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Escherichia coli K1 is part of a reservoir of adherent, invasive facultative pathogens responsible for a wide range of human and animal disease including sepsis, meningitis, urinary tract infection and inflammatory bowel syndrome. A prominent virulence factor in these diseases is the polysialic acid capsular polysaccharide (K1 antigen), which is encoded by the kps/neu accretion domain inserted near pheV at 67 map units. Some E. coli K1 strains undergo form (phase) variation involving loss or gain of O-acetyl esters at carbon positions 7 or 9 of the individual sialic acid residues of the polysialic acid chains. Acetylation is catalysed by the receptor-modifying acetyl coenzyme-A-dependent O-acetyltransferase encoded by neuO, a phase variable locus mapping near the integrase gene of the K1-specific prophage, CUS-3, which is inserted in argW at 53.1 map units. As the first E. coli contingency locus shown to operate by a translational switch, further investigation of neuO should provide a better understanding of the invasive K1 pathotype. Minimal estimates of morbidity and economic costs associated with human infections caused by extraintestinal pathogenic E. coli strains such as K1 indicate at least 6.5 million cases with attendant medical costs exceeding 2.5 billion US dollars annually in the United States alone.
Mol Microbiol 2006 May
PMID:Mobile contingency locus controlling Escherichia coli K1 polysialic acid capsule acetylation. 1667 96

Streptococcus agalactiae[group B streptococcus (GBS)] is the leading cause of neonatal pneumonia, sepsis and meningitis. An in silico genome analysis indicated that GBS strain NEM316 encodes five putative sortases, including the major class A sortase enzyme and four class C sortases. The genes encoding the class C sortases are tandemly arranged in two different loci, srtC1-C2 and srtC3-C4, with a similar genetic organization and are thought to be involved in pilus biosynthesis. Each pair of sortase genes is flanked by LPXTG protein encoding genes, two upstream and one downstream, and a divergently transcribed regulatory gene located upstream from this locus. We demonstrated that strain NEM316 expresses only the srtC3-C4 locus, which encodes three surface proteins (Gbs1474, Gbs1477 and Gbs1478) that polymerize to form appendages resembling pili. Structural and functional analysis of this locus revealed that: (i) the transcriptional activator RogB is required for expression of the srtC3-C4 operon; (ii) Gbs1477, and either SrtC3 or SrtC4 are absolutely required for pilus biogenesis; and (iii) GBS NEM316 pili are composed of three surface proteins, Gbs1477, the bona fide pilin which is the major component, Gbs1474, a minor associated component, and Gbs1478, a pilus-associated adhesin. Surprisingly, pilus-like structures can be formed in the absence of the two minor components, i.e. the putative anchor Gbs1474 or the adhesin Gbs1478. Adherence assays showed that Gbs1478 confers adhesive capacity to the pilus. This study provides the first evidence that adhesive pili are also present in Gram-positive pathogens.
Mol Microbiol 2006 Jun
PMID:Assembly and role of pili in group B streptococci. 1679 77

Two main patterns of gene expression of Streptococcus pneumoniae were observed during infection in the host by quantitative real time RT-PCR; one was characteristic of bacteria in blood and one of bacteria in tissue, such as brain and lung. Gene expression in blood was characterized by increased expression of pneumolysin, pspA and hrcA, while pneumococci in tissue infection showed increased expression of neuraminidases, metalloproteinases, oxidative stress and competence genes. In vitro situations with similar expression patterns were detected in liquid culture and in a newly developed pneumococcal model of biofilm respectively. The biofilm model was dependent on addition of synthetic competence stimulating peptide (CSP) and no biofilm was formed by CSP receptor mutants. As one of the differentially expressed gene sets in vivo were the competence genes, we exploited competence-specific tools to intervene on pneumococcal virulence during infection. Induction of the competence system by the quorum-sensing peptide, CSP, not only induced biofilm formation in vitro, but also increased virulence in pneumonia in vivo. In contrast, a mutant for the ComD receptor, which did not form biofilm, also showed reduced virulence in pneumonia. These results were opposite to those found in a bacteraemic sepsis model of infection, where the competence system was downregulated. When pneumococci in the different physiological states were used directly for challenge, sessile cells grown in a biofilm were more effective in inducing meningitis and pneumonia, while planktonic cells from liquid culture were more effective in inducing sepsis. Our data enable us, using in vivo gene expression and in vivo modulation of virulence, to postulate the distinction - from the pneumococcal point of view - between two main types of disease. During bacteraemic sepsis pneumococci resemble planktonic growth, while during tissue infection, such as pneumonia or meningitis, pneumococci are in a biofilm-like state.
Mol Microbiol 2006 Sep
PMID:Switch from planktonic to sessile life: a major event in pneumococcal pathogenesis. 1692 54

