Thus, we propose that SARS-CoV-2 can trigger barrier dysfunction through multiple avenues, including (1) during infection of virus-permissive cells, (2) through shedding of soluble S1 after enzymatic cleavage following ACE2 interactions on a cell, (3) through expression of S on the surface of infected cells that can interact with neighboring cells, and (4) through interactions with ACE2-negative non-permissive cells. This evidence concerns the gene ACE2 and infection.