Reference number : GC-2017-Q1-02288, amendment number : , agreement type : G, recipient legal name : Savchenko, Alexei (University of Calgary), recipient country : CA, recipient province : nan, recipient city : Alberta, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : A range of pathogenic and symbiotic gram-negative bacteria, varying from root nodule causing Rhizobium to important animal and human pathogens such as Salmonella and Shigella rely on the collective function of specific set of proteins called &ldquo;effector&rdquo; for colonization of their eukaryotic hosts. Delivered by multi-protein secretion systems inside the host cell, effector proteins are able to manipulate a diverse range of eukaryotic targets and systems in favor of the bacteria&rsquo;s life style and to subdue the host immune response. Very distant bacterial species often possess representatives of the same effector family indicating that the general function of these effectors can be conserved whilst also being adapted to the distinct conditions found in their different eukaryotic hosts. 
The identification of molecular function of effector proteins is essential for our advance in understanding of bacteria-host interactions and development of novel antibacterial therapies. In addition, unparalleled ability of bacterial effectors to modulate selective eukaryotic cell processes though distinctive biochemical mechanisms holds enormous potential for application in emerging field of synthetic biology. However significant portion of identified effector proteins remain functionally and structurally annotated often due to the low sequence similarity with characterised protein families. 
Opportunistic intracellular pathogen &ndash; Legionella pneumophila encodes the largest &ldquo;effector&rdquo; arsenal or effectome consisting of more than 300 proteins delivered inside the host cell via type IV B Dot/Icm secretion system. While L. pneumophila has evolved as pathogen of fresh water amoebae it is able to colonise human alveolar macrophages causing severe pneumonia, which suggest that L. pneumophila effectome targets host functions conserved across evolutionary diverse eukaryotic cell types. Recent large-scale genomics study into diverse Legionella species identifies a small subset of L. pneumophila effectors (&ldquo;core effectome&rdquo;) conserved across all characterised representatives of this genus. The function of these &ldquo;core&rdquo; effectors is not known 
We suggest elucidating the host targets of L. pneumophila &ldquo;core effectome&rdquo; using in vivo studies in model system of budding yeast Saccharomyces cerevisiae, where effectors often trigger genetically tractable phenotypes. We would next pursue detailed biochemical and structural charaterisation of molecular function of L. pneumophila effectors using optimized methodologies developed by our group in course of functional and structural genomics initiatives. Combined these studies will allow to characterize in detail the core host cell modulator in Legionella opening up the opportunities to their use in synthetic biology and biotechnology applications., program purpose french : A range of pathogenic and symbiotic gram-negative bacteria, varying from root nodule causing Rhizobium to important animal and human pathogens such as Salmonella and Shigella rely on the collective function of specific set of proteins called &ldquo;effector&rdquo; for colonization of their eukaryotic hosts. Delivered by multi-protein secretion systems inside the host cell, effector proteins are able to manipulate a diverse range of eukaryotic targets and systems in favor of the bacteria&rsquo;s life style and to subdue the host immune response. Very distant bacterial species often possess representatives of the same effector family indicating that the general function of these effectors can be conserved whilst also being adapted to the distinct conditions found in their different eukaryotic hosts. 
The identification of molecular function of effector proteins is essential for our advance in understanding of bacteria-host interactions and development of novel antibacterial therapies. In addition, unparalleled ability of bacterial effectors to modulate selective eukaryotic cell processes though distinctive biochemical mechanisms holds enormous potential for application in emerging field of synthetic biology. However significant portion of identified effector proteins remain functionally and structurally annotated often due to the low sequence similarity with characterised protein families. 
Opportunistic intracellular pathogen &ndash; Legionella pneumophila encodes the largest &ldquo;effector&rdquo; arsenal or effectome consisting of more than 300 proteins delivered inside the host cell via type IV B Dot/Icm secretion system. While L. pneumophila has evolved as pathogen of fresh water amoebae it is able to colonise human alveolar macrophages causing severe pneumonia, which suggest that L. pneumophila effectome targets host functions conserved across evolutionary diverse eukaryotic cell types. Recent large-scale genomics study into diverse Legionella species identifies a small subset of L. pneumophila effectors (&ldquo;core effectome&rdquo;) conserved across all characterised representatives of this genus. The function of these &ldquo;core&rdquo; effectors is not known 
We suggest elucidating the host targets of L. pneumophila &ldquo;core effectome&rdquo; using in vivo studies in model system of budding yeast Saccharomyces cerevisiae, where effectors often trigger genetically tractable phenotypes. We would next pursue detailed biochemical and structural charaterisation of molecular function of L. pneumophila effectors using optimized methodologies developed by our group in course of functional and structural genomics initiatives. Combined these studies will allow to characterize in detail the core host cell modulator in Legionella opening up the opportunities to their use in synthetic biology and biotechnology applications., agreement title english : Mining the Legionella core “effectome” for molecular modulators of conserved eukaryotic cell signaling, agreement title french : Mining the Legionella core “effectome” for molecular modulators of conserved eukaryotic cell signaling, agreement number : RGPIN, agreement value : 140000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada