present in the genomes of both serovars. CONCLUSION: Current microbial proteomics are generally based on the use of a single reference or type strain of a species. This study has shown the importance of incorporating a large number of strains of a species, as the diversity of the proteome in the microbial population appears to be significantly greater than expected. The characterisation of a diverse selection of strains revealed parts of the proteome of S. enterica that alter their expression while others remain stable and allowed for the identification of serovar-specific factors that have so far remained undetected by other methods.

Bacterial Proteins↗

PubMed2006

TRAF3: a new component of the TLR-signaling apparatus.

Toll-like receptors (TLRs) are key sensors of microbially derived molecules that, upon activation, provide a pathogen-specific inflammatory response, leading to an efficient eradication of microbial pathogens. An important question has been how TLRs can provide signaling diversity when challenged with genotypic and functionally distinct pathogens. Recently, two studies have shown that tumor-necrosis factor receptor-associated factor 3 (TRAF3) is an essential component of the TLR-signaling pathway, being a crucial regulator in the induction of TLR-specific inflammatory responses.

Drug Therapy↗

PubMed2006

Identification, subtyping and virulence determination of Listeria monocytogenes, an important foodborne pathogen.

Listeria monocytogenes is an opportunistic intracellular pathogen that has become an important cause of human foodborne infections worldwide. Given its close relationship to other Listeria species and its tendency to produce non-specific clinical symptoms, the availability of rapid, sensitive and specific diagnostic tests for the differentiation of L. monocytogenes from other Listeria species is helpful for selecting appropriate treatment regimens. In addition, with L. monocytogenes comprising a diversity of strains of varying pathogenicity, the ability to precisely track the strains involved in listeriosis outbreaks and speedily determine their pathogenic potential is critical for the control and prevention of further occurrences of this deadly disease. Extensive research in recent decades has revealed significant insights regarding the molecular mechanisms of L. monocytogenes infection. This in turn has facilitated the development of laboratory procedures for enhanced detection and identification of L. monocytogenes, and has also contributed to the implementation of improved control and prevention strategies against listeriosis. The purpose of this review is to summarize recent progress in the species-specific identification, subtyping and virulence determination of L. monocytogenes strains, and to discuss future research needs pertaining to these important areas of listeriosis.

Animals↗

PubMed2006

Assessing the potential of regions of the nuclear and mitochondrial genome to develop a "molecular tool box" for the detection and characterization of Phytophthora species.

Four different intergenic regions of mitochondrial DNA (mt-IGS), a fragment of the intergenic spacer (IGS) region of the rDNA (rDNA-IGS), and a fragment of the ras-related protein (Ypt1) gene were amplified and sequenced from a panel of 31 Phytophthora species representing the most significant forest pathogens and the breadth of diversity in the genus. Over 80 kbp of novel sequences were generated and alignments showed very variable (introns and non-coding regions) as well as conserved coding regions. The mitochondrial DNA regions had an AT/GC ratio ranging from 67.2 to 89.0% and were appropriate for diagnostic development and phylogeographic analysis. The IGS fragment was less variable but still appropriate to discriminate amongst some important forest pathogens. The introns of the Ypt1 gene were sufficiently polymorphic for the development of molecular markers for almost all Phytophthora species, with more conserved flanking coding regions appropriate for the design of Phytophthora genus-specific primers. In general, phylogenetic analysis of the sequence alignments grouped species in clades that matched those based on the ITS regions of the rDNA. In many cases the resolution was improved over ITS but in other cases sequences were too variable to align accurately and yielded phylograms inconsistent with other data. Key studies on the intraspecific variation and primer specificity remain. However the research has already yielded an enormous dataset for the identification, detection and study of the molecular evolution of Phytophthora species.

Base Sequence↗

PubMed2003

Yeast two-hybrid system survey of interactions between LEE-encoded proteins of enteropathogenic Escherichia coli.