The selective pressures leading to the evolution and maintenance of virulence in the case of facultative pathogens are quite unclear. For example, Escherichia coli, a commensal of the gut of warm-blooded animals and humans, can cause severe extraintestinal diseases, such as septicemia and meningitis, which represent evolutionary dead ends for the pathogen as they are associated to rapid host death and poor interhost transmission. Such infectious process has been linked to the presence of so-called "virulence genes." To understand the evolutionary forces that select and maintain these genes, we focused our study on E. coli B2 phylogenetic group strains that encompass both commensal and pathogenic (extra- and intraintestinal) strains. Multilocus sequence typing (MLST), comparative genomic hybridization of the B2 flexible gene pool, and quantification of extraintestinal virulence using a mouse model of septicemia were performed on a panel of 60 B2 strains chosen for their genetic and ecologic diversity. The phylogenetic history of the strains reconstructed from the MLST data indicates the emergence of at least 9 subgroups of strains. A high polymorphism is observed in the B2 flexible gene pool among the strains with a good correlation between the MLST-inferred phylogenetic history of the strains and the presence/absence of specific genomic regions, indicating coevolution between the chromosomal background and the flexible gene pool. Virulence in the mouse model is a highly prevalent and widespread character present in all subgroups except one. Association studies reveal that extraintestinal virulence is a multigenic process with a common set of "virulence determinants" encompassing genes involved in transcriptional regulation, iron metabolism, adhesion, lipopolysaccharide (LPS) biosynthesis, and the recently reported peptide polyketide hybrid synthesis system. Interestingly, these determinants can also be viewed as intestinal colonization and survival factors linked to commensalism as they can increase the fitness of the strains within the normal gut environment. Altogether, these data argue for an ancestral emergence of the extraintestinal virulence character that is a coincidental by-product of commensalism. Furthermore, the phenotypic and genotypic markers identified in this work will allow further epidemiological studies devoted to test the niche specialization hypothesis for the B2 phylogenetic subgroups.
Mol Biol Evol 2007 Nov
PMID:Extraintestinal virulence is a coincidental by-product of commensalism in B2 phylogenetic group Escherichia coli strains. 1770 33

Streptococcus pneumoniae is the agent responsible for infections such as pneumonia, otitis media, and meningitis. Among virulence factors, the Pneumococcal surface protein A (PspA) has been shown to be immunogenic and protective in mice, and is thus a good vaccine candidate. PspA has been classified into 6 clades and 3 families. Initially, pspA fragments, clades 1 and 3, were cloned into the pAE-6His expression vector. Proteins were expressed in Escherichia coli BL21(DE3) and purified by affinity and anion exchange chromatographies, with a yield of 11 mg/l of culture. Due to plasmid instability in E. coli, another construct using pspA1 was obtained based on pET-37b(+), which was shown to be stable in E. coli and increased the yield approximately 3-fold. Our results show good conditions for scale-up. Sera from immunized mice recognized PspA in total extracts of S. pneumoniae strains: anti-rPspA1p sera recognized native PspA clades 1 (+++), 2 (++) and 4 (+) and anti-rPspA3p sera recognized PspA clades 1 (+), 2 (+), 3 (+++) and 4 (+). The cross-reactivity pattern obtained confirms the notion that proteins from both families should be included for development of a broad-coverage vaccine; lower-cross reactivity between rPspAs of family 2 indicates that it may be necessary to include 2 proteins from this family.
Mol Biotechnol 2007 Oct
PMID:Optimizing expression of Streptococcus pneumoniae surface protein a, PspA: serocross-reactivity within families of antisera induced against clades 1 and 3. 1791 75

Extraintestinal pathogenic Escherichia coli are the cause of a diverse spectrum of invasive infections in humans and animals, leading to urinary tract infections, meningitis, or septicemia. In this study, we focused our attention on the identification of the outer membrane proteins of the pathogen in consideration of their important biological role and of their use as potential targets for prophylactic and therapeutic interventions. To this aim, we generated a DeltatolR mutant of the pathogenic IHE3034 strain that spontaneously released a large quantity of outer membrane vesicles in the culture supernatant. The vesicles were analyzed by two-dimensional electrophoresis coupled to mass spectrometry. The analysis led to the identification of 100 proteins, most of which are localized to the outer membrane and periplasmic compartments. Interestingly based on the genome sequences available in the current public database, seven of the identified proteins appear to be specific for pathogenic E. coli and enteric bacteria and therefore are potential targets for vaccine and drug development. Finally we demonstrated that the cytolethal distending toxin, a toxin exclusively produced by pathogenic bacteria, is released in association with the vesicles, supporting the recently proposed role of bacterial vesicles in toxin delivery to host cells. Overall, our data demonstrated that outer membrane vesicles represent an ideal tool to study Gram-negative periplasm and outer membrane compartments and to shed light on new mechanisms of bacterial pathogenesis.
Mol Cell Proteomics 2008 Mar
PMID:Proteomics characterization of outer membrane vesicles from the extraintestinal pathogenic Escherichia coli DeltatolR IHE3034 mutant. 1798 23

