Implication du ppGpp et du régulateur global CodY dans le déclenchement de la compétence chez streptococcus pneumoniae

Streptococcus pneumoniae (le pneumocoque) est une bactérie commensale, présente de façon asymptomatique dans le rhinopharynx de 20 % d'adultes et 50 % d'enfants. Cette bactérie peut devenir un pathogène majeur responsable de pneumonies, de méningites et de septicémies, et cause 1,5 million de morts chaque année dans le monde. Il existe deux méthodes de lutte : l'antibiothérapie et la vaccination. Ces deux stratégies se heurtent à la grande variabilité génétique du pneumocoque, essentiellement due à sa capacité à transformer naturellement. La transformation requiert le développement d'un état physiologique transitoire appelé compétence. Sa régulation met en jeu une boucle autocatalytique conduisant à l'expression des gènes de compétence. Mon travail de thèse a porté sur l'étude des mécanismes moléculaires responsables de l'initiation de la compétence. Des études menées au laboratoire ont montré l'implication indirecte de Ami (transport d'oligopeptides) dans la répression de la compétence. Les acides aminés transportés par Ami pourraient servir de jauge métabolique sentie par RelA (réponse stringente) ou par CodY. Nos résultats montrent que le ppGpp est un activateur de la compétence, mais cette molécule n'est pas le seul signal aboutissant au développement de la compétence, et que CodY pourrait être un répresseur de la compétence. De plus, nous avons montré que codY est essentiel et que son inactivation peut aboutir à la formation de structures mérodiploïdes. De plus, l'absence de CodY peut être compensée par la présence de 2 mutations, fatC et amiC, ou par d'autres mutations qui n'ont pas encore été identifiées.Streptococcus pneumoniae (the pneumococcus) is found in the nasopharynx of 20% of adults and 50% of children. The pneumococcus is a major pathogen, causing pneumonia, otitis media, meningitis and bacteriema. Every year, pneumococcal infections kill 1.5 million people worldwide. The two methods used to fight this pathogen (vaccination and antibiotherapy) can be bypassed by the high genetic variability of the pneumococcus. Natural genetic transformation is responsible for this variability and requires the pneumococcus to enter a transitory physiological state called competence. This state is based on an autocatalytic loop that induces the expression of the genes involved in competence. This thesis focusses on molecular mecanisms that lead to competence initiation in the pneumococcus. Studies carried out in our lab have shown that the Ami transporter is involved in competence regulation. Amino acids (intrenaliszed throught Ami) may be a metabolic gauge for competence regulation. Results show that ppGpp is involved in competence development activation but that other regulatory signals are also involved. The regulator CodY might be a competence repressor. On the other hand, this study has shown that codY is an essential gene and that its inactivation can lead to merodiploid formation. Furthermore, the absence of CodY can be compensated by the presence of two mutations, in the fatC and amiC genes, or by the presence of other mutations not yet characterized

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A transcription factor contributes to pathogenesis and virulence in streptococcus pneumoniae

To date, the role of transcription factors (TFs) in the progression of disease for many pathogens is yet to be studied in detail. This is probably due to transient, and generally low expression levels of TFs, which are the central components controlling the expression of many genes during the course of infection. However, a small change in the expression or specificity of a TF can radically alter gene expression. In this study, we combined a number of quality-based selection strategies including structural prediction of modulated genes, gene ontology and network analysis, to predict the regulatory mechanisms underlying pathogenesis of Streptococcus pneumoniae (the pneumococcus). We have identified two TFs (SP_0676 and SP_0927 [SmrC]) that might control tissue-specific gene expression during pneumococcal translocation from the nasopharynx to lungs, to blood and then to brain of mice. Targeted mutagenesis and mouse models of infection confirmed the role of SP_0927 in pathogenesis and virulence, and suggests that SP_0676 might be essential to pneumococcal viability. These findings provide fundamental new insights into virulence gene expression and regulation during pathogenesis.Layla K. Mahdi, Esmaeil Ebrahimie, David L. Adelson, James C. Paton, Abiodun D. Ogunniy

Implication du ppGpp et du régulateur global CodY dans le déclenchement de la compétence chez streptococcus pneumoniae

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Cost-Effectiveness Analysis of Haploidentical Vs Matched Unrelated Allogeneic Hematopoietic Stem Cells Transplantation in Patients Older Than 55 Years

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Socioeconomic deprivation is associated with decreased survival in patients with acute myeloid leukemia

