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PubMed2003

Application of proteomics to Pseudomonas aeruginosa.

The recent completion of the Pseudomonas Genome Project, in conjunction with the Pseudomonas Community Annotation Project (PseudoCAP) has fast-tracked our ability to apply the tools encompassed under the term 'proteomics' to this pathogen. Such global approaches will allow the research community to answer long-standing questions regarding the ability of Pseudomonas aeruginosa to survive diverse habitats, its high intrinsic resistance to antibiotics and its pathogenic nature towards humans. Proteomics provides an array of tools capable of confirming the expression of Open Reading Frames (ORF), the relative levels of their expression, the environmental conditions required for this expression and the sub-cellular location of the encoded gene-products. Since proteins are important cellular effectors, the biological questions we pose can be defined in terms of changes in protein expression detectable by separation to purity using two-dimensional gel electrophoresis (2-DGE) and relation to gene sequences via mass spectrometry. As such, we can compare strains with well-characterized phenotypic differences, growth under a variety of stresses, protein interactions and complexes and aid in defining proteins of unknown function. While the complete genome has only recently been finished, a number of studies have already utilized this information and examined various protein gene-products using proteomics. This review summarizes the application of proteomics to P. aeruginosa and highlights potential areas of future research, including overcoming the traditional technical limitations associated with 2-DGE. More focused approaches that target sub-cellular fractions ('sub-proteomes') prior to 2-DGE can provide further functional information. A review of current and previous proteomic projects on P. aeruginosa is presented, as well as theoretical considerations of the importance of sub-proteomic approaches to enhance these investigations.

Amino Acid Sequence↗

PubMed2006

Effects of species diversity on disease risk.

The transmission of infectious diseases is an inherently ecological process involving interactions among at least two, and often many, species. Not surprisingly, then, the species diversity of ecological communities can potentially affect the prevalence of infectious diseases. Although a number of studies have now identified effects of diversity on disease prevalence, the mechanisms underlying these effects remain unclear in many cases. Starting with simple epidemiological models, we describe a suite of mechanisms through which diversity could increase or decrease disease risk, and illustrate the potential applicability of these mechanisms for both vector-borne and non-vector-borne diseases, and for both specialist and generalist pathogens. We review examples of how these mechanisms may operate in specific disease systems. Because the effects of diversity on multi-host disease systems have been the subject of much recent research and controversy, we describe several recent efforts to delineate under what general conditions host diversity should increase or decrease disease prevalence, and illustrate these with examples. Both models and literature reviews suggest that high host diversity is more likely to decrease than increase disease risk. Reduced disease risk with increasing host diversity is especially likely when pathogen transmission is frequency-dependent, and when pathogen transmission is greater within species than between species, particularly when the most competent hosts are also relatively abundant and widespread. We conclude by identifying focal areas for future research, including (1) describing patterns of change in disease risk with changing diversity; (2) identifying the mechanisms responsible for observed changes in risk; (3) clarifying additional mechanisms in a wider range of epidemiological models; and (4) experimentally manipulating disease systems to assess the impact of proposed mechanisms.

Animals↗

PubMed1997

The role of human caliciviruses in epidemic gastroenteritis.

Members of the Caliciviridae family of small, positive-sense RNA viruses exhibit a broad host range. The Norwalk and Norwalk-like caliciviruses in this family are major etiologic agents of epidemic gastroenteritis in humans. This illness characteristically lasts 24-48 h and often occurs in group settings such as families, schools, institutions, or communities. The spread of the human caliciviruses is considered to be predominantly by person-to-person contact via the fecal-oral-route. However, the ingestion of calicivirus-contaminated food or water can result in large-scale common-source outbreaks. Many basic features concerning the biology and replication of the human caliciviruses are not known because they have not yet been grown in cell culture and the virus does not appear to replicate in animal models other than the chimpanzee. Sequence analysis of RT-PCR-generated DNA fragments derived from serotypically distinct reference strains (such as the Norwalk, Hawaii, and Snow Mountain viruses) and other circulating strains associated with gastroenteritis has provided evidence for marked genetic diversity among these viruses. Moreover, analysis of the antigenic relationships among these viruses using paired sera from individuals infected with well-characterized reference strains or from animals immunized with recombinant "virus-like particles" (VLPs) suggests that several serotypes of these viruses are circulating worldwide. The availability of molecular techniques for the detection of these fastidious viruses has enabled epidemiologic studies that have strengthened the association of human caliciviruses with acute gastroenteritis and has demonstrated a potential role for antigenic diversity in the natural history of these pathogens.

