Evidence for ACE2-utilizing coronaviruses (CoVs) related to severe acute respiratory syndrome CoV in bats

In 2002, severe acute respiratory syndrome (SARS)-coronavirus (CoV) appeared as a novel human virus with high similarity to bat coronaviruses. However, while SARS-CoV uses the human angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry, no coronavirus isolated from bats appears to use ACE2. Here we show that signatures of recurrent positive selection in the bat ACE2 gene map almost perfectly to known SARS-CoV interaction surfaces. Our data indicate that ACE2 utilization preceded the emergence of SARS-CoV-like viruses from bats. Cell-surface receptors often play a key role in defining viral hostrange. New diseases can emerge when existing viruses evolve the ability to bind the ortholog of their cell-surface receptor in a new species (1, 25, 35). Indeed, the principal genetic component defining host range in coronaviruses is the spike protein on the surface of the virus and, in particular, its receptor-binding domain (RBD) (5, 14). It is believed that the severe acute respiratory syn-drome (SARS) epidemic resulted from the zoonotic transmission of a coronavirus frombats to humans (15, 18, 32). The central role of the RBD in the SARS-coronavirus (CoV) zoonosis was crystal-lized in an experiment in which a bat coronavirus became infec