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Searched keyword : Leptospira
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Identification of Transcription Start Sites and small RNAs in Leptospira interrogans by transcriptome analysis
Leptospiral promoter regions are poorly characterized: experimentally proven transcription factor binding sites have not been described in the literature and promoter prediction algorithms and E. coli consensus sequences of DNA motifs are not appropriate for Leptospira. Identification of Transcription Start Sites (TSS) and promoters on a global scale will provide essential information on DNA motifs that are targets of RNA polymerases, sigma factors and transcription factors. RNA sequencing will also provide information on small regulatory RNAs. These small (~30-500 nt) non-coding RNAs (sRNAs) are an emerging class of post-transcriptional regulators which play a variety of important roles in many biological processes. Studies on sRNA regulation of gene expression in Leptospira are currently in their infancy. Our results will provide new insights into the transcriptional landscape of L. interrogans, including the repertoire of sRNA, and it will establish the foundation for future experimental work on gene regulation.
Recently 6 strains of Leptospira kirschneri ser grippotyphosa have been sequenced, assembled and annotated. These strains possess 99% genome similarity, but their provenance, virulence and growth characteristics remains different. We would like analyze the SNP of each strain using the SynTView/SNPView tool.
Pathogen leptospires are responsible for the zoonotic disease leptospirosis. This neglected but emerging infectious disease has a worldwide distribution and affects people from developing countries, mostly under tropical areas. The clinical manifestations of this infection range from a febrile state to a severe life-threatening form characterized by multiple organ hemorrhages. More than one million cases of leptospirosis are currently reported annually in the word, with 10% of mortality. During infection, Leptospira are confronted with dramatic adverse environmental changes such as deadly reactive oxygen species (ROS). Defenses against ROS, e.g. peroxidase activity, are crucial for Leptospira virulence. These defense mechanisms are controlled by PerR (Peroxide stress Regulator), which represses peroxidase-encoding genes. We study the role of PerR regulators in Leptospira virulence and adaptation to oxidative stress.
- The Institut Pasteur genomic taxonomy database of microbial strains (“Pasteur MLST”) is a free, publicly-accessible resource that hosts nucleotide sequence-based definitions of microbial strains, along with information on bacterial isolates (provenance data) and their genomic sequences. The Pasteur MLST database provides universal nomenclatures that are largely adopted for important pathogens (Klebsiella, Listeria, …), and represent a unifying language on strains for microbial population biology. - Unified strain taxonomies facilitate the coordinated international surveillance of bacterial pathogens. Several hundred research laboratories and public health agencies worldwide have deposited novel strain types, sequences and provenance data on their bacterial isolates. - Pasteur MLST is powered by the Open source GPL3 BIGSdb web application developed at Oxford University (Keith Jolley & Martin Maiden). (http://bigsdb.pasteur.fr ). Its evolution in terms of functionality is tightly linked to the developments of the software at Oxford U. Its evolution in terms of contents is managed by dedicated international teams of curators for each bacterial pathogenic species, coordinated by the PasteurMLST team. - The genomic taxonomies hosted at Pasteur MLST represent unique, authoritative resources that are highly valued by the community, as testified by the routine use of Pasteur MLST strain tags (e.g., K. pneumoniae ST258) in the scientific literature. Several labs (National Reference Centers or Units) of Institut Pasteur are coordinating the curation of genomic taxonomies (Klebsiella, Listeria, Corynebacteria, Bordetella, Leptospira, Yersinia, ...). The aim of the project is to obtain support from the C3BI HUB for the maintenance of the BIGSdb instance at Pasteur: deployment, upgrades, installation of API functionality developed by our partner, coping with future IT evolutions, ...
Leptospirosis is an emerging zoonotic disease, with high prevalence in tropical regions. It affects both wild and domestic animals, as well as humans, and it is disseminated by asymptomatic carriers, such as rats and mice, that contaminate water with urine. Its etiological agents are some species of the genus Leptospira, member of the phylum Spirochaetes, which are able to colonize hosts through skin injuries or mucous membranes. Once inside the host, the bacteria is able to disseminate quickly through blood and replicate inside the kidneys, provoking renal failure, hemorrhages, liver damage, among other severe potential complications. High-throughput sequencing technologies have allowed to reconstruct the genomes of hundreds of Leptospira strains, enabling comparative analyses which in turn have accelerated the understanding of the its biology. However, leptospirosis is still classified as a neglected disease and many aspects of Leptospira pathogenesis remain unknown. This project aims to strengthen and establish new collaborations between members of the Réseau International des Instituts Pasteur (RIIP) (the Institut Pasteur, France, and the Institut Pasteur Montevideo, Uruguay), in the context of an ongoing, more extensive PTR project entitled “Global diversity, genomic epidemiology and pathogen evolution of Leptospira spp.” (coordinator: Mathieu Picardeau). In the context of this PTR project, we have proposed that a PhD student from Montevideo (Ignacio Ferrés) spend a couple of months in Paris to develop some specific project goals. This internship will be directed by Dr. Mathieu Picardeau and will be performed under the supervision of Dr. Amine Ghozlane at the C3BI. Specifically, the goals of the internship are: 1) to uncover hidden Leptospira's genome diversity by analyzing public environmental metagenomics databases; and 2) to improve functional annotation of Leptospira genomes by applying comparative molecular modeling techniques developed by Dr. Ghozlane and collaborators.
