Project description DEENESFRITPL Investigating the role of viral 'hubs' in the spread of enteric infections Recent studies of infection in vivo and in vitro suggest that enteric viruses travel in groups, in inverted phosphatidylserine vesicles or at the surface of commensal bacteria. These multiple infection units (MIU) might increase the viral multiplicity of infection. The hypothesis of the EU-funded CM_GF project is that targeting MIU will inhibit enteric virus infection. The human norovirus (HNoV) is employed as a model to test the hypothesis that MIU promote HNoV infection. Researchers will develop an in vitro screening platform for small molecule inhibitors of the infection and identify bacterial species bound to HNoV in patients. Finally, they will test the efficacy of the identified inhibitors in the ex vivo and in vivo models. Show the project objective Hide the project objective Objective The last decade of research in enteric virus infection produced a body of compelling evidences that challenged the paradigm of the single infection unit, where a single virus is able to elicit infection of a target cell. Instead, observational studies of infection in vivo and in vitro suggest that enteric viruses travel in groups: in vesicles with inverted phosphatidylserine topology or at the surface of commensal bacteria. It has been proposed that both strategies increase locally the viral multiplicity of infection, thus favoring viral complementation of defective genomes. There is a lack of knowledge on the biological relevance of the so-called multiple infection unit (MIU) as it has not been mechanistically studied in physiologically relevant model of the GI tract. In addition, the MIU is a strategy employed by all the enteric viruses so far tested, therefore it might represent a valuable target for the design of broad spectrum therapeutics. The central hypothesis of this project is that targeting MIU will inhibit enteric virus infection ex vivo and in vivo. My model of enteric virus is human norovirus (HNoV) for its clinical relevance and for its well described interaction with commensal bacteria. In work package (WP)1, to gain insight on the biological relevance of MIU in ex vivo physiologically relevant models, I will test the hypothesis that MIU increases HNoV infection in human intestinal enteroids. In aim 2, I will develop an in vitro screening platform by pulldown assay with His-tagged HNoV virus-like particles to i) screen for small molecules inhibitors of the infection and ii) identify bacterial species that are bound to HNoV in stool derived from healthy volunteer and diseased patients (i.e. inflammatory bowel disease, Crohn) . In aim 3, in order to provide evidence that targeting MIU blocks viral infection, I will test the efficacy of the small molecules identified in aim 2 in the ex-vivo model established in aim 1 and/or in-vivo, in a murine model. Fields of science natural sciencesbiological sciencesmicrobiologybacteriologynatural sciencesbiological sciencesmicrobiologyvirologymedical and health sciencesclinical medicinegastroenterologyinflammatory bowel diseasenatural sciencesmathematicspure mathematicstopologynatural sciencesbiological sciencesgeneticsgenomes Keywords trans-kingdom interactions enteric viruses glycans antivirals Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2018 - Individual Fellowships Call for proposal H2020-MSCA-IF-2018 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator UNIVERSITAET zu LUEBECK Net EU contribution € 226 010,88 Address Ratzeburger allee 160 23562 Lubeck Germany See on map Region Schleswig-Holstein Schleswig-Holstein Lübeck, Kreisfreie Stadt Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Partners (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all Partner Partner organisations contribute to the implementation of the action, but do not sign the Grant Agreement. UNIVERSITY OF MICHIGAN THE REGENTS OF THE UNIVERSITY OF MICHIGAN United States Net EU contribution € 0,00 Address South street 3003 1068 46109 1274 Ann arbor See on map Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 144 607,68
