The rapid emergence of numerous SARS-CoV-2 variants poses a global threat to human health and undermines the goal of achieving herd immunity through vaccination. The overarching aim of VERSATILE is to understand the interplay between cell entry routes and host antiviral responses. This will be addressed under the kaleidoscope of the emerging SARS-CoV-2 variants. Our central hypothesis is that SARS-CoV-2 variants can use distinct entry routes to infect cells that differentially impact host antiviral responses. To test our working hypothesis, we will examine infectious entry of SARS-CoV-2 variants by complementary approaches including flow cytometry, qRT-PCR, advanced live imaging, and other high-end fluorescence-based methods. The function of the receptors and entry cofactors of SARS-CoV-2 variants will be analyzed by introducing mutations that impaired their specific functions and cellular location. Additionally, through a mutagenesis strategy in the viral envelope protein spike, VERSATILE will also have a predictive dimension on the pathogenic potential of future variants. In a final approach, our results will be used to guide the identification and characterization of new small molecule inhibitors specifically targeting each entry route used by SARS-CoV-2 variants. To mimic the anatomical site of viral transmission, where innate immune responses are triggered, we will perform our investigation in 3D polarized primary nasal and lung in vitro cell models. The study of the host defense responses will be focused on the plasmacytoid dendritic cells (pDCs) since they were identified as the predominant producers of antiviral cytokines, i.e., type-I and -III interferon, against SARS-CoV-2. VERSATILE will hence pave the way, not only for answering fundamental questions in the virology, cell biology, and immunology of SARS-CoV-2, but also for developing new antiviral strategies against circulating and future coronaviruses.