Animals↗

PubMed2004

LCMV-mediated hepatitis in rhesus macaques: WE but not ARM strain activates hepatocytes and induces liver regeneration.

Lymphocytic chorimeningitis virus (LCMV), the prototype arenavirus, and Lassa virus (LASV), causative agent of Lassa hemorrhagic fever (LHF), belong to the Old World group of the family Arenaviridae. Both viruses have extensive strain diversity and significant variations in lethality and pathogenicity for man and experimental animals. We have shown that the LHF-like infection of rhesus macaques with the WE strain of LCMV affects liver functions, induces hepatocyte proliferation, and causes a rise in IL-6 and soluble TNF receptors (sTNFR) concomitant with a rise in viremia. The levels of IL-6 and sTNFR can serve as an additional diagnostic tool for liver involvement in pathogenesis of arenavirus infection. Mucosal inoculation of rhesus macaques with LCMV-WE can result in attenuated infection with a transient viremia and liver enzyme abnormalities. The ARM strain of LCMV shares 88% amino acid homology with WE. In contrast to LCMV-WE, ARM strain does not induce manifested disease in monkeys, does not affect liver functions, and does not induce hepatocyte proliferation. Previously we demonstrated that LCMV-ARM infection protected rhesus macaques challenged with LCMV-WE. Here we have shown that the protected animals have no signs of hepatitis and hepatocyte proliferation.

Animals↗

PubMed1995

Differences in peptide binding of DR11 and DR13 microvariants demonstrate the power of minor variation in generating DR functional diversity.

The influence of subtle HLA diversification on antigen binding was explored using murine L-cell transfectants expressing alleles in the DR11/DR13 family and a panel of peptides. The levels of binding among this family of DR microvariants were as diverse as the levels of binding among distantly related DR molecules. Even a single amino acid difference between allelic products had a profound effect on peptide binding. Specific amino acid substitutions, generated using site-directed mutagenesis to alter polymorphic residues at DR beta 32, 37, 57, 58, 67, 71, 86, demonstrated that a specific change within the context of a single DR molecule differed in its effect on the binding of specific peptides. In addition, a specific amino acid substitution had a differential effect on the binding level of a peptide to different DR molecules. Each polymorphic amino acid appeared to play a role in the binding of some peptide. Studies using the amino-terminal portion of the invariant chain CLIP peptide suggested that this peptide may offer varying degrees of competition in the binding of the cellular peptide pool in cells expressing different DR molecules. Finally, the results obtained with two strain-specific peptides from an immunodominant region of a malarial parasite show differential binding to two DR13 molecules, suggesting that immune pressure may promote parasite diversity. A dynamic interaction may exist between pathogens and the immune system shaping the HLA profile in a population. Thus even subtle diversification of the HLA molecules, possibly pathogen driven, can have a substantial effect on peptide binding and immune recognition.

Alleles↗

PubMed2004

Skin infections and ageing.

Elderly individuals have an increased susceptibility to skin infections due to age-related anatomical, physiological and environmental factors. The types of organisms that cause primary skin and soft tissue infections are diverse, and include bacterial, viral and fungal pathogens as well as parasites. In the elderly, these infections and infestations may present with atypical signs and symptoms or may complicate underlying chronic skin disorders. Clinical features, investigations and management of the following important and common skin infections are described in more detail: cellulitis, erysipelas, necrotizing fasciitis, impetigo, folliculitis, furunculosis and carbunculosis, erythrasma, herpes zoster and postherpetic neuralgia, herpes simplex, warts, molluscum contagiosum, dermatophytosis of the skin, hair and nails, candidiasis, and scabies. Treatment should be based on the results of the appropriate diagnostic tests. Correct diagnosis and therapy of skin infections lead to satisfactory outcome in the majority of elderly patients.

Aging↗

PubMed2004

The evolution of HIV and its consequences.

Since the beginning of the AIDS epidemic in 1981, HIV-1 has demonstrated an amazing ability to mutate. HIV-1 was introduced into the human population in the early to mid twentieth century in central Africa. During ensuing decades, this extraordinary mutational capacity has resulted in the circulation of HIV-1 strains that are quite different from one another, yet still remarkably pathogenic. The potential impact of this viral diversity on treatment, monitoring,and vaccine development is discussed.

AIDS Vaccines↗

PubMed2026

Whole genome sequencing reveals the co-existence of blaPER-7, blaADC-52 and blaOXA-91 in multidrug resistant ST164pas/ST234oxfAcinetobacter baumannii strains in Bangladesh.

