Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 19 (COVID-19) with symptoms ranging from mild respiratory illness to severe lung injury, multi-organ failure and ultimately death. Although SARS-CoV-2 primarily infects the lungs, gastrointestinal symptoms are frequently observed and are associated with worse COVID-19 outcomes, underlying the need to also study the infection of the intestinal mucosa. New recently identified SARS-CoV-2 variants raised particular concerns worldwide due to their high transmissibility rates. They all bear mutations in the Spike protein that binds to host cells and allows virus entry. The rapid emergence of such variants highlights the urgent need to develop highly relevant and standardized experimental models to study critical aspects of SARS-CoV-2 variant infection and replication but also to screen therapeutic candidates and assess whether drugs known to affect SARS-CoV-2 parental strain entry and replication are still efficient on these variants. Our proposal aims to monitor the ability of SARS-CoV-2 variants of concern, including South Africa, United Kingdom and Brazil ones, to infect human colonic organoid-derived cell monolayers, a model of choice to study host pathogen interaction in a standardized and reproducible way closely mimicking the in vivo situation. Our proposal also aims to study the immune response of the colonic epithelium to these variants and the impact of this response on the infection process. Finally, our project will be useful to perform a first drug screening of therapeutic candidates known to interfere with infection by the SARS-CoV-2 parental strain. In conclusion, our project will help to understand how the SARS-CoV-2 mutations affect entry and replication of the virus, and defence mechanisms of the intestinal epithelium as well as virus resistance to therapeutic candidates or to interferons. In addition, our experimental model will allow to quickly investigate other potential therapeutic candidates for other types of enteric infections, which is crucial in case of rapidly spreading pathogens, such as SARS-CoV-2.