Publications by authors named "Pierre Lechat"

18 Publications

  • Page 1 of 1

SHAMAN: a user-friendly website for metataxonomic analysis from raw reads to statistical analysis.

BMC Bioinformatics 2020 Aug 10;21(1):345. Epub 2020 Aug 10.

Hub de Bioinformatique et Biostatistique - Département Biologie Computationnelle, Institut Pasteur, USR 3756 CNRS, 28 Rue Du Docteur Roux, Paris, 75015, France.

Background: Comparing the composition of microbial communities among groups of interest (e.g., patients vs healthy individuals) is a central aspect in microbiome research. It typically involves sequencing, data processing, statistical analysis and graphical display. Such an analysis is normally obtained by using a set of different applications that require specific expertise for installation, data processing and in some cases, programming skills.

Results: Here, we present SHAMAN, an interactive web application we developed in order to facilitate the use of (i) a bioinformatic workflow for metataxonomic analysis, (ii) a reliable statistical modelling and (iii) to provide the largest panel of interactive visualizations among the applications that are currently available. SHAMAN is specifically designed for non-expert users. A strong benefit is to use an integrated version of the different analytic steps underlying a proper metagenomic analysis. The application is freely accessible at http://shaman.pasteur.fr/ , and may also work as a standalone application with a Docker container (aghozlane/shaman), conda and R. The source code is written in R and is available at https://github.com/aghozlane/shaman . Using two different datasets (a mock community sequencing and a published 16S rRNA metagenomic data), we illustrate the strengths of SHAMAN in quickly performing a complete metataxonomic analysis.

Conclusions: With SHAMAN, we aim at providing the scientific community with a platform that simplifies reproducible quantitative analysis of metagenomic data.
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http://dx.doi.org/10.1186/s12859-020-03666-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430814PMC
August 2020

JASS: command line and web interface for the joint analysis of GWAS results.

NAR Genom Bioinform 2020 Mar 24;2(1):lqaa003. Epub 2020 Jan 24.

Department of Computational Biology-USR 3756 CNRS, Institut Pasteur, 75015 Paris, France.

Genome-wide association study (GWAS) has been the driving force for identifying association between genetic variants and human phenotypes. Thousands of GWAS summary statistics covering a broad range of human traits and diseases are now publicly available. These GWAS have proven their utility for a range of secondary analyses, including in particular the joint analysis of multiple phenotypes to identify new associated genetic variants. However, although several methods have been proposed, there are very few large-scale applications published so far because of challenges in implementing these methods on real data. Here, we present JASS (Joint Analysis of Summary Statistics), a polyvalent Python package that addresses this need. Our package incorporates recently developed joint tests such as the omnibus approach and various weighted sum of -score tests while solving all practical and computational barriers for large-scale multivariate analysis of GWAS summary statistics. This includes data cleaning and harmonization tools, an efficient algorithm for fast derivation of joint statistics, an optimized data management process and a web interface for exploration purposes. Both benchmark analyses and real data applications demonstrated the robustness and strong potential of JASS for the detection of new associated genetic variants. Our package is freely available at https://gitlab.pasteur.fr/statistical-genetics/jass.
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http://dx.doi.org/10.1093/nargab/lqaa003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978790PMC
March 2020

Genome Dynamics during Environmental Adaptation Reveal Strain-Specific Differences in Gene Copy Number Variation, Karyotype Instability, and Telomeric Amplification.

mBio 2018 11 6;9(6). Epub 2018 Nov 6.

Unité de Parasitologiemoléculaire et Signalisation, Institut Pasteur, Paris, France