Many Gram-negative pathogens employ a specific secretion pathway, termed type III secretion, to deliver virulence effector proteins directly to the membranes and cytosol of host eukaryotic cells. Subsequent functions of many effector proteins delivered in this manner result in subversion of host-signalling pathways to facilitate bacterial entry, survival and dissemination to neighbouring cells and tissues. Whereas the secreted components of type III secretion systems (TTSSs) from different pathogens are structurally and functionally diverse, the structural components and the secretion apparatus itself are largely conserved. TTSSs are large macromolecular assemblies built through interactions between protein components of hundreds of individual subunits. The goal of this project was to screen, using the standard yeast two-hybrid system, pair-wise interactions between components of the enteropathogenic Escherichia coli TTSS. To this end 37 of the 41 genes encoded by the LEE pathogenicity island were cloned into both yeast two-hybrid system vectors and all possible permutations of interacting protein pairs were screened for. This paper reports the identification of 22 novel interactions, including interactions between inner-membrane structural TTSS proteins; between the type III secreted translocator protein EspD and structural TTSS proteins; between established and putative chaperones and their cognate secreted proteins; and between proteins of undefined function.

Bacterial Proteins↗

PubMed1988

The treatment of gonorrhea, syphilis, chancroid, lymphogranuloma venereum, and granuloma inguinale.

The "classic" venereal diseases are a diverse group of infections caused by established pathogens. Their epidemiologies are unique and relatively well understood. Likewise, the clinical presentations, although diverse, are well defined, allowing them to be readily suspected or diagnosed. Once the clinical diagnosis is considered, laboratory support methods are available to confirm the impression. This results in the provision of specific directed therapy that is curative. The spread of disease, however, must be considered, and the sexual partners must be identified, evaluated, and, where applicable, treated to prevent spread. The reinforcement of preventative methods is also an important aspect of controlling these infections.

Anti-Bacterial Agents↗

PubMed2004

Evidence for maintenance of sex by pathogens in plants.

The predominance of outcrossing despite the substantial transmission advantage of self-fertilization remains a paradox. Theory suggests that selection can favor outcrossing if it enables the production of offspring that are less susceptible to pathogen attack than offspring produced via self-fertilization. Thus, if pathogen pressure is contributing to the maintenance of outcrossing in plants, there may be a positive correlation between the number of pathogen species attacking plant species and the outcrossing rate of the plant species. We tested this hypothesis by examining the association between outcrossing rate and the number of fungal pathogen species that attack a large, taxonomically diverse set of seed plants. We show that plant species attacked by more fungal pathogen species have higher outcrossing rates than plants with fewer enemies. This relationship persists after correcting for study bias among natural and agricultural species of plants. We also accounted for the nested hierarchy of relationships among plant lineages by conducting phylogenetically independent contrasts (PICs) within genera and families that were adequately represented in our dataset. A meta-analysis of the correlation between pathogen and outcrossing PICs shows that there is a positive correlation between pathogen species number and outcrossing rates. This pattern is consistent with the hypothesis that pathogen-mediated selection may contribute to the maintenance of outcrossing in species of seed plants.

Fungi↗

PubMed2004

Expression library immunization to discover and improve vaccine antigens.

Genetic immunization is a novel method for vaccination in which DNA is delivered into the host to drive both cellular and humoral immune responses against its protein product. While genetic immunization can be potent, it requires that one have, in hand, a gene that encodes a protective protein antigen. Therefore, for many diseases, one cannot make a genetic vaccine because no protective antigen is known or no gene for this antigen is available. This lack of candidate antigens and their genes is a considerable bottleneck in developing new vaccines against old infectious agents, new emerging pathogens, and bioweapons. To address this limitation, we developed expression library immunization (ELI) as a high-throughput technology to discover vaccine candidate genes at will, by using the immune system to screen the entire genome of a pathogen for vaccine candidate. To date, ELI has discovered new vaccine candidates from a diverse set of bacterial, fungal, and parasitic pathogens. In addition, the process of applying ELI to the genome of pathogens allows one to genetically re-engineer these antigens to convert immunoevasive pathogen proteins into immunostimulatory vaccine antigens. Therefore, ELI is a potent technology to discover new vaccines and also generate genomic vaccines with amplified, multivalent immunostimulatory capacities.

Antigen Presentation↗

PubMed2006

The diverse antioxidant systems of Helicobacter pylori.

