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

Introduction

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.

Current Research Limitations

The vast majority of in vitro studies have 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.

Knowledge Gap

Nevertheless, in-depth studies on the genes and the potent innate immune, interferon (IFN)-induced defenses regulating viral replication in such pertinent models are still lacking.

Project Overview

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.

Objectives

The objectives of InVIRium will be to:

1. Explore in depth the relationships between major human respiratory viruses: SARS-CoV-2, IAV, IBV, and RSV, and their relevant primary target cells.
2. Characterize the IFN-stimulated genes responsible for the potent antiviral state.
3. Explore the mechanisms of SARS-CoV-2 escape from the IFN system.
4. Define the landscape of host genes regulating respiratory virus infection in this physiologically relevant ALI model.

Impact

InVIRium will bring a change of paradigm in the way we study respiratory viruses by implementing cutting-edge approaches in highly pertinent human models. It will gather fundamental knowledge that is currently lacking on the interactions between viruses and their primary target cells.