We are currently witnesses to and authors of a paradigm shift in neuropathology. While classical acute and chronic neuroinflammatory diseases such as meningitis or multiple sclerosis (MS) present aspects of neurodegeneration, the disease course of progressive degenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), or stroke-mediated neuronal deficit are demonstrably affected by inflammation. These insights have immediate consequences both for research methods and for the development of novel, more efficient therapies for these diseases. In this review, we analyze the inflammatory and degenerative pathological mechanisms in the brain with particular emphasis on the classical chronic inflammatory disease MS. We demonstrate that the latest pathological considerations not only require the application of advanced research technologies to investigate new pathomechanistic pathways, but also affect the investigation, development, and monitoring of novel potential therapeutic tools.
J Mol Med (Berl) 2008 Sep
PMID:New developments in understanding and treating neuroinflammation. 1819 12

Neisseria meningitidis is a major cause of both meningitis and septicemia. Typically, isolates are characterized by using a combination of immunological phenotyping, using monoclonal and polyclonal antisera, and Sanger nucleotide sequencing of epitope-encoding variable regions, although these methods can be both time-consuming and limited by reagent availability. Herein, we describe and evaluate a novel microarray to define the porB and porA serotypes of N. meningitidis by the resequencing of variable regions in a single hybridization reaction. PCR products for each gene were amplified, pooled in equimolar concentrations, hybridized to the microarray, and analyzed using Affymetrix GeneChip DNA Analysis Software. Resequencing of the microarray data was then validated by comparison with sequencing data. Molecular profiles were generated for 50 isolates that were combinations of phenotypically typeable (ie, PorA and PorB) and non-typeable (PorB only) isolates. Microarray-generated profiles from isolates with a PorB phenotype were concordant with predicted profiles compared with a previously described typing scheme. In addition, 42% (8 of 19) of previously non-typeable samples were assigned a PorB type when tested using the microarray. The remaining isolates were novel types for which no typing antisera are currently available. The porA data were 97% concordant with Sanger nucleotide sequencing. These results suggest that that microarray resequencing may be a useful tool for the characterization of meningococci, particularly for those isolates that cannot be phenotyped, offering an alternative to conventional sequencing methods.
J Mol Diagn 2008 May
PMID:Molecular characterization of Neisseria meningitidis isolates using a resequencing DNA microarray. 1837 24

Complement Factor I (CFI) is a regulator of the classical and alternative pathways. CFI has enzymatic activity and is able to cleave C3b and C4b. Homozygous Factor I deficiency is associated with infectious and/or autoimmune diseases. Here we describe the biochemical and genetic characterization in two Spanish families with complete Factor I deficiency. In Family 1, the propositus suffered from several episodes of meningitis for more than a year. Biochemical complement studies showed undetectable Factor I levels in the propositus and in her sister, while their parents and a brother had partial Factor I deficiency and were healthy. In Family 2, three out of five children were homozygous for Factor I deficiency, two of whom suffered from meningitis and the third one from several infections. The parents and the other two siblings were healthy and heterozygous for Factor I deficiency. Molecular studies showed that the two families had different mutations at exon 5 of the Factor I gene, which codifies for module LDLr1. One mutation corresponds to a 772G>A change at the donor splice site that was originally found in a family from Northern England. The second is a new missense mutation 739T>G, that generates a Cys to Gly change.
Mol Immunol 2008 May
PMID:Molecular characterization of Complement Factor I deficiency in two Spanish families. 1837 84

Cryptococcus neoformans (Cn) is the most common cause of fungal meningitis worldwide. In infected patients, growth of the fungus can occur within the phagolysosome of phagocytic cells, especially in non-activated macrophages of immunocompromised subjects. Since this environment is characteristically acidic, Cn must adapt to low pH to survive and efficiently cause disease. In the present work, we designed, tested, and experimentally validated a theoretical model of the sphingolipid biochemical pathway in Cn under acidic conditions. Simulations of metabolic fluxes and enzyme deletions or downregulation led to predictions that show good agreement with experimental results generated post hoc and reconcile intuitively puzzling results. This study demonstrates how biochemical modeling can yield testable predictions and aid our understanding of fungal pathogenesis through the design and computational simulation of hypothetical experiments.
Mol Syst Biol 2008
PMID:Mathematical modeling of pathogenicity of Cryptococcus neoformans. 1841 84


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