Kidney organoids reveal redundancy in viral entry pathways during ACE2-dependent SARS-CoV-2 infection
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Kidney organoids reveal redundancy in viral entry pathways during ACE2-dependent SARS-CoV-2 infection. / Vanslambrouck, Jessica M.; Neil, Jessica A.; Rudraraju, Rajeev; Mah, Sophia; Tan, Ker Sin; Groenewegen, Ella; Forbes, Thomas A.; Karavendzas, Katerina; Elliott, David A.; Porrello, Enzo R.; Subbarao, Kanta; Little, Melissa H.
I: Journal of Virology, Bind 98, Nr. 3, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Kidney organoids reveal redundancy in viral entry pathways during ACE2-dependent SARS-CoV-2 infection
AU - Vanslambrouck, Jessica M.
AU - Neil, Jessica A.
AU - Rudraraju, Rajeev
AU - Mah, Sophia
AU - Tan, Ker Sin
AU - Groenewegen, Ella
AU - Forbes, Thomas A.
AU - Karavendzas, Katerina
AU - Elliott, David A.
AU - Porrello, Enzo R.
AU - Subbarao, Kanta
AU - Little, Melissa H.
N1 - Publisher Copyright: © 2024 Vanslambrouck et al.
PY - 2024
Y1 - 2024
N2 - With a high incidence of acute kidney injury among hospitalized COVID-19 patients, considerable attention has been focussed on whether SARS-CoV-2 specifically targets kidney cells to directly impact renal function, or whether renal damage is primarily an indirect outcome. To date, several studies have utilized kidney organoids to understand the pathogenesis of COVID-19, revealing the ability for SARS-CoV-2 to predominantly infect cells of the proximal tubule (PT), with reduced infectivity following administration of soluble ACE2. However, the immaturity of standard human kidney organoids represents a significant hurdle, leaving the preferred SARS-CoV-2 processing pathway, existence of alternate viral receptors, and the effect of common hypertensive medications on the expression of ACE2 in the context of SARS-CoV-2 exposure incompletely understood. Utilizing a novel kidney organoid model with enhanced PT maturity, genetic- and drug-mediated inhibition of viral entry and processing factors confirmed the requirement for ACE2 for SARS-CoV-2 entry but showed that the virus can utilize dual viral spike protein processing pathways downstream of ACE2 receptor binding. These include TMPRSS- and CTSL/CTSB-mediated non-endosomal and endocytic pathways, with TMPRSS10 likely playing a more significant role in the non-endosomal pathway in renal cells than TMPRSS2. Finally, treatment with the antihypertensive ACE inhibitor, lisinopril, showed negligible impact on receptor expression or susceptibility of renal cells to infection. This study represents the first in-depth characterization of viral entry in stem cell-derived human kidney organoids with enhanced PTs, providing deeper insight into the renal implications of the ongoing COVID-19 pandemic.
AB - With a high incidence of acute kidney injury among hospitalized COVID-19 patients, considerable attention has been focussed on whether SARS-CoV-2 specifically targets kidney cells to directly impact renal function, or whether renal damage is primarily an indirect outcome. To date, several studies have utilized kidney organoids to understand the pathogenesis of COVID-19, revealing the ability for SARS-CoV-2 to predominantly infect cells of the proximal tubule (PT), with reduced infectivity following administration of soluble ACE2. However, the immaturity of standard human kidney organoids represents a significant hurdle, leaving the preferred SARS-CoV-2 processing pathway, existence of alternate viral receptors, and the effect of common hypertensive medications on the expression of ACE2 in the context of SARS-CoV-2 exposure incompletely understood. Utilizing a novel kidney organoid model with enhanced PT maturity, genetic- and drug-mediated inhibition of viral entry and processing factors confirmed the requirement for ACE2 for SARS-CoV-2 entry but showed that the virus can utilize dual viral spike protein processing pathways downstream of ACE2 receptor binding. These include TMPRSS- and CTSL/CTSB-mediated non-endosomal and endocytic pathways, with TMPRSS10 likely playing a more significant role in the non-endosomal pathway in renal cells than TMPRSS2. Finally, treatment with the antihypertensive ACE inhibitor, lisinopril, showed negligible impact on receptor expression or susceptibility of renal cells to infection. This study represents the first in-depth characterization of viral entry in stem cell-derived human kidney organoids with enhanced PTs, providing deeper insight into the renal implications of the ongoing COVID-19 pandemic.
KW - COVID-19
KW - kidney
KW - kidney organoids
KW - SARS-CoV-2
KW - stem cells
U2 - 10.1128/jvi.01802-23
DO - 10.1128/jvi.01802-23
M3 - Journal article
C2 - 38334329
AN - SCOPUS:85188531415
VL - 98
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 3
ER -
ID: 392661471