Kidney Injury Molecule 1 Is a Receptor for SARS-CoV-2 in Lung and Kidney
Bibliographic record
Abstract
Background: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was first reported in Wuhan in 2019 and reached pandemic proportions. SARS-CoV-2-related respiratory failure and acute kidney injury (AKI) are major complications of infection. Kidney Injury Molecule-1 (KIM-1) is a scavenger receptor expressed by kidney epithelial cells and was previously reported to be a receptor for Hepatitis virus A. We hypothesized that KIM-1 is a receptor for SARS-CoV-2 and may play an important role in COVID-19 lung and kidney injury. Methods: Human lung and kidney autopsy samples were immunostained and analyzed. Liposomal nanoparticles displaying the SARS-CoV-2 spike protein on their surface (virosomes) were generated. Virosome uptake by A549 lung epithelial cells, mouse primary lung epithelial cells and human kidney tubuloids (3D structures of kidney epithelial cells) was evaluated in the presences or absence of anti-KIM-1 antibody or TW-37, a small molecule inhibitor of KIM-1-mediated endocytosis that we discovered. Protein-protein interaction characteristics between purified SARS-CoV-2 spike protein and purified KIM-1 were determined using microscale thermophoresis. HEK293 cells expressing human KIM-1 but not angiotensin-converting enzyme 2 (ACE2) were infected with live SARS-CoV-2 or pseudovirions expressing the SARS-CoV-2 spike protein. Results: KIM-1 was expressed in lung and kidney epithelial cells in COVID-19 patient autopsy samples. Human and mouse lung and kidney epithelial cells expressed KIM-1 and endocytosed spike-virosomes. Both anti-KIM-1 antibodies and TW-37 inhibited uptake. Enhanced KIM-1 expression by human kidney tubuloids increased virosome uptake. KIM-1 positive cells expressed less ACE2. Using microscale thermophoresis, the EC50 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. KIM-1-expressing HEK293 cells without ACE2 expression had increased susceptibility to infection by live SARS-CoV-2 and pseudovirions expressing spike when compared with control cells. Conclusions: KIM-1 is a receptor for SARS-CoV-2 in the lung and kidney and thus, KIM-1 inhibitors such as TW-37 can be potential therapeutics and/or prophylactic agents for COVID-19. Funding: NIDDK Support, Other NIH Support - NCATS, Government Support - Non-U.S.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".