CM_GF · Biological relevance of the multiple infection unit as a novel target for antiviral development
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-02-01 → 2022-10-31
- EU contribution
- €226,011
- Participants
- 2
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Biological relevance of the multiple infection unit as a novel target for antiviral development
Enteric viruses are a prevalent group of human pathogens with a great clinical and socio-economic impact. Recently, it has been described that in vivo infection by enteric viruses is dependent on the model of multiple infection unit (MIU), whereby multiple viral particles enter the target cell, and the chance of successful infection by complementation of defective particles is increased. The mechanisms by which enteric viruses achieve the MIU is i) by clustering in vesicles, ii) by binding indigenous bacteria of the gastrointestinal tract and iii) by aggregation. The aim of my project is to determine whether the multiple infectious unit model is a druggable target in vitro and in vivo by focusing on blocking the interaction between enteric viruses and indigenous bacteria. The positive impact of this work is the development of pan-viral small molecules that could curb infection of enteric viruses by blocking the MIU. The main objectives during the outgoing phase were the development of i) the MIU model in human intestinal enteroids and ii) the virus-bacteria screening platform.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- UNIVERSITAET zu LUEBECK · LubeckCoordinatorGermany
- REGENTS OF THE UNIVERSITY OF MICHIGAN · ANN ARBORUnited States
Links
Data: CORDIS, © European Union