Project description
Enhancing our knowledge about antiviral defences
Viral pandemics often result from adaptations of zoonotic and emergent viruses. Our cells naturally produce antiviral proteins that can provide a critical initial defence against these viruses. Interferon-stimulated genes are historically considered the main antiviral proteins. However, recent research shows that 75 % of antiviral responses are driven by antiviral proteins that are not interferon-induced but rather constitutively expressed, potentially representing the first barrier to viral infections. The ERC-funded ReThink project will investigate how these newly identified antiviral proteins function to inhibit emergent viruses, including dengue, Zika, West Nile and influenza, using clinical samples and ex vivo models. It is anticipated that the project will greatly enhance our understanding of antiviral defences and improve our pandemic preparedness.
Objective
All recent viral pandemics originated following human adaptation of zoonotic viruses. Our front-line antiviral defences are a major barrier to these viruses. Specifically, our cells encode antiviral proteins -that can be species-specific-, and directly inhibit viral entry, replication, and spread, thus influencing the outcome of infection. Current dogma states that antiviral proteins induced by interferon signalling, named interferon stimulated genes (ISGs), are the most significant front-line of defence. However, as ISGs are induced upon recognition of an already replicating virus, I hypothesize that an array of proteins that are constitutively expressed act to contain the initial wave of viral infection before the more specific and potent ISGs are expressed, thus providing a critical first-line of defence that influences pathogenesis and interspecies transmission. Supporting this hypothesis, my recent genome-wide multi-OMICs investigation of dengue (DENV) and influenza virus (IAV) restriction revealed that 75% of the proteins that inhibited viral infection are non-ISGs. Integrative analysis of these proteins revealed enrichment in general cellular pathways, -many not previously linked to viral restriction-, with significant enrichment in homeostasis maintenance. Moreover, depletion of one single of these proteins resulted in 100% mortality in infected mice, confirming their role in pathogenesis. Using DENV as a model of emergent WHO-priority virus, I will now characterize how these proteins inhibit DENV and other related (west Nile and zika) and unrelated viruses (IAV) (Objective 1). I will investigate their impact on DENV pathogenesis using attenuated and virulent clinical isolates (Objective 2) and as barriers of interspecies transmission using ex vivo models (Objective 3). Overall, this work will shift our understanding of antiviral defences, opening a new area of research that offers signatures of pathogenesis, surveillance, and broad-acting 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.
- social sciences sociology demography mortality
- natural sciences biological sciences microbiology virology
- medical and health sciences health sciences public health epidemiology pandemics
- medical and health sciences health sciences infectious diseases RNA viruses influenza
- medical and health sciences basic medicine physiology homeostasis
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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-2025-STG
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SW7 2AZ London
United Kingdom
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