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Abstract: PO0009

Kidney Injury Molecule 1 Is a Receptor for SARS-CoV-2 in Lung and Kidney

Session Information

Category: Coronavirus (COVID-19)

  • 000 Coronavirus (COVID-19)

Authors

  • Mori, Yutaro, Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Ichimura, Takaharu, Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Fink, Corby, Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
  • Aschauer, Philipp, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States
  • Padmanabha Das, Krishna Mohan, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States
  • Padera, Robert F., Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Weins, Astrid, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Dekaban, Gregory A., Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
  • Dikeakos, Jimmy D., Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
  • Nasr, Mahmoud L., Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • 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 was first reported in Wuhan in 2019 and reached pandemic proportions. SARS-CoV-2-related respiratory failure and acute kidney injury (AKI) are major complications of infection. Kidney Injury Molecule-1 (KIM-1) is a scavenger receptor expressed by kidney epithelial cells and was previously reported to be a receptor for Hepatitis virus A. We hypothesized that KIM-1 is a receptor for SARS-CoV-2 and may play an important role in COVID-19 lung and kidney injury.

Methods

Human lung and kidney autopsy samples were immunostained and analyzed. Liposomal nanoparticles displaying the SARS-CoV-2 spike protein on their surface (virosomes) were generated. Virosome uptake by A549 lung epithelial cells, mouse primary lung epithelial cells and human kidney tubuloids (3D structures of kidney epithelial cells) was evaluated in the presences or absence of anti-KIM-1 antibody or TW-37, a small molecule inhibitor of KIM-1-mediated endocytosis that we discovered. Protein-protein interaction characteristics between purified SARS-CoV-2 spike protein and purified KIM-1 were determined using microscale thermophoresis. HEK293 cells expressing human KIM-1 but not angiotensin-converting enzyme 2 (ACE2) were infected with live SARS-CoV-2 or pseudovirions expressing the SARS-CoV-2 spike protein.

Results

KIM-1 was expressed in lung and kidney epithelial cells in COVID-19 patient autopsy 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 by human kidney tubuloids increased virosome uptake. KIM-1 positive cells expressed less ACE2. Using microscale thermophoresis, the EC50 for interaction between KIM-1 and SARS-CoV-2 spike protein and the receptor binding domain were 56.2±28.8 nM and 9.95±3.10 nM, respectively. KIM-1-expressing HEK293 cells without ACE2 expression had increased susceptibility to infection by live SARS-CoV-2 and pseudovirions expressing spike when compared with control cells.

Conclusion

KIM-1 is a receptor for SARS-CoV-2 in the lung and kidney and thus, KIM-1 inhibitors such as TW-37 can be potential therapeutics and/or prophylactic agents for COVID-19.

Funding

  • NIDDK Support