SARS-CoV-2 utilization of ACE2 from different bat species allows for virus entry and replication in vitro

Briggs, Kelsey; Sweeney, Ryan; Blehert, David S.; Spackman, Erica; Suarez, David L.; Kapczynski, Darrell R.

doi:10.1016/j.virol.2023.07.002

Cited by 1 publication

(1 citation statement)

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“…This species comprises SARS-CoV-2 and more than 100 related viruses that have been identified in bats and pangolins. A subset of these viruses can use angiotensin-converting enzyme 2 (ACE2) for entry into human and animal cells [19][20][21][22][23][24][25][26][27][28][29] . However, it is not fully clear whether certain animal species can be identified as potential reservoirs or intermediate hosts for animal sarbecoviruses based on exceptionally broad receptor activity of their ACE2 orthologues.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang,

Cheng,

Krüger

et al. 2024

Preprint

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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.

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