Spike protein of SARS-CoV-2 is processed proteolytically into the S1 receptor-binding subunit and the S2 membrane fusion subunit, and SARS-CoV-2 RBD mediates virus entry into host cells via binding to ACE2.28 To better understand the association between IL-18 levels and morbidity and mortality in patients with COVID-19, we studied Spike signaling via S1 and RBD protein signaling in a pre-clinical mouse model. Here, ACE2 is linked to COVID-19.