FIG 9.

Role of host cell proteases in the cellular entry of SARS-CoV. Host cell entry of SARS-CoV can proceed via two distinct routes, dependent on the availability of cellular proteases required for activation of SARS-S. The first route is taken if no SARS-S-activating proteases are expressed at the cell surface. Upon binding of virion-associated SARS-S to ACE2, virions are taken up into endosomes, where SARS-S is cleaved and activated by the pH-dependent cysteine protease cathepsin L. The second route of activation can be pursued if the SARS-S-activating protease TMPRSS2 is coexpressed with ACE2 on the surface of target cells. Binding to ACE2 and processing by TMPRSS2 are believed to allow fusion at the cell surface or upon uptake into cellular vesicles but before transport of virions into host cell endosomes. Uptake can be enhanced upon SARS-S activation of ADAM17, which cleaves ACE2, resulting in shedding of ACE2 in culture supernatants. Since normal expression of ACE2 protects from lung injury and ACE2 levels are known to be reduced in SARS-CoV infection, the ADAM17-dependent ACE2 shedding is believed to promote lung pathogenesis. The present study suggests that the cellular uptake of SARS-CoV can also be augmented upon ACE2 cleavage by TMPRSS2. Since the entry-promoting function of ADAM17 is not undisputed and increased uptake upon ACE2 cleavage by TMPRSS2 has only been demonstrated with soluble SARS-S1, the respective arrows are shown in dashed lines.