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Results for “Pathogen diversity”

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PubMed1999

Emergence of recombinant strains of Helicobacter pylori during human infection.

Genetic recombination can be important evolutionarily in speeding the adaptation of organisms to new environments and in purging deleterious mutations. Here, we describe polymerase chain reaction (PCR), hybridization and DNA sequence-based evidence of six such exchanges between two strains of Helicobacter pylori during natural mixed infection of a patient in Lithuania. One parent strain contained the 37 kb long, virulence-associated cag pathogenicity island (PAI), and the other strain lacked this PAI. Most H. pylori from the patient had descended from the cag+ parent, but had become cag- during infection. This had resulted from transfer of DNA containing the 'empty site' allele from the cag- strain and homologous recombination, not from excision of the cag PAI without DNA transfer. Other cases of recombination involved genes for an outer membrane protein (omp5 and omp29; also called HP0227 and HP1342) and a putative phosphoenolpyruvate synthase (ppsA; HP0121). Replacement of a short patch of DNA sequence (36-124 bp) was also seen. As the chance of forming any given recombinant is small, the abundance of recombinants in this patient suggests selection for particular recombinant genotypes during years of chronic infection. We suggest that genetic exchange among unrelated H. pylori strains, as documented here, is important because of the diversity of this gastric pathogen and its human hosts. Certain H. pylori recombinants may grow better in a given host than either parent. The vigour of growth, in turn, could impact on the severity of disease that infection can elicit.

Adolescent↗

PubMed2025

Insights into the origin, hybridisation and adaptation of Candida metapsilosis hybrid pathogens.

Hybridisation is a source of genetic diversity, can drive adaptation to new niches and has been found to be a frequent event in lineages harbouring pathogenic fungi. However, little is known about the genomic implications of hybridisation nor its impact on pathogenicity-related traits. A common limitation for addressing these questions is the narrow representativity of sequenced genomes, mostly corresponding to strains isolated from infected patients. The opportunistic human pathogen Candida metapsilosis is a hybrid that descends from the crossing between unknown parental lineages. Here, we sequenced the genomes of five new C. metapsilosis isolates, one representing the first African isolate for this species, and four environmental isolates from marine niches. Our comparative genomic analyses, including a total of 29 sequenced strains, shed light on the phylogenetic relationships between C. metapsilosis hybrid isolates and show that environmental strains are closely related to clinical ones and belong to different clades, suggesting multiple independent colonisations. Furthermore, we identify a new diverging clade likely emerging from the same hybridisation event that originated two other previously described hybrid clades. Lastly, we evaluate phenotypes relevant during infection such as drug susceptibility, thermotolerance or virulence. We identify low drug susceptibility phenotypes which we suggest might be driven by loss of heterozygosity events in key genes. We discover that thermotolerance is mainly clade-dependent and find a correlation with the faecal origin of some strains which highlights the adaptive potential of the fungus as commensal.

Humans↗

PubMed2000

Assembly of complex organelles: pilus biogenesis in gram-negative bacteria as a model system.

Pathogenic bacteria assemble a variety of adhesive structures on their surface for attachment to host cells. Some of these structures are quite complex. For example, the hair-like organelles known as pili or fimbriae are generally composed of several components and often exhibit composite morphologies. In gram-negative bacteria assembly of pili requires that the subunits cross the cytoplasmic membrane, fold correctly in the periplasm, target to the outer membrane, assemble into an ordered structure, and cross the outer membrane to the cell surface. Thus, pilus biogenesis provides a model for a number of basic biological problems including protein folding, trafficking, secretion, and the ordered assembly of proteins into complex structures. P pilus biogenesis represents one of the best-understood pilus systems. P pili are produced by 80-90% of all pyelonephritic Escherichia coli and are a major virulence determinant for urinary tract infections. Two specialized assembly factors known as the periplasmic chaperone and outer membrane usher are required for P pilus assembly. A chaperone/usher pathway is now known to be required for the biogenesis of more than 30 different adhesive structures in diverse gram-negative pathogenic bacteria. Elucidation of the chaperone/usher pathway was brought about through a powerful combination of molecular, biochemical, and biophysical techniques. This review discusses these approaches as they relate to pilus assembly, with an emphasis on newer techniques.

Fimbriae, Bacterial↗

PubMed2006

A Phytophthora infestans cystatin-like protein targets a novel tomato papain-like apoplastic protease.

