Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations.
Acute Kidney Injury
/ etiology
Adult
Aged
Angiotensin-Converting Enzyme 2
/ genetics
Animals
Apoptosis
Bowman Capsule
/ cytology
COVID-19
/ complications
Chlorocebus aethiops
Female
Gene Knockout Techniques
Hospital Mortality
Hospitalization
Humans
Kidney
/ metabolism
Kidney Tubules, Proximal
/ metabolism
Male
Middle Aged
Organoids
/ metabolism
Podocytes
/ virology
Polycystic Kidney Diseases
Protein Kinase D2
/ genetics
Proteome
Receptors, Coronavirus
/ genetics
Reproducibility of Results
SARS-CoV-2
/ pathogenicity
Transcriptome
Vero Cells
Viral Tropism
Virus Replication
COVID-19
Genetic diseases
Molecular pathology
Nephrology
iPS cells
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
22 12 2021
22 12 2021
Historique:
received:
09
09
2021
accepted:
10
11
2021
pubmed:
13
11
2021
medline:
7
1
2022
entrez:
12
11
2021
Statut:
epublish
Résumé
Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.
Identifiants
pubmed: 34767537
pii: 154882
doi: 10.1172/jci.insight.154882
pmc: PMC8783682
doi:
pii:
Substances chimiques
Protein Kinase D2
0
Proteome
0
Receptors, Coronavirus
0
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R21 AI158788
Pays : United States
Organisme : NIH HHS
ID : P51 OD010425
Pays : United States
Organisme : NIDDK NIH HHS
ID : K23 DK116967
Pays : United States
Organisme : NCATS NIH HHS
ID : UH3 TR002158
Pays : United States
Organisme : NCATS NIH HHS
ID : UH3 TR003288
Pays : United States
Organisme : NIDCR NIH HHS
ID : T90 DE021984
Pays : United States
Organisme : NICHD NIH HHS
ID : R24 HD000836
Pays : United States
Organisme : NIDDK NIH HHS
ID : F31 DK130550
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI151698
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR002318
Pays : United States
Organisme : NIDDK NIH HHS
ID : UC2 DK126006
Pays : United States
Organisme : NCATS NIH HHS
ID : UG3 TR003288
Pays : United States
Organisme : NCATS NIH HHS
ID : UG3 TR002158
Pays : United States
Organisme : NHLBI NIH HHS
ID : K23 HL144916
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117914
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK130386
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK114886
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK124063
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK127553
Pays : United States
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