Kidney Injury Molecule-1 Is an Independent Receptor from ACE2 for SARS-CoV-2 in Lung and Kidney

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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. Conclusions: 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, Commercial Support - Bayer Yakuhin Ltd., Private Foundation Support, Government Support - Non-U.S.

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