Project description
A closer look at viral RNA modification and immune evasion
Viruses are responsible for many serious diseases, including COVID-19. Traditional research has mostly focused on proteins in virus-host interactions, but RNA also plays a crucial role. To protect their RNA from the host immune system, viruses have developed complex strategies like 5’ capping and internal modifications. These modifications are essential for viral survival and replication. The ERC-funded MOVIRNA project will investigate viral RNA modifications, particularly in the hepatitis C virus (HCV). It will explore how HCV uses a unique 5’ cap made from flavin adenine dinucleotide (FAD), a discovery that could reveal new ways viruses protect their RNA. The project will also study how these modifications help viruses evade immune detection.
Objective
Viruses cause significant disease, exemplified by the COVID-19 pandemic. Most studies of virus-host interactions focused on proteins, however, RNA holds great promise for basic and therapeutic exploration. Viruses evolved elaborate strategies for RNA protection, including 5’ capping and internal modification. The goal of this proposal is to discover and characterize viral RNA modifications installed by viral enzymes, including their role in innate immune evasion. This could uncover novel RNA-based mechanisms of viral replication and host modulation and lead to therapeutic targets.
Many viruses encode methyltransferases (MTases) for canonical RNA 5’ capping. Curiously, no cap was identified for hepatitis C virus (HCV), an important human pathogen. We recently found that the cellular metabolite, flavin adenine dinucleotide (FAD), is used as noncanonical initiating nucleotide by the HCV polymerase at high frequency resulting in a 5’FAD cap on HCV RNA. This is the first description of a virus using this cap type for protecting its RNA and, remarkably, the first robust description of FAD capping across any kingdom of life. In Aim 1, we will investigate the functional role of the HCV 5’FAD cap, including viral evasion of innate immune sensing and RNA stability. We will also explore the evolutionary conservation of metabolite capping across RNA viruses and explore its potential as antiviral target.
Viral MTases further perform 2’-O-methylation (2’OMe) of internal RNA residues, a modification that also may protect from innate recognition. In Aim 2, the extent of 2’OMe on viral RNA will be mapped and the individual contribution of 5’ and internal modification to innate immune evasion will be dissected.
In aggregate, these aims will uncover how viral enzymes modify the termini and internal viral RNA residues and associated evasion of innate immunity. The outcome could reshape understanding of viral RNA biology, open novel research directions and lead to antiviral targets.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences microbiology virology
- medical and health sciences health sciences public health epidemiology pandemics
- medical and health sciences health sciences infectious diseases viral diseases RNA viruses hepatitis C
- natural sciences biological sciences genetics RNA
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2023-COG
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1165 KOBENHAVN
Denmark
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