RR:C19 Evidence Scale rating by reviewer:
Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.
In this preprint, Bonventre and colleagues address the possibility that the transmembrane protein Kim-1 (aka Tim-1) is a cellular receptor for SARS-CoV-2, the causative agent of COVID-19. This is a reasonable hypothesis, as Kim-1 has been reported to serve as a receptor for several other viruses, including Ebola, Dengue and Hepatitis A viruses. Of note the first description of this protein, by Kaplan and colleagues, was as a receptor for Hepatitis A virus; hence the gene is known as HAVCR1. Bonventre and colleagues then showed that this same protein was upregulated in kidney after acute injury, which led them to name it kidney injury molecule 1 (Kim-1).
The authors first examined the expression of Kim-1 on biopsy and post-mortem lung and kidney tissue from several COVID-19 or control patients, as well as in mouse kidney. They note that there is expression of Kim-1 in both lung and kidney. At least in the kidney, this is dependent on injury, something that they confirmed in mouse. By contrast, expression of ACE2, the most well-established receptor for SARS-CoV-2, is constitutive. The authors also show the presence of SARS-CoV-2 viral antigens in both of these tissues, as expected.
The majority of the subsequent experiments involve the use of “virosomes,” i.e. liposomes carrying the spike protein of SARS-CoV-2. The authors show, using both cell lines and primary cells, that cells expressing Kim-1 display increased uptake of the SARS-CoV-2 pseudo-typed virosomes. Finally, using purified proteins in vitro, the authors show that the spike protein or RBD itself interacts with the extracellular domain of Kim-1 with a relatively high affinity (10-20 nM).
Strengths of this study include the use of primary human tissues for many experiments and the demonstration that the spike protein of SARS-CoV-2 can apparently bind to Kim-1. Weaknesses include the lack of any data with intact SARS-CoV-2 virus or data to disentangle the effects of Kim-1 from ACE2, which is also expressed by the cells that (inducibly) express Kim-1. Thus, I would suggest that the title of the preprint is still a stretch at this point, as it remains unclear whether Kim-1 is a bona fide cellular receptor for SARS-CoV-2 viral entry and infection. In conclusion, I would rate this preprint as potentially informative to the field.