Fig. 1: Viral hijack of host cellular metabolic machinery.

SARS-CoV-2 infection of a susceptible host is achieved through viral spike (S)-protein-mediated hijack of human cell surface receptors (ACE2 and/or NRP1) and cell membrane proteases. The S1-region on viral S-protein contains a receptor-binding domain (RBD) that specifically recognizes host cell surface receptor(s) and exposes the S2 site⁵⁵. For fusion with host cell membrane, the viral S-protein hijacks specific cellular proteases for activation (‘priming’) of viral S-protein at the S1/S2 region. Subsequent conformational changes to viral S-protein lead to S1 shedding by cleavage of S1/S2 fragments. This process facilitates insertion of fusion peptide (FP) into host membrane. Accordingly, proteolytic cleavage by cellular enzymes TMPRSS2 and/or furin accomplish the task of viral FP insertion into host cell membrane. Alternatively, SARS-CoV-2 could also hijack lysosomal protease cathepsin L (CTSL) for direct viral endocytosis, where the viral membrane fuses with luminal face of the endosomal membrane facilitating viral RNA transfer into the cytosol. Thus, SARS-CoV-2 could infect the human by hijacking these 5 major host cellular factors via different routes of entry and elicit a wide range of clinical outcomes. The angiotensin-converting enzyme 2 (ACE2)/TMPRSS2-mediated viral infection and/or the ACE2/CTSL-mediated endosomal route may result in full-spectrum symptomatic COVID-19. The alternative neuropilin 1 (NRP1)/furin-mediated route^62,63 may down-regulate human pain receptors and manifest as asymptomatic to mild disease outcomes.