The gastric pathogen Helicobacter pylori induces a strong inflammatory host response, yet the bacterium maintains long-term persistence in the host. H. pylori combats oxidative stress via a battery of diverse activities, some of which are unique or newly described. In addition to using the well-studied bacterial oxidative stress resistance enzymes superoxide dismutase and catalase, H. pylori depends on a family of peroxiredoxins (alkylhydroperoxide reductase, bacterioferritin co-migratory protein and a thiol-peroxidase) that function to detoxify organic peroxides. Newly described antioxidant proteins include a soluble NADPH quinone reductase (MdaB) and an iron sequestering protein (NapA) that has dual roles - host inflammation stimulation and minimizing reactive oxygen species production within H. pylori. An H. pylori arginase attenuates host inflammation, a thioredoxin required as a reductant for many oxidative stress enzymes is also a chaperon, and some novel properties of KatA and AhpC were discovered. To repair oxidative DNA damage, H. pylori uses an endonuclease (Nth), DNA recombination pathways and a newly described type of bacterial MutS2 that specifically recognizes 8-oxoguanine. A methionine sulphoxide reductase (Msr) plays a role in reducing the overall oxidized protein content of the cell, although it specifically targets oxidized Met residues. H. pylori possess few stress regulator proteins, but the key roles of a ferric uptake regulator (Fur) and a post-transcriptional regulator CsrA in antioxidant protein expression are described. The roles of all of these antioxidant systems have been addressed by a targeted mutant analysis approach and almost all are shown to be important in host colonization. The described antioxidant systems in H. pylori are expected to be relevant to many bacterial-associated diseases, as genes for most of the enzymes carrying out the newly described roles are present in a number of pathogenic bacteria.

Animals↗

PubMed2006

Isolation of human antibody repertoires with preservation of the natural heavy and light chain pairing.

The humoral immune system in higher vertebrates is unique in its ability to generate highly diverse antibody responses against most pathogens as well as against certain malignancies. Several technologies have been developed to exploit this vast source of potentially therapeutic antibodies, including hybridoma technology, phage display and yeast display. Here, we present a novel, high-throughput technology (the Symplex Technology) for rapid direct cloning and identification of human antigen-specific high-affinity antibodies from single antibody-producing cells of immune individuals. The utility of the technology was demonstrated by isolation of diverse sets of unique high-affinity antibodies against tetanus toxoid and influenza virus from immunized volunteers. Hence, the Symplex Technology is a new method for the rapid isolation of high-affinity antibodies directly from humans.

Escherichia coli↗

PubMed2026

The Wild Soybean C3HC4-Type RING Zinc-Finger Protein ZFP4 Enhances Resistance to Soybean Mosaic Virus.

Soybean [Glycine max (L.) Merr.] is a globally important source of protein and edible oil, but is severely threatened by soybean mosaic virus (SMV). Wild soybean [Glycine soja Sieb. & Zucc.], the wild ancestor of cultivated soybean, exhibits high genetic diversity and strong resistance to pathogens. In this study, we identified a novel SMV resistance locus RSC7-4 and its candidate gene ZFP4 from wild soybean, encoding a C3HC4-type RING zinc-finger protein. The knockout mutants of ZFP4 showed enhanced susceptibility to SMV strains SC7 and SC3, while its overexpressing lines conferred resistance without yield penalty; ZFP4 mediates resistance by inhibiting GSTT1 to increase glutathione and reduce excessive reactive oxygen species accumulation. Domestication analysis revealed reduced genetic diversity of ZFP4 in cultivated soybean, with the resistant ZFP4Hap1 underutilized in breeding. In summary, this study provides not only excellent genetic resources for SMV-resistant soybean breeding but also new insights into the regulatory mechanisms of soybean resistance to SMV.

ZFP4↗

PubMed2006

The use of comparative genomic hybridization to characterize genome dynamics and diversity among the serotypes of Shigella.

BACKGROUND: Compelling evidence indicates that Shigella species, the etiologic agents of bacillary dysentery, as well as enteroinvasive Escherichia coli, are derived from multiple origins of Escherichia coli and form a single pathovar. To further understand the genome diversity and virulence evolution of Shigella, comparative genomic hybridization microarray analysis was employed to compare the gene content of E. coli K-12 with those of 43 Shigella strains from all lineages. RESULTS: For the 43 strains subjected to CGH microarray analyses, the common backbone of the Shigella genome was estimated to contain more than 1,900 open reading frames (ORFs), with a mean number of 726 undetectable ORFs. The mosaic distribution of absent regions indicated that insertions and/or deletions have led to the highly diversified genomes of pathogenic strains. CONCLUSION: These results support the hypothesis that by gain and loss of functions, Shigella species became successful human pathogens through convergent evolution from diverse genomic backgrounds. Moreover, we also found many specific differences between different lineages, providing a window into understanding bacterial speciation and taxonomic relationships.

DNA, Bacterial↗