KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney

Abstract

SARS-CoV-2 precipitates respiratory distress by infection of airway epithelial cells and is often accompanied by acute kidney injury. We report that Kidney Injury Molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1) is expressed in lung and kidney epithelial cells in COVID-19 patients and is a receptor for SARS-CoV-2. Human and mouse lung and kidney epithelial cells express KIM-1 and endocytose nanoparticles displaying the SARS-CoV-2 spike protein (virosomes). Uptake was inhibited both by anti-KIM-1 antibodies and by TW-37, our newly discovered inhibitor of KIM-1-mediated endocytosis. Enhanced KIM-1 expression by human kidney tubuloids increased uptake of virosomes. KIM-1 positive cells express less angiotensin-converting enzyme 2 (ACE2), the well-known receptor for SARS-CoV-2. Using microscale thermophoresis, the EC50 for KIM-1-SARS-CoV-2 spike protein, and receptor binding domain (RBD) interactions, were 19 and 10 nM respectively. Thus KIM-1 is an alternative receptor to ACE2 for SARS-CoV-2. KIM-1 targeted therapeutics may prevent and/or treat COVID-19.

Interferon-regulated genetic programs and JAK/STAT pathway activate the intronic promoter of the short ACE2 isoform in renal proximal tubules

“…Some of the significantly upregulated genes are known to be regulators of renal injury, but belong to divergent pathways, either driving inflammation like IRF1 or TLR4 ( Wang et al, 2009 ; Wu et al, 2007 ) or attenuating it like IL4 and IL15 signaling ( Eini et al, 2010 ; Zhang et al, 2017 ). Recently, Ichimura et al ( Ichimura et al, 2020 ) reported that KIM-1 ( HAVCR1 ) might serve as an additional SARS-CoV-2 receptor. KIM-1 is usually upregulated in kidney injury models, but interferon treatment alone did not yield increase in its expression.…”

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

“…Thus, in addition to ACE2, several other membrane components have been proposed to function as co-receptors or attachment sites for SARS-CoV and SARS-CoV-2. These include Cluster of Differentiation 147 (CD147), also known as Basigin (BSG) [ [242] , [243] , [244] , [245] ], Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), also known as Cluster of Differentiation 209 (CD209) [ [246] , [247] , [248] , [249] , [250] , [251] ], Neuropilin-1 [ 252 , 253 ], glycosaminoglycans [ 254 ], heparan sulphate [ 255 ], and kidney injury molecule-1 [ 256 ]. Interestingly, in reconstituted lipid membranes devoid of ACE2, binding of the S1 subunit of SARS-CoV-2 spike protein to neutral phospholipid membranes and liposomes was reported to cause mechanical destabilization and membrane permeabilization in a receptor-independent manner [ 257 ].…”

Will SARS-CoV-2 Infection Elicit Long-Lasting Protective or Sterilising Immunity? Implications for Vaccine Strategies (2020)

“…Alternatively, the viral particle can be endocytosed and enter the endosome/lysosomal pathway, where cathepsin L has been found to activate S protein and trigger fusion (15). Other host factors have been suggested to facilitate SARS-CoV-2 cell entry (18)(19)(20)(21)(22)(23)(24). Interestingly, Neuropilin-1 (NRP1), highly present in human respiratory and olfactory epithelium, has been shown to potentiate SARS-CoV-2 infectivity in the presence of ACE2 and TMPRSS2 by interacting with the furin-cleaved spike (25).…”