Kidney organoids reveal redundancy in viral entry pathways during ACE2-dependent SARS-CoV-2 infection

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  • Jessica M. Vanslambrouck
  • Jessica A. Neil
  • Rajeev Rudraraju
  • Sophia Mah
  • Ker Sin Tan
  • Ella Groenewegen
  • Thomas A. Forbes
  • Katerina Karavendzas
  • David A. Elliott
  • Enzo R. Porrello
  • Kanta Subbarao
  • Little, Melissa Helen

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.

OriginalsprogEngelsk
TidsskriftJournal of Virology
Vol/bind98
Udgave nummer3
Antal sider16
ISSN0022-538X
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We acknowledge the Victorian Government Department of Jobs Precincts and Regions (DJPR) for funding through the Victorian COVID-19 Research Fund and The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), which is supported by a Novo Nordisk Foundation grant (NNF21CC0073729). This research was also supported by the National Health and Medical Research Council (GNT1156440). E.R.P. and K.S. are supported by National Health and Medical Research Council Investigator Grants (GNT2008376 and APP1177174) and M.H.L. held a NHMRC Senior Principal Research Fellowship (GNT1136085).

Funding Information:
We acknowledge MCRI Operational Infrastructure Support and the Fox Medical Research Foundation MCRI Genome Editing Facility for the generation of pluripotent stem cell lines. We thank the Murdoch Children’s Research Institute Translational Genomics Unit for 10x single cell library preparation and sequencing; Dr Sean Wilson for training and support in the analysis of single cell RNA sequencing data; Matthew Burton and the Murdoch Children’s Research Institute Microscopy Core; Dr Sara Howden and the MCRI iPSC Derivation and Gene Editing Core; Dr Matt Gartner for technical advice related to infection experiments; Victorian Infectious Diseases Reference Laboratory (VIDRL) for provision of SARS-CoV-2 VIC01 virus and Professor Ralph Baric (UNC Chapel Hill) for providing the GFP-tagged SARS-CoV-2 WA1 virus.

Publisher Copyright:
© 2024 Vanslambrouck et al.

ID: 392661471