There is emerging evidence that the proteolytic machinery of plants plays important roles in defense against pathogens. The oomycete pathogen Phytophthora infestans, the agent of the devastating late blight disease of tomato (Lycopersicon esculentum) and potato (Solanum tuberosum), has evolved an arsenal of protease inhibitors to overcome the action of host proteases. Previously, we described a family of 14 Kazal-like extracellular serine protease inhibitors from P. infestans. Among these, EPI1 and EPI10 bind and inhibit the pathogenesis-related (PR) P69B subtilisin-like serine protease of tomato. Here, we describe EPIC1 to EPIC4, a new family of P. infestans secreted proteins with similarity to cystatin-like protease inhibitor domains. Among these, the epiC1 and epiC2 genes lacked orthologs in Phytophthora sojae and Phytophthora ramorum, were relatively fast-evolving within P. infestans, and were up-regulated during infection of tomato, suggesting a role during P. infestans-host interactions. Biochemical functional analyses revealed that EPIC2B interacts with and inhibits a novel papain-like extracellular cysteine protease, termed Phytophthora Inhibited Protease 1 (PIP1). Characterization of PIP1 revealed that it is a PR protein closely related to Rcr3, a tomato apoplastic cysteine protease that functions in fungal resistance. Altogether, this and earlier studies suggest that interplay between host proteases of diverse catalytic families and pathogen inhibitors is a general defense-counterdefense process in plant-pathogen interactions.

Algal Proteins↗

PubMed1999

Diverse range of gene activity during Arabidopsis thaliana leaf senescence includes pathogen-independent induction of defense-related genes.

To determine the range of gene activities associated with leaf senescence, we have identified genes that show preferential transcript accumulation during this developmental stage. The mRNA levels of a diverse array of gene products increases during leaf senescence, including a protease, a ribosomal protein, two cinnamyl alcohol dehydrogenases, a nitrilase and glyoxalase II. Two of the genes identified are known to be pathogen-induced. The senescence specificity of each gene was determined by characterization of transcript accumulation during leaf development and in different tissues. The increased expression of nitrilase in senescent leaves is paralleled by an increase in free indole-3-acetic acid (IAA) levels. Additionally, we have demonstrated that the induction of defense-related genes during leaf senescence is pathogen-independent and that salicylic acid accumulation is not essential for this induction. Our data indicate that the induction of certain genes involved in plant defense responses is a component of the leaf senescence program.

Antifungal Agents↗

PubMed2000

Candida albicans RIM101 pH response pathway is required for host-pathogen interactions.

The ability of Candida albicans to respond to diverse environments is critical for its success as a pathogen. The RIM101 pathway controls gene expression and the yeast-to-hyphal transition in C. albicans in response to changes in environmental pH in vitro. In this study, we found that the RIM101 pathway is necessary in vivo for pathogenesis. First, we show that rim101(-)/rim101(-) and rim8(-)/rim8(-) mutants have a significant reduction in virulence using the mouse model of hematogenously disseminated systemic candidiasis. Second, these mutants show a marked reduction in kidney pathology. Third, the rim101(-)/rim101(-) and rim8(-)/rim8(-) mutants show defects in the ability to damage endothelial cells in situ. Finally, we show that an activated allele of RIM101, RIM101-405, is a suppressor of the rim8(-) mutation in vivo as it rescues the virulence, histological, and endothelial damage defects of the rim8(-)/rim8(-) mutant. These results demonstrate that the RIM101 pathway is required for C. albicans virulence in vivo and that the function of Rim8p in pathogenesis is to activate Rim101p.

Animals↗

PubMed2004

Genetic diversity and virulence potential of environmental Vibrio cholerae population in a cholera-endemic area.

To understand the evolutionary events and possible selection mechanisms involved in the emergence of pathogenic Vibrio cholerae, we analyzed diverse strains of V. cholerae isolated from environmental waters in Bangladesh by direct enrichment in the intestines of adult rabbits and by conventional laboratory culture. Strains isolated by conventional culture were mostly (99.2%) negative for the major virulence gene clusters encoding toxin-coregulated pilus (TCP) and cholera toxin (CT) and were nonpathogenic in animal models. In contrast, all strains selected in rabbits were competent for colonizing infant mice, and 56.8% of these strains carried genes encoding TCP alone or both TCP and CT. Ribotypes of toxigenic O1 and O139 strains from the environment were similar to pandemic strains, whereas ribotypes of non-O1 non-O139 strains and TCP(-) nontoxigenic O1 strains diverged widely from the seventh pandemic O1 and the O139 strains. Results of this study suggest that (i) the environmental V. cholerae population in a cholera-endemic area is highly heterogeneous, (ii) selection in the mammalian intestine can cause enrichment of environmental strains with virulence potential, (iii) pathogenicity of V. cholerae involves more virulence genes than currently appreciated, and (iv) most environmental V. cholerae strains are unlikely to attain a pandemic potential by acquisition of TCP and CT genes alone. Because most of the recorded cholera pandemics originated in the Ganges Delta region, this ecological setting presumably favors extensive genetic exchange among V. cholerae strains and thus promotes the rare, multiple-gene transfer events needed to assemble the critical combination of genes required for pandemic spread.

