Project description
ZAPping viruses
Human cells have evolved various immune mechanisms to inhibit virus replication and minimise their spread. One of these strategies involves the zinc-finger antiviral proteins (ZAP) which target viral RNAs through recognition of CpG dinucleotides. Funded by the Marie Skłodowska-Curie Actions programme, the EXPL ANTIVIR ENDONUC project aims to exploit the therapeutic potential of ZAPs by delineating their mechanism of action. Researchers will identify which ZAP cofactors are responsible for RNAse activity against major respiratory viral pathogens. Moreover, the work will involve screening of various compounds for their potential to maintain the antiviral activity of ZAP.
Objective
The human zinc finger antiviral protein (ZAP) is capable of inhibiting several major human pathogens, including Influenza A virus and SARS-CoV-2. ZAP specifically targets CpG dinucleotides in RNAs and might be one of the reasons why CpGs are strongly suppressed in the human genome. Successful viruses, such as HIV-1 and SARS-CoV-2, mimic human CpG suppression to partially evade the inhibitory effects of ZAP. However, especially under conditions of infection or inflammation when ZAP is expressed at high levels, it inhibits both CpG containing viral as well as cellular RNAs. Importantly, ZAP itself does not possess RNAse activity and is dependent on cofactors, such as KHNYN, to destroy viral RNAs. KHNYN is tightly regulated and inactivated by MALT-1, a cellular protease representing an important target in cancer immunotherapies. Although some progress has been made, the identity of ZAP cofactors as well as their mechanism(s) of action and therapeutic potential are poorly understood. This proposal aims to combine the expertise of the applicant (mechanistic studies of ZAP and RNA-targeting factors) and the host (respiratory viruses and antiviral drug development) to define how ZAP-dependent and independent antiviral endonucleases restrict major respiratory viral pathogens. In addition, it will be examined whether MALT-1 inhibitors that are currently in clinical trials against cancers allow to enhance and maintain the antiviral activity of ZAP and its cofactors thus offering prospects for the treatment of respiratory infections. Finally, potential side-effects on cellular RNAs and their impact on immune signalling, cell activation and infection outcome will be determined. The project will combine innovative CRISPR/Cas9 genome editing, in vitro virus infection platforms, novel functional assays and state-of-the-art deep sequencing technologies to significantly advance the knowledge on antiviral RNAses and to clarify whether they can be strengthened for antiviral therapy.
Fields of science
- natural sciencesbiological sciencesmicrobiologyvirology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health scienceshealth sciencesinfectious diseasesRNA virusescoronaviruses
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-AG-UN - HORIZON Unit GrantCoordinator
89081 Ulm
Germany