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Abstract: SA-OR02

Selective Tropism of SARS-CoV-2 in Genome-Edited Kidney Organoids Reveals Nephropathic and Therapeutic Effects

Session Information

Category: Coronavirus (COVID-19)

  • 000 Coronavirus (COVID-19)

Authors

  • Helms, Louisa, University of Washington, Seattle, Washington, United States
  • Juliar, Benjamin A., University of Washington, Seattle, Washington, United States
  • Himmelfarb, Jonathan, University of Washington, Seattle, Washington, United States
  • Freedman, Benjamin S., University of Washington, Seattle, Washington, United States
Background

Kidneys are critical target organs of SARS-CoV-2 infection and COVID-19 disease, but whether renal effects are due to direct infection via ACE2 or indirect damage to other organs is unknown. The added risk of pre-existing polycystic kidney disease and efficacy of proposed therapeutics are not yet clear and difficult to assess in patients, animals, or cells. Organoids provide a gene editable platform to assess SARS-CoV-2 kidney infection and its tropism, pathophysiology, and effects of COVID-19 therapeutics.

Methods

Kidney organoids were differentiated from control, PKD2-/-, or ACE2-/- stem cells, and infected with WA1/2020 SARS-CoV-2 ± mNeonGreen transgene. Organoids were infected under BSL3 conditions with supernatant collected for plaque assays and analyzed with immunofluorescence or RNA was extracted. Remdesivir was added post infection, or de novo designed LCB1 Spike binder proteins were pre-incubated with SARS-CoV-2 prior to infection.

Results

SARS-CoV-2 specifically infected organoid proximal tubules, producing bulbous cells with disrupted markers. In ACE2-/- kidney organoids, viral replication was reduced by 85%. In PKD2-/- organoids, cyst-lining epithelial cells were infected at comparable levels to healthy controls. Remdesivir treatment reduced viral replication by 71.4%. Pre-incubation of LCB1 spike binder peptides prevented viral replication at ≥ 0.3 µM and significantly reduced detectable SARS-CoV-2 infection.

Conclusion

Proximal tubular kidney epithelium is susceptible to SARS-CoV-2 infection. ACE2 is the primary entry receptor for SARS-CoV-2 infection, but alternate pathways facilitate low levels of infection. PKD cysts can be infected comparably to controls. Remdesivir and LCB1 treatment can protect kidney epithelium from SARS-CoV-2 replication via distinct mechanisms. This work provides insight into susceptibility of kidneys to SARS-CoV-2 and the effectiveness of current and developing therapeutics for treating COVID-19.

Funding

  • Other U.S. Government Support