As already mentioned, circulating sACE2 protein shedding independent on virus contact has been also described either spontaneously when ACE2 transcription is upregulated or upon cytokine activation; it is therefore likely that in the bloodstreams ACE2 proteins are available to bind to both free S1 fragments and SARS-CoV-2 particles, finally leading to more and more S1-sACE2 and SARS-CoV-2-sACE2 complexes bearing enzymatic active sACE2 (see Figure later in the Section 4).