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Investigating Virus-Host Interplay in Human Primary Models of Genetically Modified Respiratory Epithelium

Project description

Primary respiratory viruses and their target cells

Respiratory viruses like influenza and coronaviruses spread rapidly and pose health risks. Most studies rely on cancer cell lines, which poorly mimic human respiratory cells. Ex vivo models of airway epithelial tissues cultured at the air-liquid interface provide a better representation but lack in-depth research on immune responses and on genes that regulate viral replication. The ERC-funded InVIRium project will combine expertise in human airway epithelial tissue generation, CRISPR screening, and virology to investigate interactions between major respiratory viruses – SARS-CoV-2, Influenza A and B, and Respiratory Syncytial Virus – and their target, primary cells. The project aims to identify interferon-stimulated genes that promote an antiviral state, explore how SARS-CoV-2 evades the interferon response, and uncover the landscape of host genes that regulate viral infections.

Objective

Respiratory viruses can rapidly spread worldwide with a devastating impact, as dramatically highlighted by the COVID-19 pandemic. In addition to the pandemic threat posed by influenza A viruses (IAV) or coronaviruses, respiratory viruses, including IAV, influenza B virus (IBV), seasonal coronaviruses and respiratory syncytial virus (RSV), are the cause of yearly epidemics, with a huge impact on human health. The vast majority of in vitro studies has been performed with model cancer cell lines. However, they share limited features with the primary cells found within the human respiratory epithelium. Robust and relevant, ex vivo models of human primary airway epithelia, cultured at the air-liquid interface (ALI) have been developed over the years and nicely recapitulate the structure and composition of the in vivo respiratory epithelium. Nevertheless, in depth studies on the genes and the potent innate immune, interferon (IFN)-induced, defences regulating viral replication in such pertinent models are still lacking. The InVIRium project will address this knowledge gap by combining a newly acquired expertise in the generation and gene editing of human ALI airway epithelia, with a strong expertise in CRISPR screens and virology. The objectives of InVIRium will be to explore in depth the relationships between major human respiratory viruses, SARS-CoV-2, IAV, IBV and RSV, and their relevant, primary target cells. InVIRium will characterize the IFN-stimulated-genes responsible for the potent antiviral state, explore the mechanisms of SARS-CoV-2 escape from the IFN system and define the landscape of host genes regulating respiratory virus infection in this physiologically relevant ALI model. InVIRium will bring a change of paradigm in the way we study respiratory viruses, by implementing cutting-edge approaches in highly pertinent human models and will gather fundamental knowledge that is currently lacking on the interactions between viruses and their primary target cells.

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: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.

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Host institution

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Net EU contribution
€ 2 475 808,00
Address
RUE DE TOLBIAC 101
75654 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Total cost
€ 2 475 808,00

Beneficiaries (1)

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