Search

Your search keyword '"Karavendzas K"' showing total 2 results
Start Over Author "Karavendzas K" Publisher american society for microbiology
2 results on '"Karavendzas K"'

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

Author

Liu, S-L, Vanslambrouck, JM, Neil, JA, Rudraraju, R, Mah, S, Tan, KS, Groenewegen, E, Forbes, TA, Karavendzas, K, Elliott, DA, Porrello, ER, Subbarao, K, Little, MH, Liu, S-L, Vanslambrouck, JM, Neil, JA, Rudraraju, R, Mah, S, Tan, KS, Groenewegen, E, Forbes, TA, Karavendzas, K, Elliott, DA, Porrello, ER, Subbarao, K, and Little, MH

Abstract

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.

Published
2024

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

Author

Vanslambrouck JM, Neil JA, Rudraraju R, Mah S, Tan KS, Groenewegen E, Forbes TA, Karavendzas K, Elliott DA, Porrello ER, Subbarao K, and Little MH

Subjects
Humans, COVID-19 complications, COVID-19 virology, Lisinopril pharmacology, Lisinopril metabolism, Pandemics, Spike Glycoprotein, Coronavirus metabolism, Peptidyl-Dipeptidase A metabolism, Angiotensin-Converting Enzyme Inhibitors pharmacology, Acute Kidney Injury etiology, Acute Kidney Injury metabolism, Acute Kidney Injury virology, Kidney Tubules, Proximal cytology, Kidney Tubules, Proximal drug effects, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal virology, Receptors, Coronavirus metabolism, Models, Biological, Serine Endopeptidases metabolism, Endosomes drug effects, Endosomes metabolism, Endosomes virology, Gene Expression Regulation drug effects, Stem Cells cytology, Angiotensin-Converting Enzyme 2 metabolism, Kidney cytology, Kidney drug effects, Kidney metabolism, Kidney virology, Organoids cytology, Organoids drug effects, Organoids metabolism, Organoids virology, SARS-CoV-2 metabolism, SARS-CoV-2 pathogenicity, Virus Internalization drug effects
Abstract

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., Importance: Utilizing a human iPSC-derived kidney organoid model with improved proximal tubule (PT) maturity, we identified the mechanism of SARS-CoV-2 entry in renal cells, confirming ACE2 as the sole receptor and revealing redundancy in downstream cell surface TMPRSS- and endocytic Cathepsin-mediated pathways. In addition, these data address the implications of SARS-CoV-2 exposure in the setting of the commonly prescribed ACE-inhibitor, lisinopril, confirming its negligible impact on infection of kidney cells. Taken together, these results provide valuable insight into the mechanism of viral infection in the human kidney., Competing Interests: E.R.P. is a co-founder and scientific advisor of and holds equity in Dynomics, a biotechnology company focused on the development of heart failure therapeutics. The other authors declare no conflict of interest.

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results