Abstract: FR-PO1119
Kidney Injury Molecule-1 Is an Independent Receptor from ACE2 for SARS-CoV-2 in Lung and Kidney
Session Information
- COVID-19 - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Coronavirus (COVID-19)
- 000 Coronavirus (COVID-19)
Authors
- Mori, Makiko, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
- Mori, Yutaro, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
- Fink, Corby, Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
- Ichimura, Takaharu, Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Sako, Keisuke, Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Nakao, Yuki, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
- Weins, Astrid, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Uchida, Shinichi, Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
- Bonventre, Joseph V., Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 continues to contribute to a world-wide pandemic. SARS-CoV-2-associated respiratory failure and acute kidney injury are major complications of infection. KIM-1 is a scavenger receptor expressed by renal epithelial cells and has been reported to be a receptor for several viruses. We hypothesized that KIM-1 is a receptor for SARS-CoV-2 and may play an essential role in COVID-19 lung and kidney injury.
Methods
Human lung and kidney autopsy samples were immunostained and analyzed. Uptake of “virosomes”, liposomal nanoparticles displaying the SARS-CoV-2 spike protein, by A549 lung epithelial cells, mouse primary lung epithelial cells, and human kidney tubular organoids was evaluated in the presence or absence of anti-KIM-1 antibody or TW-37, a KIM-1-mediated endocytosis inhibitor. Protein-protein interaction characteristics between purified SARS-CoV-2 spike protein and purified KIM-1 were determined using flow cytometry-based immunoprecipitation. HEK293 cells expressing human KIM-1 but not functional angiotensin-converting enzyme 2 (ACE2), a known receptor, were infected with live SARS-CoV-2. ACE2 complete knockout HEK293 cells were produced and exposed to the SARS-CoV-2 spike protein.
Results
KIM-1 was expressed in lung and kidney epithelial cells in COVID-19 patient samples. Human and mouse lung and kidney epithelial cells expressed KIM-1 and endocytosed spike-virosomes. Both anti-KIM-1 antibodies and TW-37 inhibited uptake. Enhanced KIM-1 expression in human kidney tubular organoids increased virosome uptake. Purified SARS-CoV-2 spike protein and KIM-1 bound to each other and TW-37 inhibited the binding. KIM-1-expressing HEK293 cells without functional ACE2 expression had increased susceptibility to infection by live SARS-CoV-2 when compared with control cells. KIM-1-expressing ACE2 knockout HEK293 cells internalized SARS-CoV-2 spike protein.
Conclusion
KIM-1 is an independent receptor from ACE2 for SARS-CoV-2 in the lung and kidney based on ACE2 knockout cell condition. TW-37 can be potential therapeutic agent and/or prophylactic agent for COVID-19.
Funding
- NIDDK Support – Bayer Yakuhin Ltd.