ACE2-independent sarbecovirus cell entry can be supported by TMPRSS2-related enzymes and can reduce sensitivity to antibody-mediated neutralization

Zhang L, Cheng HH, Krüger N, Hörnich B, Graichen L, Hahn AS, Schulz S, Jäck HM, Stankov MV, Behrens GM, Müller MA, Drosten C, Mörer O, Winkler MS, Qian ZH, Pöhlmann S, Hoffmann M (2024)

Publication Type: Journal article

Publication year: 2024

Journal

PLoS Pathogens Public Library of Science

Book Volume: 20

Article Number: e1012653

Journal Issue: 11

DOI: 10.1371/journal.ppat.1012653

Abstract

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 while trypsin protected entry driven by a third S protein from neutralization by S2H97. Similarly, plasma from quadruple vaccinated individuals neutralized entry driven by all S proteins studied, and availability 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, can be supported by TMPRSS2-related proteases and may be associated with antibody evasion.

Authors with CRIS profile

Sebastian Schulz Professur für Immunologie Hans-Martin Jäck Department of Molecular Immunology

Additional Organisation(s)

FAU Profilzentrum Licht.Materie.Quantentechnologien (FAU LMQ)

Involved external institutions

Universitätsklinikum Göttingen DE Germany (DE) Institute of Pathogen Biology (IPB), CAMS & PUMC CN China (CN) Deutsches Primatenzentrum (DPZ), Leibniz-Institut für Primatenforschung DE Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE)

How to cite

APA:

Zhang, L., Cheng, H.H., Krüger, N., Hörnich, B., Graichen, L., Hahn, A.S.,... Hoffmann, M. (2024). ACE2-independent sarbecovirus cell entry can be supported by TMPRSS2-related enzymes and can reduce sensitivity to antibody-mediated neutralization. PLoS Pathogens, 20(11). https://doi.org/10.1371/journal.ppat.1012653

MLA:

Zhang, Lu, et al. "ACE2-independent sarbecovirus cell entry can be supported by TMPRSS2-related enzymes and can reduce sensitivity to antibody-mediated neutralization." PLoS Pathogens 20.11 (2024).

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