This has included acquisition of the ability for heparin sulfate mediated infection of an ACE2-negative human lung epithelial as a result of the E484D mutation in the RBD [31], indeed in vitro evolution of SARS-CoV-2 to higher infectivity through more efficient binding to heparin sulfate has been reported [32], and in vivo reduction of intestinal ACE2 expression did not impact SARS-CoV-2 infection or severity [33], further suggesting the contribution of other cellular entry mechanisms. This evidence concerns the gene ACE2 and severe acute respiratory syndrome.