EXPL ANTIVIR ENDONUC · Role and modulation of Zinc-finger antiviral protein and antiviral Regnase-1-like endonucleases
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2022-11-01 → 2024-10-31
- EU contribution
- €173,847
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
Role and modulation of Zinc-finger antiviral protein and antiviral Regnase-1-like endonucleases
This project aimed to uncover how components of human innate immunity, Zinc-finger antiviral protein (ZAP) and Regnase-1-like endonucleases protect us from viral infections. Viral infections, such as those caused by Human Immunodeficient Virus, Influenza and SARS-CoV-2, cause significant global health and economic challenges. Current antiviral therapeutic options are limited and often have a selective activity. This highlights the need for innovative approaches that act against a broad range of viruses by harnessing the natural antiviral responses of the human body. The objectives of this project were to characterize the antiviral potential of Regnase-1-like endonucleases and ZAP and identify their targets during virus infection. Furthermore, we investigated the therapeutic potential of pharmacological MALT1 inhibitors to enhance the natural ZAP and endonuclease activity. The pathway to impact involved a four-part work plan: ranking endonuclease antiviral activities, assessing their efficacy against different human viruses, mapping their RNA targets, and evaluating the effect of MALT1 inhibitors on viral infection. Through advanced techniques such as next-generation sequencing, CRISPR-Cas9 genome editing, and primary cell based infection models, the project aimed to uncover immune mechanisms that could inform novel antiviral treatment strategies. The expected impacts include providing a framework for developing broadly acting antiviral therapies and contributing to our understanding of immune regulation, with potential applications in managing autoimmune diseases and cancer. These outcomes address pressing global health challenges and aim to mitigate the substantial burden of respiratory viral diseases.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- UNIVERSITAET ULM · UlmCoordinatorGermany
Links
- View on CORDIS
- DOI: 10.3030/101062524
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e50af384d9&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5129b02f3&appId=PPGMS
Data: CORDIS, © European Union