OBJECTIVE: Acinetobacter baumannii (A. baumannii) has emerged as a critical multidrug-resistant (MDR) pathogen with the capacity to persist in diverse ecological niches. Environmental reservoirs in densely populated settings such as Dhaka, Bangladesh, may play a significant role in sustaining and disseminating antimicrobial resistance (AMR). This study aimed to characterize the genomic and phenotypic features of MDR A. baumannii isolates recovered from urban water bodies. METHODS: Three environmental isolates of A. baumannii were subjected to antimicrobial susceptibility testing, biofilm and serum resistance assays, whole-genome sequencing and analysis. Comprehensive genome analysis was carried out emphasizing on antimicrobial resistance genes, virulence factor genes, multi-locus sequence type, integron, prophage and mobile genetic elements. RESULTS: Phenotypically, all the three isolates showed serum resistance and biofilm forming capacity. All the three isolates were identified as ST164pas/ST234oxf. The antimicrobial resistance genes investigation revealed that all the three isolates had co-existence of beta lactam resistance genes blaPER-7, blaADC-52 and blaOXA-91. The isolates had gyrA (S81L) and parC (V104I/D105E) mutations associated with fluoroquinolone resistance. Several prophage regions were found in the strains and A. baumannii ML1 harbored AMR genes inside prophage regions. All the isolates harbored integron 1 in their genome. Comparative genome analysis of the Bangladeshi ST164pas/ST234oxf strains revealed a high degree of genomic conservation. CONCLUSION: The findings from this study highlighted environmental water bodies as reservoirs for MDR A. baumannii and emphasize the need for targeted One Health surveillance and improved wastewater management to limit resistance dissemination.

Journal Article↗

PubMed2005

Evidence for structural plasticity of heavy chain complementarity-determining region 3 in antibody-ssDNA recognition.

Anti-DNA antibodies play important roles in the pathogenesis of autoimmune diseases. They also represent a unique and relatively unexplored class of DNA-binding protein. Here, we present a study of conformational changes induced by DNA binding to an anti-ssDNA Fab known as DNA-1. Three crystal structures are reported: a complex of DNA-1 bound to dT3, and two structures of the ligand-free Fab. One of the ligand-free structures was determined from crystals exhibiting perfect hemihedral twinning, and the details of structure determination are provided. Unexpectedly, five residues (H97-H100A) in the apex of heavy chain complementarity-determining region 3 (HCDR3) are disordered in both ligand-free structures. Ligand binding also caused a 2-4A shift of the backbone of Tyr L92 and ordering of the L92 side-chain. In contrast, these residues are highly ordered in the Fab/dT3 complex, where Tyr H100 and Tyr H100A form intimate stacking interactions with DNA bases, and L92 forms the 5' end of the binding site. The structures suggest that HCDR3 is very flexible and adopts multiple conformations in the ligand-free state. These results are discussed in terms of induced fit and pre-existing equilibrium theories of ligand binding. Our results allow new interpretations of existing thermodynamic and mutagenesis data in terms of conformational entropy and the volume of conformational space accessible to HCDR3 in the ligand-free state. In the context of autoimmune disease, plasticity of the ligand-free antibody could provide a mechanism by which anti-DNA antibodies bind diverse host ligands, and thereby contribute to pathogenicity.

Antibodies, Antinuclear↗

PubMed2005

Neutral-red reaction is related to virulence and cell wall methyl-branched lipids in Mycobacterium tuberculosis.

Searching for virulence marking tests for Mycobacterium tuberculosis, Dubos and Middlebrook reported in 1948 that in an alkaline aqueous solution of neutral-red, the cells of the virulent H37Rv M. tuberculosis strain fixed the dye and became red in color, whereas the cells of the avirulent H37Ra M. tuberculosis strain remained unstained. In the 1950 and 1960s, fresh isolates of M. tuberculosis were tested for this neutral-red cytochemical reaction and it was reported that they were neutral-red positive, whereas other mycobacteria of diverse environmental origins that were non-pathogenic for guinea pigs were neutral-red negative. However, neutral-red has not really been proven to be a virulence marker. To test if virulence is in fact correlated to neutral-red, we studied a clinical isolate of M. tuberculosis that was originally neutral-red positive but, after more than 1 year passing through culture mediums, turned neutral-red negative. We found that, in comparison to the original neutral-red positive strain, this neutral-red negative variant was attenuated in two murine models of experimental tuberculosis. Lipid analysis showed that this neutral-red negative natural mutant lost the capacity to synthesize pthiocerol dimycocerosates, a cell wall methyl-branched lipid that has been related to virulence in M. tuberculosis. We also studied the neutral-red of different gene-targeted M. tuberculosis mutants unable to produce pthiocerol dimycocerosates or other cell wall methyl-branched lipids such as sulfolipids, and polyacyltrehaloses. We found a negative neutral-red reaction in mutants that were deficient in more than one type of methyl-branched lipids. We conclude that neutral-red is indeed a marker of virulence and it indicates important perturbations in the external surface of M. tuberculosis cells.

