Molecular mechanism of PVR (CD155) immunological pathways in viral and tumor pathogenesis (PVRreg)
Molecular mechanisms of PVR (CD155) immunological pathways in viral and tumor pathogenesis
Project title: Molecular mechanisms of PVR (CD155) immunological pathways in viral and tumor pathogenesis
Grantor: Croatian Science Foundation
Grantor’s website: www.hrzz.hr
Coordinator: Prof. Dr. Tihana Lenac Roviš
Prof. Dr. Astrid Krmpotić
Total funding: 853.000,00 HRK
The project is focused on the role of PVR (poliovirus receptor) which serves as a ligand for both inhibitory (TIGIT) and activating (DNAM-1 and Tactile) receptors. The evidence has been accumulated indicating the role of PVR and its receptors in immune surveillance including the control of viral infections, tumors, as well as in pathogenesis of autoimmune diseases. Of note is that PVR is constitutively expressed on the majority of somatic cells, while its receptors are expressed on the majority of lymphocyte population. In many respects the interaction of PVR with its paired set of inhibitory and activating receptors resemble the interaction of paired co-stimulatory immune cell receptors and their cellular ligands (B7/CD28/CTLA-4). These co-stimulatory molecules have been the subject of intensive studies that resulted in immunoregulatory pharmaceutical agents for use in humans.
The studies proposed here are based on the finding that human cytomegalovirus (HCMV) affects the surface expression of PVR (Nat Immunol. 2005) and on our preliminary results indicating that mouse cytomegalovirus (MCMV) also downregulates mouse PVR. Thus, we first focused on the identification of MCMV gene(s) (proteins) involved in the PVR regulation, but also on the consequence of this viral regulation on antiviral immune response in vivo. To that aim we will generate MCMV mutants lacking viral regulators and test their in vivo susceptibility to components of innate and acquired immune response. We expect that the results obtained will further broaden the knowledge of PVR regulation and its significance in immune control, which will eventually help to translate this knowledge to developing new immunotherapeutic tools. Namely, one aim of this project is to engineer antibody specific for human PVR in order to be used as a tool in targeted tumor therapy. This idea is based on the fact that many tumors over-express PVR, which could be used in antibody mediated uptake of anti-tumor compounds.