KIM-1/TIM-1 is a receptor for SARS-CoV-2 in Lung and Kidney
Cardiff University review virology
First Author: Takaharu Ichimura
Journal/preprint name: medRxiv
Paper DOI: https://doi.org/10.1101/2020.09.16.20190694
Tags: In-vitro, Kidney, Lung, Acute Kidney Injury, Viral Uptake
This study highlights how uptake of SARS-Cov-2 virosomes into human alveolar basal epithelial cells and pig kidney lines was significantly reduced upon blockade of KIM-1. Equally, the uptake of SARS-CoV-2 virosomes increased upon upregulation of KIM-1 on human tubuloids and KIM-1 was shown to bind to SARS-CoV-2 spike protein ectodomain in-vitro. Overall, these observations suggest that KIM-1 may be a receptor for SARS-CoV-2 in both the lung and kidney.
KIM-1 was shown to be expressed in the autopsy lung samples of 10/11 patients who had died from SARS-CoV-2 infection; equally, 3 live biopsies of infected patients and 14/30 post-mortem biopsies showed KIM-1 expression
Uptake of fluorescent SARS-Cov-2 virosomes into A549 human alveolar basal epithelial cells was significantly reduced with anti-KIM-1 IgG or with TW-37, an inhibitor of KIM-1 mediated endocytosis; comparable observations were made using mouse primary lung epithelial cells
SARS-CoV-2 virosomes were uptaken into pig kidney lines expressing human KIM-1, an effect that did not occur in controls without KIM-1 expression and that was shown to be independent of ACE2 expression
KIM-1 expressing cells of human three dimensional tubuloids endocytosed SARS-Cov-2 virosomes, and effect that was enhanced when KIM-1 expression was increased
Finally, KIM-1 was shown to bind to the SARS-CoV-2 spike protein ectodomain and GST-RBD in-vitro, with an EC50 of 19nM and 10nM respectively.
Impact for COVID-19 research:
Implies that KIM-1 facilitated endocytosis of SARS-CoV-2 may contribute to the development of acute kidney injury, a major complication of SARS-CoV-2 infection, associated with higher morbidity and mortality of the virus. Given this, targeted treatment directed at KIM-1 may be therapeutic/prophylactic for acute kidney injury occurring secondary to SARS-CoV-2 infection
Study Type: In-vitro
Key Techniques: SARS-CoV-2 fluorescent virosomes composed of liposomes conjugate to spike ectodomain; internalization assay of virosomes; human renal tubuloids as a three-dimensional in-vitro model of kidneys
No assessment of KIM-1 expression of healthy volunteers was assessed, likely due to the difficult of obtaining kidney biopsies from healthy volunteers. Despite clearly shown in-vitro, assessing the contribution of KIM-1 to acute kidney injury using an in-vivo model would have strengthened their claims. Likewise, it would have been interesting to see if blocking KIM-1, either via antibody block or with TW-37, reduced uptake of virosomes into tubuloids.