MuV causes the highly contagious mumps disease in children characterized by swollen salivary glands. In adults, it also infects gonadal tissue giving rise to orchitis and oophoritis, and in the long run causes infertility. MuV is highly neurotropic and the cause of meningitis and encephalitis, with signs of subclinical infections in up to 50% after vaccination. Like other paramyxovirinae, MuV is a small virus. It only encodes seven genes giving rise to nine proteins, one of them is the short hydrophobic (SH) protein which is a membrane protein of 57 residues (6.8 KDa). Like the SH proteins of related paramyxoviruses, MuV-SH is dispensable for virus growth in tissue culture. Nevertheless, it acts as a viral antagonist to the host's innate immune system, through inhibition tumor necrosis factor α (TNF-α) release from infected cells and prevention of TNF-α- and interleukin-1β (IL-1β) mediated nuclear factor κB (NF-κB) activation.
Seven transmembrane (7TM) G protein-coupled receptors (GPCRs) are important drug targets. Large DNA viruses (herpes- and pox-) assign large parts of their genomes to exploit GPCRs, however, no such mechanism has yet been described for small viruses (like the paramyxovirinae). The adhesion and barrier-forming receptor ADGRA3 (previously known as GPR125) is widely expressed in the human body with particularly high expression in the choroid plexus. Combined with the subclass B2 defining adhesive properties, this expression pattern is of particular interest, as the choroid plexus, besides being the organ that produces cerebrospinal fluid (CSF), constitutes the main epithelium in the BCSF barrier. The choroid plexus epithelium expresses specific transporter systems that combined with its pinocytotic activity regulate the transchoroidal crossing of substances into the ventricles. We have previously developed a method for choroid plexus explants to study these mechanisms. Several studies have ascribed a role of the BCSF barrier for immune cells and pathogens’ entry into the brain. From the ventricles, the pathogens can elicit inflammatory reactions in the brain, ultimately leading to diseases like meningitis and meningoencephalitis. The transchoroidal crossing into the brain of pathogens can either be 1) transcellular with penetration through the cell, 2) via an opening of tight junctions in a paracellular manner, or 3) through highjacked infected phagocytic host cells (as a “Trojan horse” strategy).
When expressed in cultured cells, we have previously shown that ADGRA3 undergoes constitutive clathrin-mediated, arrestin-independent internalization; however, at present, no G protein-dependent signaling has been described for ADGRA3.
In the VIREX project we have tested the groundbreaking hypothesis that the ADGRA3 (originally known as GPR125) is central for the organ damage caused by mumps virus (MuV) via an interaction with the MuV-encoded SH-protein.
We have studied:
The functional consequences of ADGRA3-SH-interaction at a single cell, organ and whole body level within the context of MuV infection.
The structural requirements for the ADGRA3-MuV interaction using NMR and resolution of crystal structure in preparation for future drug design.
