Kidney injury molecule 1 is a receptor for SARS-COV-2

ABSTRACT

Background: Acute kidney injury (AKI) is a common feature of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2. Kidney Injury Molecule-1 (KIM-1) has been reported to be a receptor for Hepatitis A virus. KIM-1 is a scavenger receptor in kidney epithelial cells. We hypothesized that KIM-1 is a receptor for SARS-CoV-2 and may play an important role in COVID-19-associated AKI. Methods: Liposomal nanoparticles displaying the SARS-CoV-2 spike protein trimer (S1 and S2) on their surface (virosomes) were generated. We evaluated spike protein and virosome uptake by human KIM-1 expressing kidney epithelial cells and human kidney tubuloids, 3D structures of kidney epithelial cells. KIM-1-mediated uptake was compared to uptake by ACE2, a well-known receptor for SARS-CoV-2. Our recently discovered specific KIM-1 uptake inhibitor, JB-1 was tested for its ability to block virosomes uptake by KIM-1 expressing cells. KIM-1 expression was augmented in the tubuloids by infection with adenovirus vector carrying human KIM-1 cDNA to examine if the virosome uptake was enhanced. Protein-protein interaction characteristics between purified SARS-CoV-2 spike protein and S1 binding domain and purified KIM-1 were determined using microscale thermopheresis. Results: KIM-1 expression on kidney epithelial cells markedly enhanced virosome uptake, despite no change in ACE2 expression. This KIM-1 specific uptake was inhibited by JB-1. Human kidney tubuloids also endocytosed virosomes, and tubuloids with enhanced KIM-1 expression secondary to infection of KIM-1-adenovirus had increased uptake of virosomes. Using microscale thermopheresis the Kd 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. Conclusions: KIM-1 is a receptor for SARS-CoV-2. KIM-1 specific uptake of the SARS-CoV-2- virosomes suggests that KIM-1 confers efficient SARS-CoV-2 binding in kidney epithelial cells when these cells are expressing KIM-1. The KIM-1 dependent virosome uptake by 3D tubuloids indicates that this can be a valuable human cell model for studying SARS-CoV-2 interactions and testing for inhibitors. KIM-1 inhibitors, such as JB-1, can be potential therapeutics SARS-CoV-2 for COVID-19. Kidney tubular intraluminal and systemic circulating levels of KIM-1 ectodomain may be protective by acting as decoy receptor for the virus.