Protozoan parasites of the genus adapt to environmental change through chromosome and gene copy number variations. Only little is known about external or intrinsic factors that govern genomic adaptation. Here, by conducting longitudinal genome analyses of 10 new clinical isolates, we uncovered important differences in gene copy number among genetically highly related strains and revealed gain and loss of gene copies as potential drivers of long-term environmental adaptation in the field. In contrast, chromosome rather than gene amplification was associated with short-term environmental adaptation to culture. Karyotypic solutions were highly reproducible but unique for a given strain, suggesting that chromosome amplification is under positive selection and dependent on species- and strain-specific intrinsic factors. We revealed a progressive increase in read depth towards the chromosome ends for various isolates, which may represent a nonclassical mechanism of telomere maintenance that can preserve integrity of chromosome ends during selection for fast growth. Together our data draw a complex picture of genomic adaptation in the field and in culture, which is driven by a combination of intrinsic genetic factors that generate strain-specific phenotypic variations, which are under environmental selection and allow for fitness gain. Protozoan parasites of the genus cause severe human and veterinary diseases worldwide, termed leishmaniases. A hallmark of biology is its capacity to adapt to a variety of unpredictable fluctuations inside its human host, notably pharmacological interventions, thus, causing drug resistance. Here we investigated mechanisms of environmental adaptation using a comparative genomics approach by sequencing 10 new clinical isolates of the , , and complexes that were sampled across eight distinct geographical regions. Our data provide new evidence that parasites adapt to environmental change in the field and in culture through a combination of chromosome and gene amplification that likely causes phenotypic variation and drives parasite fitness gains in response to environmental constraints. This novel form of gene expression regulation through genomic change compensates for the absence of classical transcriptional control in these early-branching eukaryotes and opens new venues for biomarker discovery.
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http://dx.doi.org/10.1128/mBio.01399-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222132PMC
November 2018

Characterization of LE3 and LE4, the only lytic phages known to infect the spirochete Leptospira.

Sci Rep 2018 08 6;8(1):11781. Epub 2018 Aug 6.

Institut Pasteur, Unité Biologie des Spirochètes, Paris, France.

Leptospira is a phylogenetically unique group of bacteria, and includes the causative agents of leptospirosis, the most globally prevalent zoonosis. Bacteriophages in Leptospira are largely unexplored. To date, a genomic sequence is available for only one temperate leptophage called LE1. Here, we sequenced and analysed the first genomes of the lytic phages LE3 and LE4 that can infect the saprophyte Leptospira biflexa using the lipopolysaccharide O-antigen as receptor. Bioinformatics analysis showed that the 48-kb LE3 and LE4 genomes are similar and contain 62% genes whose function cannot be predicted. Mass spectrometry led to the identification of 21 and 23 phage proteins in LE3 and LE4, respectively. However we did not identify significant similarities with other phage genomes. A search for prophages close to LE4 in the Leptospira genomes allowed for the identification of a related plasmid in L. interrogans and a prophage-like region in the draft genome of a clinical isolate of L. mayottensis. Long-read whole genome sequencing of the L. mayottensis revealed that the genome contained a LE4 phage-like circular plasmid. Further isolation and genomic comparison of leptophages should reveal their role in the genetic evolution of Leptospira.
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http://dx.doi.org/10.1038/s41598-018-29983-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078989PMC
August 2018

LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition.

PLoS Pathog 2017 12 6;13(12):e1006725. Epub 2017 Dec 6.

Institut Pasteur, Unité Biologie et Génétique de la Paroi Bactérienne, Paris, France.

Leptospirosis is a widespread zoonosis, potentially severe in humans, caused by spirochetal bacteria, Leptospira interrogans (L. interrogans). Host defense mechanisms involved in leptospirosis are poorly understood. Recognition of lipopolysaccharide (LPS) and lipoproteins by Toll-Like Receptors (TLR)4 and TLR2 is crucial for clearance of leptospires in mice, yet the role of Nucleotide Oligomerization Domain (NOD)-like receptors (NOD)1 and NOD2, recognizing peptidoglycan (PG) fragments has not previously been examined. Here, we show that pathogenic leptospires escape from NOD1 and NOD2 recognition both in vitro and in vivo, in mice. We found that leptospiral PG is resistant to digestion by certain hydrolases and that a conserved outer membrane lipoprotein of unknown function, LipL21, specific for pathogenic leptospires, is tightly bound to the PG. Leptospiral PG prepared from a mutant not expressing LipL21 (lipl21-) was more readily digested than the parental or complemented strains. Muropeptides released from the PG of the lipl21- mutant, or prepared using a procedure to eliminate the LipL21 protein from the PG of the parental strain, were recognized in vitro by the human NOD1 (hNOD1) and NOD2 (hNOD2) receptors, suggesting that LipL21 protects PG from degradation into muropeptides. LipL21 expressed in E. coli also resulted in impaired PG digestion and NOD signaling. We found that murine NOD1 (mNOD1) did not recognize PG of L. interrogans. This result was confirmed by mass spectrometry showing that leptospiral PG was primarily composed of MurTriDAP, the natural agonist of hNOD1, and contained only trace amounts of the tetra muropeptide, the mNOD1 agonist. Finally, in transgenic mice expressing human NOD1 and deficient for the murine NOD1, we showed enhanced clearance of a lipl21- mutant compared to the complemented strain, or to what was observed in NOD1KO mice, suggesting that LipL21 facilitates escape from immune surveillance in humans. These novel mechanisms allowing L. interrogans to escape recognition by the NOD receptors may be important in circumventing innate host responses.
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http://dx.doi.org/10.1371/journal.ppat.1006725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764436PMC
December 2017

