
Animal sarbecoviruses can infect human cells through ACE2-dependent and ACE2-independent pathways, with the latter pathway reducing susceptibility to antibody-mediated neutralization.


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The COVID-19 pandemic, caused by SARS-CoV-2, demonstrated that zoonotic transmission of animal sarbecoviruses threatens human health but the determinants of transmission are incompletely understood. Here, we show that most spike (S) proteins of horseshoe bat and Malayan pangolin sarbecoviruses employ ACE2 for entry, with human and raccoon dog ACE2 exhibiting broad receptor activity. The insertion of a multibasic cleavage site into the S proteins increased entry into human lung cells driven by most S proteins tested, suggesting that acquisition of a multibasic cleavage site might increase infectivity of diverse animal sarbecoviruses for the human respiratory tract. In contrast, two bat sarbecovirus S proteins drove cell entry in an ACE2-independent, trypsin-dependent fashion and several ACE2-dependent S proteins could switch to the ACE2-independent entry pathway when exposed to trypsin. Several TMPRSS2-related cellular proteases but not the insertion of a multibasic cleavage site into the S protein allowed for ACE2-independent entry in the absence of trypsin and may support viral spread in the respiratory tract. Finally, the pan-sarbecovirus antibody S2H97 enhanced cell entry driven by two S proteins and this effect was reversed by trypsin. Similarly, plasma from quadruple vaccinated individuals neutralized entry driven by all S proteins studied, and use of the ACE2-independent, trypsin-dependent pathway reduced neutralization sensitivity. In sum, our study reports a pathway for entry into human cells that is ACE2-independent, supported by TMPRSS2-related proteases and associated with antibody evasion.

### Competing Interest Statement

S.P. and M.H. conducted contract research (testing of vaccinee plasma for neutralizing activity against SARS-CoV-2) for Valneva unrelated to this work. G.M.N.B. served as advisor for Moderna and S.P. served as advisor for BioNTech, unrelated to this work. The authors declare no competing interests. M.S.W. received funding from Sartorius AG (Goettingen, Germany) from GRIFOLS SA (Barcelona, Spain), Sphingotec (Henningsdorf, Germany), Inflammatix (Sunnyvale, CA, USA) and the German Research Foundation (Bonn, Germany). He is in the advisory board of Amomed (Wien, Austria) and Gilead Science Inc. (Foster City, CA, USA).

ACE2-independent sarbecovirus cell entry is supported by TMPRSS2-related enzymes and reduces sensitivity to antibody-mediated neutralization

diverse-animal-sarbecoviruses-can-infect-human-cells-through-ace2-dependent-and-ace2-independent-pathways-impacting-antibody-neutralization


Diverse Animal Sarbecoviruses Can Infect Human Cells Through ACE2-Dependent and ACE2-Independent Pathways, Impacting Antibody Neutralization
