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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - VIREX (Mumps VIRus EXploitation of the human adhesion receptor GPR125)

Teaser

Summary

Mumps virus is a re-emerging pathogen that causes painful inflammatory symptoms, such as parotitis
(salivary gland infection) and orchitis (testis infection). It is highly neurotropic with evidence of brain
infection in half of cases and clinical evidence in up to 10%. It is a small RNA virus belonging to the family
of paramyxoviridae that includes e.g. viruses for measles and pneumonia, all having a huge impact on global
economics and human health. Current vaccine programs have not managed to eliminate mumps and
infections occur also in vaccinated individuals.
Seven transmembrane (7TM) receptors are important drug targets. Large DNA viruses (herpes- and pox-)
assign large parts of their genomes to exploit 7TM receptors. No such mechanism has however yet been
described for small viruses.
We are in the process in this interdisciplinary project to test the groundbreaking hypothesis
that the adhesion 7TM receptor GPR125 is central for the organ damage caused by mumps virus via an
interaction with the mumps virus-encoded short-hydrophobic (SH)-protein.
We study:

1) the functional consequences of GPR125-SH-interaction at a single cell, organ and whole body level
within the context of mumps virus infection.
2) The structural requirements for the GPR125-mumps virus interaction using NMR and resolution of
crystal structure in preparation for future drug design.

This project has tremendous perspectives as SH-proteins are present also in other viruses. The SH-GPR125 complex might
thus represent a general principle for organ damage and a mode of action more generally amenable to
therapeutic interference.

Work performed

We established in vitro experiments to study the SH-protein/GPR125 interaction and to characterise the SH-protein.
Most importantly we discovered that the SH-protein encoded by mumps virus is a viroporin (membrane channel) and the activity can be inhibited by a viroporin inhibitor.
GPR125 is highly expressed in the blood-CSF barrier (choroid plexus, one of the blood brain barriers). To study mumps virus infected immune cells migrating through the choroid plexus we established choroid plexus organoids as new 3D in vitro model.

We established mouse models as in vivo model for our proof of concept studies to investigate if the SH-protein encoded by mumps virus is essential for virus entry into organs and for a general characterisation of the adhesion G protein-coupled receptor GPR125.

Final results

We are working with new method for example organoids as 3D in vitro models, as well as state of the art in vivo models, including injections of adeno-assicated virus for specific delivery of shRNA to knock down GPR125 in the choroid plexus of the mouse.

We expect to understand more at the end of the project about the general role of GPR125 and its potential barrier function and if the interaction of the mumps virus encoded SH-protein with GPR125 is essential for virus entry into organs.