Animals↗

PubMed2006

RAC/ROP GTPases: 'hubs' for signal integration and diversification in plants.

RAC/ROP GTPases are a family of plant-specific signaling molecules solely representing the Ras and Rho family of Ras-related G proteins in plants. RAC/ROPs potentially interact with cell surface-associated signal perception apparatus for a broad range of extracellular stimuli, including hormones, pathogen elicitors and abiotic stress, and mediate diverse cellular pathways in response to these signals. They are also known to interact with multiple effectors, affecting cellular and biochemical systems that regulate actin dynamics, reactive oxygen species production, proteolysis, and gene expression. RAC/ROPs are, thus, ideally suited as integrators for multiple signals and as coordinators of diverse cellular pathways to control growth, differentiation, development and defense responses. Recent findings that suggest how RAC/ROP signaling activity is regulated and how functional specificity can be achieved are discussed here.

Arabidopsis Proteins↗

PubMed2003

Discrepancy between macroscopic and microscopic transitional zones in Hirschsprung's disease with reference to the type of RET/GDNF/SOX10 gene mutation.

BACKGROUND/PURPOSE: Recent studies have found that Hirschsrung's disease is caused by diverse genomic abnormalities. To clarify whether these pathogenic variations influence the distribution and function of enteric ganglia, the authors studied the morphology of the macroscopic and microscopic transitional zone in Hirschsprung's disease with reference to the type of genetic mutation. METHODS: In 120 patients with Hirschsprung's disease, the location and morphology of the gut caliber change were recorded, and the enteric nervous system was investigated histologically using biopsy specimens. The DNA sequences of all the RET/GDNF/NTN and SOX10 coding regions were determined using the direct DyeDeoxy Terminator Cycle method. RESULTS: In RET mutation carriers, the gut caliber change was almost identical to the histologic transition in cases of short segment aganglionosis, whereas these were markedly dissociated in cases exhibiting extensive aganglionosis. In contrast, SOX10 mutation carriers had a very long histologic transition and exhibited no caliber change. CONCLUSIONS: The type of genetic mutation responsible for Hirschsprung's disease influences the postnatal distribution and function of enteric ganglia. The data on discrepancy between macroscopic and microscopic transitions may enable us to concentrate the sites of the leveling biopsy more accurately especially in cases of long type intestinal aganglionosis carrying RET gene mutation.

Colon↗

PubMed2002

Phage display as a novel screening method to identify extracellular proteins.

Extracellular proteins are involved in many diverse and essential cell functions and in pathogenic bacteria, and they may also serve as virulence factors. Therefore, there is a need for methods that identify the genes encoding this group of proteins in a bacterial genome. Here, we present such a method based on the phage display technology. A novel gene III-based phagemid vector, pG3DSS, was constructed that lacks the signal sequence which normally orientates the encoded fusion protein to the Escherichia coli cell membrane, where it is assembled into the phage particle. When randomly fragmented DNA is inserted into this vector, only phagemids containing an insert encoding a signal sequence will give rise to phage particles displaying a fusion protein. These phages also display an E-tag epitope in fusion with protein III, which enables isolation of phages displaying a fusion protein, using antibodies against the epitope. From a library constructed from Staphylococcus aureus chromosomal DNA, genes encoding secreted as well as transmembrane proteins were isolated, including adhesins, enzymes and transport proteins.

Amino Acid Sequence↗

PubMed1999

Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation.

Iron plays a central role in the metabolism of all cells. This is evident by its major contribution to many diverse functions, such as DNA replication, bacterial pathogenicity, photosynthesis, oxidative stress control and cell proliferation. In mammalian systems, control of intracellular iron homeostasis is largely due to posttranscriptional regulation of binding by iron-regulatory RNA-binding proteins (IRPs) to iron-responsive elements (IREs) within ferritin and transferrin receptor (TfR) mRNAs. the TfR transports iron into cells and the iron is subsequently stored within ferritin. IRP binding is under tight control so that it responds to changes in intracellular iron requirements in a coordinate manner by differentially regulating ferritin mRNA translational efficiency and TfR mRNA stability. Several different stimuli, as well as intracellular iron levels and oxidative stress, are capable of regulating these RNA-protein interactions. In this mini-review, we shall concentrate on the mechanisms underlying modulation of the interaction of IRPs and the ferritin IRE and its role in regulating ferritin gene expression.