Listeriomics: an Interactive Web Platform for Systems Biology of .

mSystems 2017 Mar-Apr;2(2). Epub 2017 Mar 14.

Département de Biologie Cellulaire et Infection, Institut Pasteur, Unité des Interactions Bactéries-Cellules, Paris, France; INSERM, U604, Paris, France; INRA, USC2020, Paris, France.

As for many model organisms, the amount of omics data produced has recently increased exponentially. There are now >80 published complete genomes, around 350 different transcriptomic data sets, and 25 proteomic data sets available. The analysis of these data sets through a systems biology approach and the generation of tools for biologists to browse these various data are a challenge for bioinformaticians. We have developed a web-based platform, named Listeriomics, that integrates different tools for omics data analyses, i.e., (i) an interactive genome viewer to display gene expression arrays, tiling arrays, and sequencing data sets along with proteomics and genomics data sets; (ii) an expression and protein atlas that connects every gene, small RNA, antisense RNA, or protein with the most relevant omics data; (iii) a specific tool for exploring protein conservation through the phylogenomic tree; and (iv) a coexpression network tool for the discovery of potential new regulations. Our platform integrates all the complete species genomes, transcriptomes, and proteomes published to date. This website allows navigation among all these data sets with enriched metadata in a user-friendly format and can be used as a central database for systems biology analysis. In the last decades, has become a key model organism for the study of host-pathogen interactions, noncoding RNA regulation, and bacterial adaptation to stress. To study these mechanisms, several genomics, transcriptomics, and proteomics data sets have been produced. We have developed Listeriomics, an interactive web platform to browse and correlate these heterogeneous sources of information. Our website will allow listeriologists and microbiologists to decipher key regulation mechanism by using a systems biology approach.
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http://dx.doi.org/10.1128/mSystems.00186-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350546PMC
March 2017

Multiple major disease-associated clones of Legionella pneumophila have emerged recently and independently.

Genome Res 2016 11 23;26(11):1555-1564. Epub 2016 Sep 23.

Institut Pasteur, Biologie des Bactéries Intracellulaires, 75015, Paris, France.

Legionella pneumophila is an environmental bacterium and the leading cause of Legionnaires' disease. Just five sequence types (ST), from more than 2000 currently described, cause nearly half of disease cases in northwest Europe. Here, we report the sequence and analyses of 364 L. pneumophila genomes, including 337 from the five disease-associated STs and 27 representative of the species diversity. Phylogenetic analyses revealed that the five STs have independent origins within a highly diverse species. The number of de novo mutations is extremely low with maximum pairwise single-nucleotide polymorphisms (SNPs) ranging from 19 (ST47) to 127 (ST1), which suggests emergences within the last century. Isolates sampled geographically far apart differ by only a few SNPs, demonstrating rapid dissemination. These five STs have been recombining recently, leading to a shared pool of allelic variants potentially contributing to their increased disease propensity. The oldest clone, ST1, has spread globally; between 1940 and 2000, four new clones have emerged in Europe, which show long-distance, rapid dispersal. That a large proportion of clinical cases is caused by recently emerged and internationally dispersed clones, linked by convergent evolution, is surprising for an environmental bacterium traditionally considered to be an opportunistic pathogen. To simultaneously explain recent emergence, rapid spread and increased disease association, we hypothesize that these STs have adapted to new man-made environmental niches, which may be linked by human infection and transmission.
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http://dx.doi.org/10.1101/gr.209536.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088597PMC
November 2016

Intron retention-dependent gene regulation in Cryptococcus neoformans.

