Proteolytic control of the SARS-CoV-2 furin cleavage site defines the phenotypic evolution from the pandemic to endemic state
Abstract
The successive emergence of SARS-CoV-2 variants with altered tissue tropism has progressively decoupled transmissibility from lower respiratory tract pathogenicity. Omicron lineages transmit exceptionally well whilst limiting severe lung disease. Here, we demonstrate that this phenotype has evolved through two temporally distinct tissue-specific proteolytic controls at the Spike (S) furin cleavage site (FCS). At the virion level, cell-type-dependent furin-mediated FCS hyper-cleavage depletes S in lung but not nasal epithelial cells. At the infected cell membrane during cell-cell spread, TMPRSS2 mediates S FCS cleavage but is negatively regulated in the presence of ACE2. Tissue-specific solute carriers SLC6A19 and SLC6A20 sequester ACE2, thereby relieving inhibition of TMPRSS2 and enabling S FCS cleavage during cell-cell spread. Critically, whilst all SARS-CoV-2 lineages benefit from this latter pathway, Omicron variants have evolved exclusive dependence on it, a strategic consolidation that focuses S proteolytic activation to TMPRSS2 alone. The combined outcomes of S protein regulation across viral and cell membranes reveal how tissue-specific proteolytic optimisation drives Omicron's transmission fitness advantage in the upper respiratory tract but at the cost of heavy attenuation in the lower respiratory tract.
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BibTeX
@misc{aggarwal2026proteolytic,
title = {{Proteolytic control of the SARS-CoV-2 furin cleavage site defines the phenotypic evolution from the pandemic to endemic state}},
author = {A. Aggarwal and S. Ognenovska and T. Ison and C. Fichter and V. Milogiannakis and M. Afzal and A. Ospina-Stella and D. Asarnow and A. L. Morgan and S. Waters and T. Boecking and B. Ng and C. Esneau and N. Bartlett and A. Naik and S. poehlmann and M. Hoffmann and S. Broer and A. Broer and M. D. Johansen and R. Brink and L. M. burrell and S. K. patel and S. Ellis and M. wehrhahn and A. Ginn and E. Martinez and M. J. Churchill and T. A. Angelovich and W. Rawlinson and M. Yeang and G. Walker and C. Foster and J. Kok and V. Sintchenko and R. Rocket and W. Asquith and R. Parry and J. D. Sng and G. Neely and C. Moreno and M. Spence and C. Jackson and L. Loo and Y.-J. Park and C. Gibson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753140},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753140v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Proteolytic control of the SARS-CoV-2 furin cleavage site defines the phenotypic evolution from the pandemic to endemic state
AU - A. Aggarwal
AU - S. Ognenovska
AU - T. Ison
AU - C. Fichter
AU - V. Milogiannakis
AU - M. Afzal
AU - A. Ospina-Stella
AU - D. Asarnow
AU - A. L. Morgan
AU - S. Waters
AU - T. Boecking
AU - B. Ng
AU - C. Esneau
AU - N. Bartlett
AU - A. Naik
AU - S. poehlmann
AU - M. Hoffmann
AU - S. Broer
AU - A. Broer
AU - M. D. Johansen
AU - R. Brink
AU - L. M. burrell
AU - S. K. patel
AU - S. Ellis
AU - M. wehrhahn
AU - A. Ginn
AU - E. Martinez
AU - M. J. Churchill
AU - T. A. Angelovich
AU - W. Rawlinson
AU - M. Yeang
AU - G. Walker
AU - C. Foster
AU - J. Kok
AU - V. Sintchenko
AU - R. Rocket
AU - W. Asquith
AU - R. Parry
AU - J. D. Sng
AU - G. Neely
AU - C. Moreno
AU - M. Spence
AU - C. Jackson
AU - L. Loo
AU - Y.-J. Park
AU - C. Gibson
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753140
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753140v1
AB - The successive emergence of SARS-CoV-2 variants with altered tissue tropism has progressively decoupled transmissibility from lower respiratory tract pathogenicity. Omicron lineages transmit exceptionally well whilst limiting severe lung disease. Here, we demonstrate that this phenotype has evolved through two temporally distinct tissue-specific proteolytic controls at the Spike (S) furin cleavage site (FCS). At the virion level, cell-type-dependent furin-mediated FCS hyper-cleavage depletes S in lung but not nasal epithelial cells. At the infected cell membrane during cell-cell spread, TMPRSS2 mediates S FCS cleavage but is negatively regulated in the presence of ACE2. Tissue-specific solute carriers SLC6A19 and SLC6A20 sequester ACE2, thereby relieving inhibition of TMPRSS2 and enabling S FCS cleavage during cell-cell spread. Critically, whilst all SARS-CoV-2 lineages benefit from this latter pathway, Omicron variants have evolved exclusive dependence on it, a strategic consolidation that focuses S proteolytic activation to TMPRSS2 alone. The combined outcomes of S protein regulation across viral and cell membranes reveal how tissue-specific proteolytic optimisation drives Omicron's transmission fitness advantage in the upper respiratory tract but at the cost of heavy attenuation in the lower respiratory tract.
ER -