Little more than a year since the start of the COVID-19 pandemic, we are just beginning to understand how SARS-CoV-2 can overcome host cell entry barriers, outsmart the human immune response, and will evolve in the wake of increasing herd immunity. A major concern is the emergence of variants, which escape immune barriers gradually established through ongoing vaccination campaigns. Another major conundrum of SARSCoV- 2 infections is the very high patient-to-patient variability in disease severity. Our consortium unites key complementary expertises, ranging from the atomic to the systemic level, that will be applied to address knowledge gaps in the SARS-CoV-2 interactions with the human host at an internationally competitive level. The specific unanswered questions that we aim to address within this project concern the evolution potential of the virus and the impact of mutations on virus entry and replication fitness, neutralization by nanobodies or vaccine-raised immune responses, tropism at the cellular and tissue level, polarization of the immune response and the influence of co-morbidities.