Sci Rep 2016 08 31;6:32252. Epub 2016 Aug 31.

Institut Pasteur, Unité Biologie des ARN des Pathogènes Fongiques, Département de Mycologie, F-75015, Paris, France.

The biological impact of alternative splicing is poorly understood in fungi, although recent studies have shown that these microorganisms are usually intron-rich. In this study, we re-annotated the genome of C. neoformans var. neoformans using RNA-Seq data. Comparison with C. neoformans var. grubii revealed that more than 99% of ORF-introns are in the same exact position in the two varieties whereas UTR-introns are much less evolutionary conserved. We also confirmed that alternative splicing is very common in C. neoformans, affecting nearly all expressed genes. We also observed specific regulation of alternative splicing by environmental cues in this yeast. However, alternative splicing does not appear to be an efficient method to diversify the C. neoformans proteome. Instead, our data suggest the existence of an intron retention-dependent mechanism of gene expression regulation that is not dependent on NMD. This regulatory process represents an additional layer of gene expression regulation in fungi and provides a mechanism to tune gene expression levels in response to any environmental modification.
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http://dx.doi.org/10.1038/srep32252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006051PMC
August 2016

Species- and Strain-Specific Adaptation of the HSP70 Super Family in Pathogenic Trypanosomatids.

Genome Biol Evol 2016 07 2;8(6):1980-95. Epub 2016 Jul 2.

Unité de Parasitologie moléculaire et Signalisation, Department of Parasites and Insect Vectors, Institut Pasteur and INSERM U1201, Paris, France

All eukaryotic genomes encode multiple members of the heat shock protein 70 (HSP70) family, which evolved distinctive structural and functional features in response to specific environmental constraints. Phylogenetic analysis of this protein family thus can inform on genetic and molecular mechanisms that drive species-specific environmental adaptation. Here we use the eukaryotic pathogen Leishmania spp. as a model system to investigate the evolution of the HSP70 protein family in an early-branching eukaryote that is prone to gene amplification and adapts to cytotoxic host environments by stress-induced and chaperone-dependent stage differentiation. Combining phylogenetic and comparative analyses of trypanosomatid genomes, draft genome of Paratrypanosoma and recently published genome sequences of 204 L. donovani field isolates, we gained unique insight into the evolutionary dynamics of the Leishmania HSP70 protein family. We provide evidence for (i) significant evolutionary expansion of this protein family in Leishmania through gene amplification and functional specialization of highly conserved canonical HSP70 members, (ii) evolution of trypanosomatid-specific, non-canonical family members that likely gained ATPase-independent functions, and (iii) loss of one atypical HSP70 member in the Trypanosoma genus. Finally, we reveal considerable copy number variation of canonical cytoplasmic HSP70 in highly related L. donovani field isolates, thus identifying this locus as a potential hot spot of environment-genotype interaction. Our data draw a complex picture of the genetic history of HSP70 in trypanosomatids that is driven by the remarkable plasticity of the Leishmania genome to undergo massive intra-chromosomal gene amplification to compensate for the absence of regulated transcriptional control in these parasites.
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http://dx.doi.org/10.1093/gbe/evw140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943205PMC
July 2016

Public T cell receptors confer high-avidity CD4 responses to HIV controllers.

J Clin Invest 2016 06 25;126(6):2093-108. Epub 2016 Apr 25.

The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure.
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http://dx.doi.org/10.1172/JCI83792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887161PMC
June 2016

Streptococcus agalactiae clones infecting humans were selected and fixed through the extensive use of tetracycline.

Nat Commun 2014 Aug 4;5:4544. Epub 2014 Aug 4.

Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.