Animals↗

PubMed2006

The TolC homologue of Brucella suis is involved in resistance to antimicrobial compounds and virulence.

Brucella spp., like other pathogens, must cope with the environment of diverse host niches during the infection process. In doing this, pathogens evolved different type of transport systems to help them survive and disseminate within the host. Members of the TolC family have been shown to be involved in the export of chemically diverse molecules ranging from large protein toxins to small toxic compounds. The role of proteins from the TolC family in Brucella and other alpha-2-proteobacteria has been explored little. The gene encoding the unique member of the TolC family from Brucella suis (BepC) was cloned and expressed in an Escherichia coli mutant disrupted in the gene encoding TolC, which has the peculiarity of being involved in diverse transport functions. BepC fully complemented the resistance to drugs such as chloramphenicol and acriflavine but was incapable of restoring hemolysin secretion in the tolC mutant of E. coli. An insertional mutation in the bepC gene strongly affected the resistance phenotype of B. suis to bile salts and toxic chemicals such as ethidium bromide and rhodamine and significantly decreased the resistance to antibiotics such as erythromycin, ampicillin, tetracycline, and norfloxacin. Moreover, the B. suis bepC mutant was attenuated in the mouse model of infection. Taken together, these results suggest that BepC-dependent efflux processes of toxic compounds contribute to B. suis survival inside the host.

Animals↗

PubMed2006

Control of graft-versus-host disease by regulatory T cells: which level of antigen specificity?

Regulatory T cells (Tregs) are essential to suppress harmful self-reactive T cell responses. A paper in this issue of the European Journal of Immunology analyzes the role of Tregs in preventing syngeneic graft-versus-host disease (sGVHD). In this Commentary, we address the role of antigen specificity of Tregs in this context as well as future protocols for successful allogeneic grafts transplantation. Such ideal interventions will hopefully retain a diverse repertoire of pathogen-specific T cells, while maintenance of self-, foreign- and alloantigen-specific Tregs ensures life-long graft tolerance.

Animals↗

PubMed2006

Helicobacter pylori CagA -- a bacterial intruder conspiring gastric carcinogenesis.

Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is delivered from the bacterium into the cytoplasm of the bacterium-attached gastric epithelial cell via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, translocated CagA functions as a scaffolding adaptor that interacts with a number of host proteins involved in cell signaling in both tyrosine phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, of which gain-of-function mutations have recently been found in human malignancies. Through the complex formation, SHP-2 is catalytically activated and induces morphological transformation that is associated with increased cell motility. In addition to the perturbation of intracellular signaling, CagA disrupts the apical junctional complex that regulates the cell-cell contact and maintains the integrity of the epithelial structure. These CagA activities may collectively cause cellular dysfunctions that promote accumulation of multiple genetic changes involved in malignant transformation. Further elucidation of host cell signaling targeted by CagA should provide a new paradigm for 'bacterial carcinogenesis' and also give insights into general understanding of inflammation-mediated cancers. Clinically, detailed studies on the relationship between structural diversity and degree of pathogenic activity of CagA should make it possible to identify a high-risk group for gastric carcinoma among H. pylori-infected populations through cagA genotyping.

Adenocarcinoma↗

PubMed1992

Specific infectivity and host resistance have predicated potyviral and pathotype nomenclature but relate less to taxonomy.

The names of potyviruses and viral-strains have represented the occurrence of predominant pathotypes on predominant crop genotypes. Thus virus nomenclature, but not viral taxonomy, has been decisively influenced by plant-genotype susceptibility and indirectly by host genetic resistance. REsistance to infection (i.e., host range) continues to serve a practical role in differentiating recognized viruses. Plant genes that confer disease tolerance or viral resistance remain a principal means of viral pathotype differentiation, as well as a principal control measure against major viral pathogens. Degrees of genetic diversity among isolates of recognized viruses should not be underestimated, and any system of viral taxonomy should be prepared for flexibility at the species level.

