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BSG/CD147 and ACE2 receptors facilitate SARS-CoV-2 infection of human iPS cell-derived kidney podocytes

Titilola D. Kalejaiye, Rohan Bhattacharya, Morgan A. Burt, Tatianna Travieso, Arinze E. Okafor, View ORCID ProfileXingrui Mou, Maria Blasi, View ORCID ProfileSamira Musah
doi: https://doi.org/10.1101/2021.11.16.468893
Titilola D. Kalejaiye
1Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC
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Rohan Bhattacharya
1Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC
2Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC
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Morgan A. Burt
1Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC
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Tatianna Travieso
3Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC
4Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC
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Arinze E. Okafor
1Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC
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Xingrui Mou
1Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC
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Maria Blasi
3Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC
4Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC
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Samira Musah
1Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC
2Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC
5Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC
6Developmental and Stem Cell Biology Program, Duke University, Durham, NC
7Department of Cell Biology, Duke University, Durham, NC
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  • ORCID record for Samira Musah
  • For correspondence: samira.musah@duke.edu
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Abstract

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which was declared a pandemic by the World Health Organization (WHO) in March 2020. The disease has caused more than 5.1 million deaths worldwide. While cells in the respiratory system are frequently the initial target for SARS-CoV-2, clinical studies suggest that COVID-19 can become a multi-organ disease in the most severe cases. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often affected in severe COVID-19, remains poorly understood.

Method In this study, we employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes. We studied uptake of the live SARS-CoV-2 virus as well as pseudotyped viral particles by human iPS cell derived podocytes using qPCR, western blot, and immunofluorescence. Global gene expression and qPCR analyses revealed that human iPS cell-derived podocytes express many host factor genes (including ACE2, BSG/CD147, PLS3, ACTR3, DOCK7, TMPRSS2, CTSL CD209, and CD33) associated with SARS-CoV-2 binding and viral processing.

Result Infection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed viral uptake by the cells at low Multiplicity of Infection (MOI of 0.01) as confirmed by RNA quantification and immunofluorescence studies. Our results also indicate that direct infection of human iPS cell-derived podocytes by SARS-CoV-2 virus can cause cell death and podocyte foot process retraction, a hallmark of podocytopathies and progressive glomerular diseases including collapsing glomerulopathy observed in patients with severe COVID-19 disease. Additionally, antibody blocking experiments identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes.

Conclusion These results show that SARS-CoV-2 can infect kidney glomerular podocytes in vitro. These results also show that the uptake of SARS-CoV-2 by kidney podocytes occurs via multiple binding interactions and partners, which may underlie the high affinity of SARS-CoV-2 for kidney tissues. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.

Significant statement Many patients with COVID19 disease exhibit multiorgan complications, suggesting that SARS-CoV-2 infection can extend beyond the respiratory system. Acute kidney injury is a common COVID-19 complication contributing to increased morbidity and mortality. Still, SARS-Cov-2 affinity for specialized kidney cells remain less clear. By leveraging our protocol for stem cell differentiation, we show that SARS-CoV-2 can directly infect kidney glomerular podocytes by using multiple Spike-binding proteins including ACE2 and BSG/CD147. Our results also indicate that infection by SARS-CoV-2 virus can cause podocyte cell death and foot process effacement, a hallmark of podocytopathies including collapsing glomerulopathy observed in patients with severe COVID-19 disease. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 17, 2021.
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BSG/CD147 and ACE2 receptors facilitate SARS-CoV-2 infection of human iPS cell-derived kidney podocytes
Titilola D. Kalejaiye, Rohan Bhattacharya, Morgan A. Burt, Tatianna Travieso, Arinze E. Okafor, Xingrui Mou, Maria Blasi, Samira Musah
bioRxiv 2021.11.16.468893; doi: https://doi.org/10.1101/2021.11.16.468893
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BSG/CD147 and ACE2 receptors facilitate SARS-CoV-2 infection of human iPS cell-derived kidney podocytes
Titilola D. Kalejaiye, Rohan Bhattacharya, Morgan A. Burt, Tatianna Travieso, Arinze E. Okafor, Xingrui Mou, Maria Blasi, Samira Musah
bioRxiv 2021.11.16.468893; doi: https://doi.org/10.1101/2021.11.16.468893

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