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

This study reports that KIM-1/TIM-1 serves as an alternative host receptor for SARS-CoV-2 entry. Reviewers find this study lacks experimental evidence that substantiates these claims. Findings should not be regarded as actionable.

Published onOct 23, 2020
Review 2: "KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney"

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.

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Review:

KIM1 (perhaps better known as TIM1) is well-documented to act as an attachment factor for multiple enveloped viruses, doing so by binding phosphatidylserine moieties on the surface of the virus (Evans & Liu, 2020; Jemielity et al., 2013). Whether it is a bona fide receptor for any virus is less clear. Ichimura and colleagues claim in this preprint that KIM1/TIM1 is a receptor for SARS-CoV2, the cause of the current COVID-19 pandemic, and they propose a role for it in the pathogenesis of COVID-19-associated kidney disease. The authors show there is relatively high expression of KIM1/TIM1 in lung and kidney tissues from patients with COVID-19 disease. However, the established SARS-CoV2 receptor, ACE2 (Hoffmann et al., 2020), was also present, and no data are presented that would suggest the virus is using anything other than ACE2 to enter cells, if it does establish infection in the kidney as some have suggested.

More interesting are data the authors present indicating that KIM1/TIM1 binds with high affinity to the SARS-CoV2 spike protein, S, the viral protein that interacts with the ACE2 receptor and mediates fusion with the cell membrane to initiate entry of the virus. They show cells expressing TIM1/KIM1 take up liposomes displaying the spike protein ectodomain (‘virosomes’) and that this uptake is blocked by both antibody to TIM1 and an inhibitor of KIM1/TIM1 endocytosis, TW-37. Importantly, the authors point out that their virosomes do not contain phosphatidylserine, and thus virosome uptake appears to be primarily driven by S protein binding to TIM1. Using microscale thermophoresis, they confirm this and report a KIM1/TIM1-ectodomain interaction EC50 of ~19 nM. These data are convincing enough, but it is important to note the highly artificial nature of the virosomes used by the authors to study this interaction. It remains to be seen if it is relevant in the context of infectious virus entry. There is more to a bona fide receptor than simply binding the virus, and a major question is whether the binding of TIM1/KIM1 to S triggers the conformational changes needed for membrane fusion. To confirm that TIM1 is indeed a receptor for SARS-CoV2, it must be shown that KIM1/TIM1 can render cells lacking ACE2 expression permissive for infection with SARS-CoV2, and that TIM1/KIM1 does more than just mediate attachment and endocytosis of an artificial virus surrogate.

In summary, the authors have shown that KIM1/TIM1 binds the SARS-CoV2 spike protein in vitro with high affinity and that it can mediate cellular uptake of liposomes displaying the spike protein on their surface. However, accepting the authors’ claim that TIM1 is a receptor for SARS-CoV2 must await further studies using infectious virus.

 

Evans, J. P., & Liu, S. L. (2020). Multifaceted Roles of TIM-Family Proteins in Virus–Host Interactions. In Trends in Microbiology. https://doi.org/10.1016/j.tim.2019.10.004

Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N. H., Nitsche, A., Müller, M. A., Drosten, C., & Pöhlmann, S. (2020). SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. https://doi.org/10.1016/j.cell.2020.02.052

Jemielity, S., Wang, J. J., Chan, Y. K., Ahmed, A. A., Li, W., Monahan, S., Bu, X., Farzan, M., Freeman, G. J., Umetsu, D. T., DeKruyff, R. H., & Choe, H. (2013). TIM-family Proteins Promote Infection of Multiple Enveloped Viruses through Virion-associated Phosphatidylserine. PLoS Pathogens. https://doi.org/10.1371/journal.ppat.1003232

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