Determine how the interaction between SARS-CoV-2 spike protein and angiotensin-converting enzyme 2 (ACE2) affect viral spread and the severity of COVID‑19 outcomes.
The proposed research focuses on investigating why the SARS-CoV-2 variant, B.1.1.7 that have higher binding affinity to Angiotensin Converting Enzyme 2 (ACE2) on host cells are associated with increased viral spread and mortality rates. ACE2, the main receptor for HCoV-NL63 (common cold virus), SARS-CoV-1 and SARS-CoV-2, is also a key regulator of the renin-angiotensin system (RAS) regulating systemic vascular resistance, which is enhanced in COVID‑19 patients with severe disease outcomes. While most studies continue to focus on ACE2’s role in RAS, its role in immune modulation and the signal transduction property of its intracellular subdomains have been overlooked. Viral spread is associated with reduced immune response in controlling viral infection and replication and COVID‑19 severity is associated with exaggerated inflammation causing damages of critical tissues. ACE2’s contribution in preventing inflammation is evident from study of SARS-CoV-1 infection and reduced surface ACE2 expression that is associated with the severity of SARS-CoV-2 infection. Moreover, unlike SARS-CoV-1 and -2, HCoV-NL63 (common cold virus) did not trigger ACE2 shedding. It remains unclear, to what extend SARS-CoV-2-triggered ACE2-shedding affects the inflammation observed in coronavirus infection and viral replication in infected cells. The observation that B.1.1.7, exhibiting enhanced binding affinity for ACE2 caused exacerbated transmissibility and mortality without affecting disease severity further emphasized the urgency to define how SARS-CoV-2 and its VoC modulate the immune activation and cell signalling mediated by ACE2. This knowledge is especially critical for better patient-management and when targeting ACE2 as prophylactic therapeutic strategies to halt the disease progression towards excessive inflammation and acute respiratory distress syndrome during SARS-CoV-2 infection.
