Reference number : GC-2017-Q1-01528, amendment number : , agreement type : G, recipient legal name : McKay, Derek (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 : The effects of parasitic helminths (worms) are felt in Canada, where domestic livestock, companion animals and humans can suffer from infection with helminths. As anti-worm drug resistance arises and spreads there is an unmet need for new approaches to parasitic helminths: they are of major socio-economic impact in Canada and globally in, for example, reduced animal well-being and productivity. Parasitic helminth and host have co-evolved and unraveling the bi-directional communication between the two will yield ways to enhance anti-worm responses and/or minimize co-morbidities. I use the tapeworm Hymenolepis diminuta -mouse model to define: (a) fundamental immune reactions aimed at eradicating the parasite; and, (2) mechanisms by which the helminth seeks to block the hosts' attempts to eliminate it. 
 Immunity consists of two main arms that function in unison to combat microbial and helminth infections: innate and adaptive. It is well-known that adaptive immunity is critical for the expulsion of worms from the gut; however, innate immunity initiates and directs adaptive immunity. Data on the innate immune response to helminth parasites is lacking. Addressing this gap in knowledge I focus on gut bacteria, the epithelium, and neutrophils as key elements of innate immunity that have been largely ignored with respect to infection with parasitic helminths: available data are descriptive and shed little light on if/how such changes in the gut affect the outcome of infection. Using cutting-edge methods and models established in my lab, or that of my collaborators, a series of studies will be conducted under the Guiding Hypothesis that analysis of the H. diminuta -mouse model will reveal novel aspects of immune regulation to advance knowledge of host-parasite interactions than can be translated into new approaches to parasitism and immune modulation. 
 
 Aims : 
 [1] To determine if, then how, infection with H. diminuta perturbs the gut bacteria and if these changes are important in the H. diminuta -elicited suppression of inflammation in the gut. 
 
 [2] To determine if H. diminuta directly affects epithelial cells to promote T-helper 2 immunity. 
 
 [3] To determine if exposure to H. diminuta -derived molecules promote development of a regulatory neutrophil (an acute inflammatory phagocyte typically associated with killing of bacteria and collateral damage to host tissue). 
 
 Outcome &amp; Significance . Preliminary data reveal that each of these innate immune elements are changed by, or directly respond to infection with H. diminuta or a crude extract of the worm. Defining how such changes mold adaptive immunity to promote worm expulsion can revolutionize how helminth-host interactions are viewed, ultimately impacting the development of novel strategies to manipulate the mammalian immune response to combat infection with helminth parasites, reduce tissue damage (or promote tissue repair) and manage any co-morbidity., program purpose french : The effects of parasitic helminths (worms) are felt in Canada, where domestic livestock, companion animals and humans can suffer from infection with helminths. As anti-worm drug resistance arises and spreads there is an unmet need for new approaches to parasitic helminths: they are of major socio-economic impact in Canada and globally in, for example, reduced animal well-being and productivity. Parasitic helminth and host have co-evolved and unraveling the bi-directional communication between the two will yield ways to enhance anti-worm responses and/or minimize co-morbidities. I use the tapeworm Hymenolepis diminuta -mouse model to define: (a) fundamental immune reactions aimed at eradicating the parasite; and, (2) mechanisms by which the helminth seeks to block the hosts' attempts to eliminate it. 
 Immunity consists of two main arms that function in unison to combat microbial and helminth infections: innate and adaptive. It is well-known that adaptive immunity is critical for the expulsion of worms from the gut; however, innate immunity initiates and directs adaptive immunity. Data on the innate immune response to helminth parasites is lacking. Addressing this gap in knowledge I focus on gut bacteria, the epithelium, and neutrophils as key elements of innate immunity that have been largely ignored with respect to infection with parasitic helminths: available data are descriptive and shed little light on if/how such changes in the gut affect the outcome of infection. Using cutting-edge methods and models established in my lab, or that of my collaborators, a series of studies will be conducted under the Guiding Hypothesis that analysis of the H. diminuta -mouse model will reveal novel aspects of immune regulation to advance knowledge of host-parasite interactions than can be translated into new approaches to parasitism and immune modulation. 
 
 Aims : 
 [1] To determine if, then how, infection with H. diminuta perturbs the gut bacteria and if these changes are important in the H. diminuta -elicited suppression of inflammation in the gut. 
 
 [2] To determine if H. diminuta directly affects epithelial cells to promote T-helper 2 immunity. 
 
 [3] To determine if exposure to H. diminuta -derived molecules promote development of a regulatory neutrophil (an acute inflammatory phagocyte typically associated with killing of bacteria and collateral damage to host tissue). 
 
 Outcome &amp; Significance . Preliminary data reveal that each of these innate immune elements are changed by, or directly respond to infection with H. diminuta or a crude extract of the worm. Defining how such changes mold adaptive immunity to promote worm expulsion can revolutionize how helminth-host interactions are viewed, ultimately impacting the development of novel strategies to manipulate the mammalian immune response to combat infection with helminth parasites, reduce tissue damage (or promote tissue repair) and manage any co-morbidity., agreement title english : Host-parasite interactions as a model to define immunological regulatory pathways, agreement title french : Host-parasite interactions as a model to define immunological regulatory pathways, agreement number : RGPIN, agreement value : 240000.0, 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