Immunity, Innate↗

PubMed1996

Diversity of the polar lipids of the food-borne pathogen Listeria monocytogenes.

Listeria monocytogenes is a Gram-positive bacterium that can adapt to high salinity and cold. Because the membrane lipids may play a role in its survival and adaptation, we have examined the polar lipids of L. monocytogenes. Extraction of total lipids from L. monocytogenes yielded 7 +/- 1 mg/mL wet cells. Polar lipids represented 64% of total lipids and contained 9% lipid-phosphorus. Polar lipids were separated into 14 components by two-dimensional thin-layer chromatography. Eight components (88% of polar lipids) contained lipid-phosphorus; among these was one major component (34% of polar lipids). Two other phospholipids were ninhydrin-positive components and accounted for 15% of the polar lipids. Orcinol staining revealed two glyco- or sulfo-lipids accounting for 9% of polar lipids. Five components (4% of polar lipids) were amino components free of phosphorus. The major component contained 46% of its fatty acids as 15:0 anteiso, 24% as 17: 0 anteiso, and 11% as 15:0 iso. The fatty acid profile of the remaining polar lipids was variable, consisting primarily of 16:0, 18:0, 15:0 anteiso, and 17:0 anteiso. Their unsaturation level was < or = 20%; however, the major phosphoaminolipid component was 46% unsaturated. The ratios of 15:0 anteiso/17:0 anteiso and 15:0 anteiso/15:0 iso were similar in all classes, averaging 1.5 and 4.5, respectively. Since the adaptation process to stressful environments involves activation of a membrane transport system for the protectant glycine betaine, the membrane lipids may play a role in enabling transport.

Chromatography, High Pressure Liquid↗

PubMed2006

Revisiting the molecular evolutionary history of Shigella spp.

The theory that Shigella is derived from multiple independent origins of Escherichia coli (Pupo et al. 2000) has been challenged by recent findings that the virulence plasmids (VPs) and the chromosomes share a similar evolutionary history (Escobar-Paramo et al. 2003), which suggests that an ancestral VP entered an E. coli strain only once, which gave rise to Shigella spp. In an attempt to resolve these conflicting theories, we constructed three phylogenetic trees in this study: a robust chromosomal tree using 23 housekeeping genes from 46 strains of Shigella and enteroinvasive E. coli (EIEC), a chromosomal tree using 4 housekeeping genes from 19 EcoR strains and 46 Shigella/EIEC strains, and a VP tree using 5 genes outside of the VP cell-entry region from 38 Shigella/EIEC strains. Both chromosomal trees group Shigella into three main clusters and five outliers, and strongly suggest that Shigella has multiple origins within E. coli. Most strikingly, the VP tree shows that the VPs from two main Shigella clusters, C1 and C2, are more closely related, which contradicts the chromosomal trees that place C2 and C3 next to each other but C1 at a distance. Additionally, we have identified a complete tra operon of the F-plasmid in the genome sequence of an EIEC strain and found that two other EIEC strains are also likely to possess a complete tra operon. All lines of evidence support an alternative multiorigin theory that transferable diverse ancestral VPs entered diverse origins of E. coli multiple times during a prolonged period of time, resulting in Shigella species with diverse genomes but similar pathogenic properties.

Chromosomes, Bacterial↗

PubMedDate not supplied

Identification of gene sequences overexpressed in senescent and Werner syndrome human fibroblasts.

The phenotype of replicative senescence is a dominant trait in human diploid fibroblasts (HDF). Therefore, we have sought to identify overexpressed and/or newly expressed causal genes by constructing and screening a subtracted cDNA library derived from polyA+RNA of prematurely senescent Werner syndrome (WS) HDF. We have identified 15 cDNA clones that are overexpressed in senescent and WS HDF. Among them are six known sequences coding for: acid sphingomyelinase, fibronectin, SPARC, nm23-metastasis suppressor protein, and two translation factors, eIF-2 beta and EF-1 alpha. Among the 10 unknown clones are: S1-5, which encodes a secreted protein containing EGF-like domains and paradoxically stimulates DNA synthesis of young HDF in an autocrine and paracrine manner, S1-3, which encodes a protein containing "zinc finger" domains, suggesting nucleic acid binding properties; S1-15, which shows sequence similarities to human alpha 2-chimerin; and S2-6, which represents a new member of the LIM family of proteins. The other five clones do not have any significant homology to known sequences. Steady-state mRNA levels of all gene sequences thus far studied are elevated in both WS and senescent normal HDF when compared to young HDF, which suggests that senescent and WS HDF enter a final common pathway where multiple gene overexpression may generate diverse antiproliferative mechanisms and pathogenic sequelae.