Streptococcus agalactiae (Group B Streptococcus, GBS) is a commensal of the digestive and genitourinary tracts of humans that emerged as the leading cause of bacterial neonatal infections in Europe and North America during the 1960s. Due to the lack of epidemiological and genomic data, the reasons for this emergence are unknown. Here we show by comparative genome analysis and phylogenetic reconstruction of 229 isolates that the rise of human GBS infections corresponds to the selection and worldwide dissemination of only a few clones. The parallel expansion of the clones is preceded by the insertion of integrative and conjugative elements conferring tetracycline resistance (TcR). Thus, we propose that the use of tetracycline from 1948 onwards led in humans to the complete replacement of a diverse GBS population by only few TcR clones particularly well adapted to their host, causing the observed emergence of GBS diseases in neonates.
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http://dx.doi.org/10.1038/ncomms5544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538795PMC
August 2014

Comparison of widely used Listeria monocytogenes strains EGD, 10403S, and EGD-e highlights genomic variations underlying differences in pathogenicity.

mBio 2014 Mar 25;5(2):e00969-14. Epub 2014 Mar 25.

For nearly 3 decades, listeriologists and immunologists have used mainly three strains of the same serovar (1/2a) to analyze the virulence of the bacterial pathogen Listeria monocytogenes. The genomes of two of these strains, EGD-e and 10403S, were released in 2001 and 2008, respectively. Here we report the genome sequence of the third reference strain, EGD, and extensive genomic and phenotypic comparisons of the three strains. Strikingly, EGD-e is genetically highly distinct from EGD (29,016 single nucleotide polymorphisms [SNPs]) and 10403S (30,296 SNPs), and is more related to serovar 1/2c than 1/2a strains. We also found that while EGD and 10403S strains are genetically very close (317 SNPs), EGD has a point mutation in the transcriptional regulator PrfA (PrfA*), leading to constitutive expression of several major virulence genes. We generated an EGD-e PrfA* mutant and showed that EGD behaves like this strain in vitro, with slower growth in broth and higher invasiveness in human cells than those of EGD-e and 10403S. In contrast, bacterial counts in blood, liver, and spleen during infection in mice revealed that EGD and 10403S are less virulent than EGD-e, which is itself less virulent than EGD-e PrfA*. Thus, constitutive expression of PrfA-regulated virulence genes does not appear to provide a significant advantage to the EGD strain during infection in vivo, highlighting the fact that in vitro invasion assays are not sufficient for evaluating the pathogenic potential of L. monocytogenes strains. Together, our results pave the way for deciphering unexplained differences or discrepancies in experiments using different L. monocytogenes strains. IMPORTANCE Over the past 3 decades, Listeria has become a model organism for host-pathogen interactions, leading to critical discoveries in a broad range of fields, including bacterial gene regulation, cell biology, and bacterial pathophysiology. Scientists studying Listeria use primarily three pathogenic strains: EGD, EGD-e, and 10403S. Despite many studies on EGD, it is the only one of the three strains whose genome has not been sequenced. Here we report the sequence of its genome and a series of important genomic and phenotypic differences between the three strains, in particular, a critical mutation in EGD's PrfA, the main regulator of Listeria virulence. Our results show that the three strains display differences which may play an important role in the virulence differences observed between the strains. Our findings will be of critical relevance to listeriologists and immunologists who have used or may use Listeria as a tool to study the pathophysiology of listeriosis and immune responses.
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http://dx.doi.org/10.1128/mBio.00969-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977354PMC
March 2014

The intestinal microbiota interferes with the microRNA response upon oral Listeria infection.

mBio 2013 Dec 10;4(6):e00707-13. Epub 2013 Dec 10.

Institut Pasteur, Unité des Interactions Bactéries-Cellules, Paris, France.