Erratum inCorrigendum to "Socioeconomic deprivation is associated with decreased survival in patients with acute myeloid leukemia" [Cancer Epidemiol. 66 (2020) 101699].Le Floch AC, Eisinger F, D'Incan E, Rey J, Charbonnier A, Caymaris L, Stoler M, Mancini J, Boher JM, Sfumato P, Vey N.Cancer Epidemiol. 2020 Dec;69:101832. doi: 10.1016/j.canep.2020.101832. Epub 2020 Oct 14.PMID: 33067156 No abstract available.International audienceBackground: Socioeconomic deprivation is associated with poor prognosis in patients with solid tumors. However, few studies have assessed the association between socioeconomic parameters and prognosis in Acute Myeloid Leukemia (AML), and these report conflicting results. Our monocentric study assessed the impact of socioeconomic deprivation using the validated EPICES (Evaluation of Deprivation and Inequalities in Health Examination Centers) score in a prospective cohort of intensively treated AML patients.Methods: EPICES questionnaires were given to patients receiving intensive chemotherapy for newly diagnosed AML at the Paoli Calmettes Institute between July 2012 and December 2014. Study participants were categorized as non-deprived (score <30.17), deprived (score 30.17-48.51), or very-deprived (score ≥ 48.52). The primary endpoint was Overall Survival (OS). The independence of EPICES score effects was analyzed via Cox regression with adjustment for confounding factors.Results: 209 AML patients received the questionnaire, 149 (71.3 %) patients responded. The median EPICES score was 23.6; 26.8 % and 10.1 % of patients were deprived and very deprived, respectively. OS was 23.16 months (95 %CI [17.15-33.31]). According to multivariate analysis, a very-deprived EPICES score, European Leukemia Net categories, age, smoking, and the absence of allogeneic stem cell transplantation were independent factors associated with decreased OS.Conclusion: Our results underscore the importance of integrating nonbiological factors in the prognostic stratification of AML patients. The very deprived population exhibited worse OS, confirming that socioeconomic parameters play a role in patient outcomes in AML. Very deprived patients with AML should receive specific attention and adapted clinical management

Ecological and social basis for the development of a sand barrier breaching model in Laguna de Rocha, Uruguay

Special thanks to Hugo Inda for technical support, and to Carolina Cabrera and Lucía Nogueira for helping with the references. We also thank two anonymous reviewers for valuable comments and suggestions. This study was made possible through the partial financial support from DINAMA-UCC/SNAP (MVOTMA/Uruguay), Fundación de Amigos de las Lagunas Costeras de Rocha (Uruguay), Interamerican Institute for Global Change (IAI-CRN; 3038/SAFER Project), and International Development Research Centre (IDRC-Climate Change & Water Program; Grant 6923001).Sand barrier complex dynamics play a key role in defining coastal lagoon structure and functioning. Artificial manipulation of these dynamics for biased reasons (e.g., controlling floods, improving fisheries) aggravates conflicts between stakeholders and introduces potential threats to their conservation. This is the case at Laguna de Rocha, Uruguay, a protected area with international recognition, where the sand barrier opening has been the focus of a long-term conflict. A cooperative effort of scientists, authorities, and local stakeholders produced a breaching protocol, aimed to reduce conflicts while preserving the natural hydrodynamics of the system and its associated ecological processes. Historical information and present perceptions about the sand barrier breach were collected, and geomorphological and hydrological studies were carried out. Reconstruction of the historical management of the breaching practice showed that the artificial opening started in the 1950s and that the original procedure, performed by fishermen and cattle ranchers, was gradually left under to managers to, and it is presently performed with heavy machinery. Since the 1980s, inappropriate opening practices may have produced negative effects on the physical and biological structure of the lagoon. Geomorphological studies revealed the sand barrier as a highly vulnerable component of the lagoon and suggested that new opening sites could eventually develop over the long term, given the predictions of climate change and sea level rise. The hydrological approach provided an understanding of the processes driving the opening mechanism and the extent of the flooding of private and public lands. These results outlined the basis for the protocol, to support managers in deciding when to perform the opening, based on a reduced set of indicators (water depth, sand barrier berm elevation, and rainfall forecasts). Reaching a consensus was mainly based upon the existence, for more than 15 years, of a participatory advisory group discussing local environmental problems. The new sand barrier breaching protocol is a significant improvement over the previous situation, and can be generalized for application in similar contexts

Natural Genetic Transformation Generates a Population of Merodiploids in Streptococcus pneumoniae.

Contains fulltext : 119152.pdf (publisher's version ) (Open Access)Partial duplication of genetic material is prevalent in eukaryotes and provides potential for evolution of new traits. Prokaryotes, which are generally haploid in nature, can evolve new genes by partial chromosome duplication, known as merodiploidy. Little is known about merodiploid formation during genetic exchange processes, although merodiploids have been serendipitously observed in early studies of bacterial transformation. Natural bacterial transformation involves internalization of exogenous donor DNA and its subsequent integration into the recipient genome by homology. It contributes to the remarkable plasticity of the human pathogen Streptococcus pneumoniae through intra and interspecies genetic exchange. We report that lethal cassette transformation produced merodiploids possessing both intact and cassette-inactivated copies of the essential target gene, bordered by repeats (R) corresponding to incomplete copies of IS861. We show that merodiploidy is transiently stimulated by transformation, and only requires uptake of a approximately 3-kb DNA fragment partly repeated in the chromosome. We propose and validate a model for merodiploid formation, providing evidence that tandem-duplication (TD) formation involves unequal crossing-over resulting from alternative pairing and interchromatid integration of R. This unequal crossing-over produces a chromosome dimer, resolution of which generates a chromosome with the TD and an abortive chromosome lacking the duplicated region. We document occurrence of TDs ranging from approximately 100 to approximately 900 kb in size at various chromosomal locations, including by self-transformation (transformation with recipient chromosomal DNA). We show that self-transformation produces a population containing many different merodiploid cells. Merodiploidy provides opportunities for evolution of new genetic traits via alteration of duplicated genes, unrestricted by functional selective pressure. Transient stimulation of a varied population of merodiploids by transformation, which can be triggered by stresses such as antibiotic treatment in S. pneumoniae, reinforces the plasticity potential of this bacterium and transformable species generally