The severe acute respiratory syndrome (SARS)-coronavirus (CoV) 2, SARS-CoV-2, led to the world-spread CoV-induced disease 2019 (COVID-19) in early 2020. The emergence of SARS-CoV-2 variants poses a global threat to human health and undermines the goal of achieving herd immunity through vaccination. Among the fundamental aspects of SARS-CoV-2 biology that remain to be discovered at the molecular level, cell entry in connection with the host defense response is an important objective for improving and developing effective treatments against SARS-CoV-2 and all related variants. VERSATILE proposes to fill the gap of knowledge about these mechanisms, with the ultimate goal of providing predictive guidance on new SARS-CoV-2 variants to prepare for future emergence.