Unlabelled: The intestinal tract is the largest reservoir of microbes in the human body. The intestinal microbiota is thought to be able to modulate alterations of the gut induced by enteropathogens, thereby maintaining homeostasis. Listeria monocytogenes is the agent of listeriosis, an infection transmitted to humans upon ingestion of contaminated food. Crossing of the intestinal barrier is a critical step of the infection before dissemination into deeper organs. Here, we investigated the role of the intestinal microbiota in the regulation of host protein-coding genes and microRNA (miRNA or miR) expression during Listeria infection. We first established the intestinal miRNA signatures corresponding to the 10 most highly expressed miRNAs in the murine ileum of conventional and germfree mice, noninfected and infected with Listeria. Next, we identified 6 miRNAs whose expression decreased upon Listeria infection in conventional mice. Strikingly, five of these miRNA expression variations (in miR-143, miR-148a, miR-200b, miR-200c, and miR-378) were dependent on the presence of the microbiota. In addition, as is already known, protein-coding genes were highly affected by infection in both conventional and germfree mice. By crossing bioinformatically the predicted targets of the miRNAs to our whole-genome transcriptomic data, we revealed an miRNA-mRNA network that suggested miRNA-mediated global regulation during intestinal infection. Other recent studies have revealed an miRNA response to either bacterial pathogens or commensal bacteria. In contrast, our work provides an unprecedented insight into the impact of the intestinal microbiota on host transcriptional reprogramming during infection by a human pathogen.

Importance: While the crucial role of miRNAs in regulating the host response to bacterial infection is increasingly recognized, the involvement of the intestinal microbiota in the regulation of miRNA expression has not been explored in detail. Here, we investigated the impact of the intestinal microbiota on the regulation of protein-coding genes and miRNA expression in a host infected by L. monocytogenes, a food-borne pathogen. We show that the microbiota interferes with the microRNA response upon oral Listeria infection and identify several protein-coding target genes whose expression correlates inversely with that of the miRNA. Further investigations of the regulatory networks involving miR-143, miR-148a, miR-200b, miR-200c, and miR-378 will provide new insights into the impact of the intestinal microbiota on the host upon bacterial infection.
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http://dx.doi.org/10.1128/mBio.00707-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870255PMC
December 2013

SynTView - an interactive multi-view genome browser for next-generation comparative microorganism genomics.

BMC Bioinformatics 2013 Sep 22;14:277. Epub 2013 Sep 22.

Institut Pasteur, Plate-forme Bioanalyse Génomique, 28 rue du Docteur Roux, Paris, Cedex 15 75724, France.

Background: Dynamic visualisation interfaces are required to explore the multiple microbial genome data now available, especially those obtained by high-throughput sequencing - a.k.a. "Next-Generation Sequencing" (NGS) - technologies; they would also be useful for "standard" annotated genomes whose chromosome organizations may be compared. Although various software systems are available, few offer an optimal combination of feature-rich capabilities, non-static user interfaces and multi-genome data handling.

Results: We developed SynTView, a comparative and interactive viewer for microbial genomes, designed to run as either a web-based tool (Flash technology) or a desktop application (AIR environment). The basis of the program is a generic genome browser with sub-maps holding information about genomic objects (annotations). The software is characterised by the presentation of syntenic organisations of microbial genomes and the visualisation of polymorphism data (typically Single Nucleotide Polymorphisms - SNPs) along these genomes; these features are accessible to the user in an integrated way. A variety of specialised views are available and are all dynamically inter-connected (including linear and circular multi-genome representations, dot plots, phylogenetic profiles, SNP density maps, and more). SynTView is not linked to any particular database, allowing the user to plug his own data into the system seamlessly, and use external web services for added functionalities. SynTView has now been used in several genome sequencing projects to help biologists make sense out of huge data sets.

Conclusions: The most important assets of SynTView are: (i) the interactivity due to the Flash technology; (ii) the capabilities for dynamic interaction between many specialised views; and (iii) the flexibility allowing various user data sets to be integrated. It can thus be used to investigate massive amounts of information efficiently at the chromosome level. This innovative approach to data exploration could not be achieved with most existing genome browsers, which are more static and/or do not offer multiple views of multiple genomes. Documentation, tutorials and demonstration sites are available at the URL: http://genopole.pasteur.fr/SynTView.
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http://dx.doi.org/10.1186/1471-2105-14-277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849071PMC
September 2013

Impact of lactobacilli on orally acquired listeriosis.

Proc Natl Acad Sci U S A 2012 Oct 24;109(41):16684-9. Epub 2012 Sep 24.

Unité des Interactions Bactéries-Cellules, Institut Pasteur, 75015 Paris, France.