Adult↗

PubMed1996

Characterization of Escherichia coli strains isolated from environmental water habitats and from stool samples of healthy volunteers.

This study was undertaken to determine the frequency of pathogenic Escherichia coli strains among wild-type E. coli strain isolates from the microbial flora of healthy volunteers and from natural residential water habitats of a defined geographic area. In total, 131 stool and 95 water isolates as well as 14 E.coli K12 strains were examined for DNA sequences specific for 20 different genes encoding E. coli pathogenicity factors, including adherence factors, toxins, invasins, capsules and iron uptake systems. The expression of the corresponding pathogenicity factors was also investigated. No pathogenicity factors were found to be present in the tested E. coli K12 strains. In contrast, 41.0% of the water samples and 63.4% of the stool samples contained pathogenicity factors specific for extraintestinal E. coli pathogens. While no virulence determinants specific for intestinal E. coli pathogens were found among the investigated environmental water isolates, 4.5% of the stool samples contained either only intestinal or both intestinal and extraintestinal virulence genes. Both the prevalence of the virulence genes and the expression of the corresponding pathogenicity factors were, in general, higher in stool than in water samples. These findings might indicate the prevalence of different clonal types and/or differential regulation of pathogenicity factor expression in diverse ecological niches.

Adult↗

PubMed2006

Re-shaping the T cell repertoire: TCR editing and TCR revision for good and for bad.

Protection against the universe of pathogens requires a functional, diverse T cell repertoire. However, the price that is paid for an evolved, effective immune system includes the potential danger of generating autoaggressive T cells. Autoimmune diseases result from inherent breach of tolerance to self-antigens leading to disruption of the regulatory to autoaggressive T cell homeostatic balance. The immune system has evolved mechanisms to control those processes. For T cells, positive and negative selection in the thymus assures that only fully functional, non-self-reactive T cells will populate the periphery. Failure of this central tolerance would result in autoaggressive T cells escaping into the periphery. However, other means of escaping negative selection can occur in the periphery, i.e., TCR revision, or the altering of TCR expression after thymic egress. Here the potential benefits, i.e., expansion and re-shaping of the T cell repertoire as potentiated by TCR editing and revision are considered. Furthermore, the potential to develop autoaggressive TCR and thus enhance autoimmunity is considered.

Animals↗

PubMed2005

Antifungal constituents of northern prickly ash, Zanthoxylum americanum mill.

Leaf, fruit, stem, bark and root of Zanthoxylum americanum were investigated for antifungal activity with 11 strains of fungi representing diverse opportunistic and systemic pathogens, including Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. All extracts demonstrated a broad spectrum of antifungal activity and inhibited at least eight fungal species in a disk diffusion assay (600 microg/disk). Antifungal activity was light-dependent, with fruit and leaf extracts most active in general. The presence of light-mediated compounds, such as psoralen, 8-methoxypsoralen and imperatorin in extracts of different organs was confirmed by RP-HPLC. A high furanocoumarin content was detected in fruit and leaf and low furanocoumarin levels were found in bark and wood. A high positive correlation was observed between total furanocoumarin content and fungal inhibition zones (r2=0.902, p<0.001). The results provide a phytochemical basis for the very widespread use of Z. americanum in indigenous North American ethnomedical tradition for conditions that may be related to fungal infections.

Antifungal Agents↗

PubMed2005

Toll-like receptors and their role in the trophoblast.

The aim of this review is to discuss the role of Toll-like receptors at the maternal-fetal interface and the capacity of trophoblast cells to initiate innate immune responses towards infection. The maternal-fetal interface represents an immunologically unique site that must promote tolerance to the allogenic fetus, whilst maintaining host defense against a diverse array of possible pathogens. Clinical studies have shown a strong association between certain complications of pregnancy and intrauterine infections. Therefore, innate immune responses against microorganisms at the maternal-fetal interface may have a significant impact on the success of a pregnancy. There is growing evidence that trophoblast cells are able to recognize and respond to pathogens through the expression of Toll-like receptors, an important part of innate immunity. This review will discuss the role of Toll-like receptors at the maternal-fetal interface, the potential for trophoblast cells to function as components of the innate immune system and the impact TLR-mediated trophoblast responses may have on pregnancy outcome.

Adult↗