Project description
Understanding the mechanisms underlying viral infections’ lowering of DNase levels
According to the World Health Organization, approximately 67 % of people globally under the age of 50 have a herpes simplex virus type 1 (HSV-1) infection, the main cause of oral herpes and a cause of genital herpes. DNA nucleases (DNases) are enzymes that degrade DNA. Theoretically, host DNases can degrade the HSV-1 DNA (genome). With the support of the Marie Skłodowska-Curie Actions programme, the REDAVIP project will further investigate its preliminary finding that HSV-1 infection lowers the levels of the DNASE2B protein. Specifically, the project will attempt to restore the DNase’s anti-viral capacity by understanding the mechanisms underlying HSV-1’s effect on DNase levels and then screening drugs to restore them.
Objective
Every individual carries at least a herpesvirus causing mild to serious diseases without definitive cure. Although in theory, herpesvirus genomes can be degraded by host DNA nucleases (DNASEs), the ER preliminary data has evidenced DNASE2B protein levels to decrease upon herpes simplex virus-1 (HSV-1) infection. In order to restore DNASEs anti-viral potential, REDAVIP aims to 1) uncover the susceptibility of DNASEs to HSV-1, 2) gain mechanistic insights of HSV-1 proteins and DNASEs interaction, and 3) screen drugs restoring host DNASEs so the vDNA can be cleared from the organism. To do so, REDAVIP will assess DNASEs’ endogenous levels upon infection by immunoblot and enrich them with immunoprecipitation to identify interacting viral protein(s) by mass spectrometry collaborating internationally. Afterwards, their minimal interacting surfaces will be determined and disrupted with in silico drug library screens collaborating internationally. Then, a tripartite fluorescence complementation assay will confirm the disruption of this pathogenic interaction in cellula. Candidate compounds restoring the DNASEs ability of degrading vDNA will be validated by plaque assays for IP protection, since they may represent a first step towards an overdue cure against herpesviral infections and life quality improvement, especially for an ageing population. Given the ambitious and novel objectives, the ER applies her multidisciplinary expertise to propose mitigation strategies that will ensure experimental feasibility and multiple outputs. This work will allow the ER to transfer her knowledge acquired through European laboratories to the acceptor institution, and progress from basic to translational research to learn and ensure a revenue of invested funds. The findings will be broadly disseminated to improve the ER soft skills. Uncovering how host DNASEs are impaired during herpesvirus infection using HSV-1 as a model is an asset to find novel antivirals against further viruses.
Fields of science
- natural sciencesbiological sciencesmicrobiologyvirology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
- medical and health scienceshealth sciencesinfectious diseasesDNA viruses
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
03202 Elche
Spain