Finely tuned sensory systems enable bacteria to sense and respond to fluctuating environments, coordinating adaptive changes in metabolic pathways and physiological outputs. For pathogenic Leptospira, signaling pathways allow a timely expression of virulence factors during the successive steps of infection of a mammal host. As the bacteria is excreted by its host, signaling pathways enable switching the expression towards factors promoting survival in the environment. A unifying theme across bacterial species is that biofilm formation coincides with the synthesis of the cellular signaling molecule bis-(3?-5?)-cyclic dimeric guanosine monophosphate (c-di-GMP) and this feature seems to be conserved in Leptospira. Our current work shows that the c-di-GMP regulation pathway is a major regulatory network involved in biofilm formation, virulence and motility in the pathogen Leptospira interrogans. Biofilm production and virulence expression is quite variable across the leptospira genus (highly virulent species, low virulent species and saprophytes species showing increase biofilm production). We would like to explore how the c-di-GMP metabolism, and the many genes associated with its synthesis, and degradation have evolved across the leptospira genus. We believe that understanding the evolutionary relationship of the c-di-GMP metabolism genes in the Leptospira genus would help us to understand the contribution of this second messenger to pathogenesis and biofilm formation in the Leptospira genus
Research of SNPs to explain the non virulent phenotype of a mutant of L. interrogans serovar Manilae L495 affecting the expression of a protein not involved in virulence
We are studying mutants of L. interrogans obtained after random mutagenesis (M58) along with complemented mutant strain (C5M58), constructed using a secondary random mutagenesis. The M58 mutant was found non virulent in gerbils and mice, but the C5M58 strain showing restored expression of the protein, is also non virulent. We have another mutant strain (M1901) in the same gene that retained its virulence, which is the expected phenotype. We are interested in findings SNPs present in both mutant M58 and complemented C5M58 strains that are absent from the parental L495 and M1901. This approach could give hints about the gene(s) involved in the loss of virulence.
Pathogen leptospires are responsible for the zoonotic disease leptospirosis. This neglected but emerging infectious disease has a worldwide distribution and affects people from developing countries, mostly under tropical areas. The clinical manifestations of this infection range from a febrile state to a severe life-threatening form characterized by multiple organ hemorrhages. More than one million cases of leptospirosis are currently reported annually in the word, with 10% of mortality. Leptospira penetrate hosts and rapidly disseminate to target organs (including kidney, liver, lungs) throughout the bloodstream. They are not obligatory intracellular pathogen but they can transiently persist inside macrophages. Due to the difficulty of gene inactivation in pathogen Leptospira, their study is hampered and limited. Thus, their virulence mechanisms and how they survive inside hosts remain largely unknown. During infection, Leptospira are confronted with dramatic adverse environmental changes such as deadly reactive oxygen species (ROS). Defenses against ROS, e.g. peroxidase activity, are crucial for Leptospira virulence. In previous studies, we have identified by RNASeq the cellular factors solicited by Leptospira interrogans to adapt to an oxidative stress and determined the regulons of the two peroxide stress regulators PerR1 and PerR2. We aim now at studying how small non coding RNAs participate in the adaptive response to oxidative stress in pathogen Leptospira. Regulation of any predicted small non coding RNAs will be examined in the RNASeq data we have already obtained.
Pathogen leptospires are responsible for the zoonotic disease leptospirosis. During infection, Leptospira are confronted with dramatic adverse environmental changes such as deadly reactive oxygen species (ROS). Defenses against ROS, e.g. peroxidase activity, are crucial for Leptospira virulence and the adaptive response to ROS is controlled by PerR regulators. We aim at studying how small non-coding RNA participate in the adaptive response to oxidative stress in pathogen Leptospira.
Study of the role of cyclic dimeric guanosine mono-phosphate (c-di-GMP) in the regulation of virulence and biofilm formation in Leptospira interrogans
Leptospirosis is a re-emerging zoonosis that affects more than one million people and causes nearly 60,000 deaths per year worldwide. This disease transmitted to humans via an environment contaminated by bacteria of the genus Leptospira has a record incidence in Oceania. Pathogenic leptospires are able to survive for several weeks in the environment. The production of a biofilm allows them to efficiently resist to hostile conditions and would explain their persistence in the environment. Our recent work has shown that the regulation of biofilm formation is under the control of cyclic di-GMP, an intracellular second messenger recognized as a signaling molecule coordinating the transition between motile (planktonic) and sessile (biofilm) life styles. This project aims to determine the role of cyclic di-GMP in the regulation of pathogenesis and biofilm formation in Leptospira interrogans in order to better understand the environmental survival of this pathogenic bacterium.
Pathogen leptospires are responsible for the zoonotic disease leptospirosis. This neglected but emerging infectious disease has a worldwide distribution and affects people from developing countries, mostly under tropical areas. The clinical manifestations of this infection range from a febrile state to a severe life-threatening form characterized by multiple organ hemorrhages. More than one million cases of leptospirosis are currently estimated annually in the word, with 10% of mortality. Pathogenic Leptospira are well-equipped to sustain the oxidative stress encountered when infecting their hosts. We aim at exploring the regulatory and genetic network allowing pathogenic Leptospira to adapt to superoxide, one of the deadly infection-related oxidants. We have obtained RNASeq data of Leptospira in the presence of superoxide and we aim at mapping the non-coding RNA that participate in the adaptive response to superoxide.