Listeria monocytogenes is a foodborne pathogen that crosses the intestinal barrier and disseminates within the host. Here, we report a unique comprehensive analysis of the impact of two Lactobacillus species, Lactobacillus paracasei CNCM I-3689 and Lactobacillus casei BL23, on L. monocytogenes and orally acquired listeriosis in a gnotobiotic humanized mouse model. We first assessed the effect of treatment with each Lactobacillus on L. monocytogenes counts in host tissues and showed that each decreases L. monocytogenes systemic dissemination in orally inoculated mice. A whole genome intestinal transcriptomic analysis revealed that each Lactobacillus changes expression of a specific subset of genes during infection, with IFN-stimulated genes (ISGs) being the most affected by both lactobacilli. We also examined microRNA (miR) expression and showed that three miRs (miR-192, miR-200b, and miR-215) are repressed during L. monocytogenes infection. Treatment with each Lactobacillus increased miR-192 expression, whereas only L. casei association increased miR-200b and miR-215 expression. Finally, we showed that treatment with each Lactobacillus significantly reshaped the L. monocytogenes transcriptome and up-regulated transcription of L. monocytogenes genes encoding enzymes allowing utilization of intestinal carbon and nitrogen sources in particular genes involved in propanediol and ethanolamine catabolism and cobalamin biosynthesis. Altogether, these data reveal that the modulation of L. monocytogenes infection by treatment with lactobacilli correlates with a decrease in host gene expression, in particular ISGs, miR regulation, and a dramatic reshaping of L. monocytogenes transcriptome.
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http://dx.doi.org/10.1073/pnas.1212809109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478606PMC
October 2012

CandidaDB: a multi-genome database for Candida species and related Saccharomycotina.

Nucleic Acids Res 2008 Jan 26;36(Database issue):D557-61. Epub 2007 Nov 26.

Unité Biologie et Pathogénicité Fongiques, INRA USC2019, Institut Pasteur, Paris, France.

CandidaDB (http://genodb.pasteur.fr/CandidaDB) was established in 2002 to provide the first genomic database for the human fungal pathogen Candida albicans. The availability of an increasing number of fully or partially completed genome sequences of related fungal species has opened the path for comparative genomics and prompted us to migrate CandidaDB into a multi-genome database. The new version of CandidaDB houses the latest versions of the genomes of C. albicans strains SC5314 and WO-1 along with six genome sequences from species closely related to C. albicans that all belong to the CTG clade of Saccharomycotina-Candida tropicalis, Candida (Clavispora) lusitaniae, Candida (Pichia) guillermondii, Lodderomyces elongisporus, Debaryomyces hansenii, Pichia stipitis-and the reference Saccharomyces cerevisiae genome. CandidaDB includes sequences coding for 54 170 proteins with annotations collected from other databases, enriched with illustrations of structural features and functional domains and data of comparative analyses. In order to take advantage of the integration of multiple genomes in a unique database, new tools using pre-calculated or user-defined comparisons have been implemented that allow rapid access to comparative analysis at the genomic scale.
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http://dx.doi.org/10.1093/nar/gkm1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2238939PMC
January 2008

GenoList: an integrated environment for comparative analysis of microbial genomes.

Nucleic Acids Res 2008 Jan 21;36(Database issue):D469-74. Epub 2007 Nov 21.

Plate-forme Intégration et Analyse Génomiques, Pasteur Génopole Ile-de-France, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France.

The multitude of bacterial genome sequences being determined has generated new requirements regarding the development of databases and graphical interfaces: these are needed to organize and retrieve biological information from the comparison of large sets of genomes. GenoList (http://genolist.pasteur.fr/GenoList) is an integrated environment dedicated to querying and analyzing genome data from bacterial species. GenoList inherits from the SubtiList database and web server, the reference data resource for the Bacillus subtilis genome. The data model was extended to hold information about relationships between genomes (e.g. protein families). The web user interface was designed to primarily take into account biologists' needs and modes of operation. Along with standard query and browsing capabilities, comparative genomics facilities are available, including subtractive proteome analysis. One key feature is the integration of the many tools accessible in the environment. As an example, it is straightforward to identify the genes that are specific to a group of bacteria, export them as a tab-separated list, get their protein sequences and run a multiple alignment on a subset of these sequences.
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http://dx.doi.org/10.1093/nar/gkm1042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2238853PMC
January 2008