Animals↗

PubMed2004

Pathogenic Escherichia coli.

Few microorganisms are as versatile as Escherichia coli. An important member of the normal intestinal microflora of humans and other mammals, E. coli has also been widely exploited as a cloning host in recombinant DNA technology. But E. coli is more than just a laboratory workhorse or harmless intestinal inhabitant; it can also be a highly versatile, and frequently deadly, pathogen. Several different E. coli strains cause diverse intestinal and extraintestinal diseases by means of virulence factors that affect a wide range of cellular processes.

Animals↗

PubMed2001

Mutation of luxS affects growth and virulence factor expression in Streptococcus pyogenes.

Adaptive responses of bacteria that involve sensing the presence of other bacteria are often critical for proliferation and the expression of virulence characteristics. The autoinducer II (AI-2) pathway has recently been shown to be a mechanism for sensing other bacteria that is highly conserved among diverse bacterial species, including Gram-positive pathogens. However, a role for this pathway in the regulation of virulence factors in Gram-positive pathogens has yet to be established. In this study, we have inactivated luxS, an essential component of the AI-2 pathway, in the Gram-positive pathogen Streptococcus pyogenes. Analyses of the resulting mutants revealed the aberrant expression of several virulence properties that are regulated in response to growth phase, including enhanced haemolytic activity, and a dramatic reduction in the expression of secreted proteolytic activity. This latter defect was associated with a reduced ability to secrete and process the precursor of the cysteine protease (SpeB) as well as a difference in the timing of expression of the protease. Enhanced haemolytic activity of the luxS strain was also shown to be linked with an increased expression of the haemolysin S-associated gene sagA. Disruptions of luxS in these mutants also produced a media-dependent growth defect. Finally, an allelic replacement analysis of an S. pyogenes strain with a naturally occurring insertion of IS1239 in luxS suggested a mechanism for modulation of virulence during infection. Results from this study suggest that luxS makes an important contribution to the regulation of S. pyogenes virulence factors.

Animals↗

PubMed2001

The incompatibility between the PlcR- and AtxA-controlled regulons may have selected a nonsense mutation in Bacillus anthracis.

Bacillus anthracis, Bacillus thuringiensis and Bacillus cereus are members of the Bacillus cereus group. These bacteria express virulence in diverse ways in mammals and insects. The pathogenic properties of B. cereus and B. thuringiensis in mammals results largely from the secretion of non-specific toxins, including haemolysins, the production of which depends upon a pleiotropic activator PlcR. In B. anthracis, PlcR is inactive because of a nonsense mutation in the plcR gene. This suggests that the phenotypic differences between B. anthracis on the one hand and B. thuringiensis and B. cereus on the other could result at least partly from loss of the PlcR regulon. We expressed a functional PlcR in B. anthracis. This resulted in the transcriptional activation of genes weakly expressed in the absence of PlcR. The transcriptional activation correlated with the induction of enzymatic activities and toxins including haemolysins. The toxicity of a B. anthracis PlcR+ strain was assayed in the mouse subcutaneous and nasal models of infection. It was no greater than that of the parental strain, suggesting that the PlcR regulon has no influence on B. anthracis virulence. The PlcR regulon had dramatic effects on the sporulation of a B. anthracis strain containing the virulence plasmid pXO1. This resulted from incompatible interactions with the major AtxA-controlled virulence regulon. We propose that the PlcR-controlled regulon in B. anthracis has been counterselected on account of its disadvantageous effects.

Animals↗

PubMed2002

The gene: the polymerase chain reaction and its clinical application.

Chromosomal DNA transfers and stores information regarding the structure and function of the cell. Genetic information, encoded within sequences of nucleotides that compose DNA, is grouped into functional units called genes. Genetic diseases are caused by changes in the chromosomal DNA, leading to a change in the quantity or function of the protein gene product. In the past, genetic diagnosis was limited by the availability of sufficient quantity and quality of DNA and the absence of an efficient amplification procedure. The polymerase chain reaction (PCR), an inexpensive, rapid, and accurate means of amplifying DNA, is already making a major contribution to the diagnostic sciences. PCR techniques have been widely used in diverse applications, including molecular analysis of microbial pathogens, inheritable diseases and syndromes, and neoplasms. The purpose of this article is to 1) Review gene structure and function, 2) review principles of PCR technology and its applications in molecular biology, and 3) discuss an experimental clinical application of PCR to identify novel infectious agents responsible for odontogenic infections.

Bacteria↗