Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, observational, and non-randomized open label interventional study
- Hebrew University of Jerusalem, Israel
- Barzilai Medical Center, Israel
- Sheba Medical Center, Israel
- Shamir (Assaf Harofeh) Medical Center, Israel
- Broad Institute, United States
- Jerusalem College of Technology, Israel
- Tel Aviv Sourasky Medical Center, Israel
- Policlinico S.Orsola-Malpighi, Italy
- Università degli Studi di Milano, Italy
- Niguarda Hospital, Italy
- University of Pennsylvania, United States
- BioStats Statistical Consulting Ltd, Israel
Abstract
Background: Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention.
Methods: We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran's Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care.
Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARa-dependent mechanism in both alpha and delta variants. Analysis of 3,233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period.
Conclusions: Taken together, our data suggest that pharmacological modulation of PPARa should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials.
Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003).
Clinical trial number: NCT04661930.
Data availability
Software resources: Our custom Cell Analysis CellProfiler® Pipeline is available on https://github.com/avnere/Single-Cell-Analysis-CellProfiler-Pipeline.
-
Transcriptional response to SARS-CoV-2 infectionNCBI Gene Expression Omnibus, GSE147507.
-
Single-cell landscape of bronchoalveolar immune cells in COVID-19 patientsNCBI Gene Expression Omnibus, GSE145926.
-
Primary Human Airway Epithelial Cultures infected with SARS-CoV-2NCBI Gene Expression Omnibus, GSE147507.
Article and author information
Author details
Funding
European Research Council (681870)
- Yaakov Nahmias
Nikoh Foundation
- Yaakov Nahmias
Sam and Rina Frankel
- Yaakov Nahmias
Abbott (FENOC0003)
- Yaakov Nahmias
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Michael Czech, University of Massachusetts Medical School, United States
Ethics
Human subjects: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.In the observational studies - the Israeli study was approved by the local institutional review board of the Hadassah Medical Center (IRB approval number no. HMO 0247-20) and the local institutional review board of the Ichilov Medical Center (IRB approval number no. 0282-20-TLV). The Italian study was reviewed by the local ethical board (AVEC) of the IRCSS S.Orsola-Malpighi University Hospital (approval number no. code LLD-RP2018).The American study was reviewed by the local institutional review board of the Corporal Michael J. Crescenz VA Medical Center (IRB approval number 01654).The interventional study was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonisation E6 and the principles of the Declaration of Helsinki or local regulations, whichever afforded greater patient protection. The study was reviewed and approved by the Barzilai Medical Center Research Ethics Committee (0105-20-BRZ).Statistical analysis of the Israeli studies was done by BioStats Statistical Consulting Ltd. (Maccabim, Israel), funded by the sponsor. Data management is performed in compliance with GCP and 21 CFR part 1. Statistical analyses and reporting are performed in compliance with E6 GCP, E9, and ISO 14155. Independently validated by the author. Statistical analysis of the Italian study was done by Prof. Arrigo Cicero and Dr. Chiara Pavanello. Statistical analysis of the US study was done by Prof. Jordana Cohen.
Version history
- Preprint posted: August 12, 2021 (view preprint)
- Received: May 3, 2022
- Accepted: January 26, 2023
- Accepted Manuscript published: January 27, 2023 (version 1)
- Version of Record published: February 17, 2023 (version 2)
Copyright
© 2023, Ehrlich et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 811
- views
-
- 137
- downloads
-
- 5
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, observational, and non-randomized open label interventional study
eLife 12:e79946.
https://doi.org/10.7554/eLife.79946
Further reading
-
- Cell Biology
Endogenous tags have become invaluable tools to visualize and study native proteins in live cells. However, generating human cell lines carrying endogenous tags is difficult due to the low efficiency of homology-directed repair. Recently, an engineered split mNeonGreen protein was used to generate a large-scale endogenous tag library in HEK293 cells. Using split mNeonGreen for large-scale endogenous tagging in human iPSCs would open the door to studying protein function in healthy cells and across differentiated cell types. We engineered an iPS cell line to express the large fragment of the split mNeonGreen protein (mNG21-10) and showed that it enables fast and efficient endogenous tagging of proteins with the short fragment (mNG211). We also demonstrate that neural network-based image restoration enables live imaging studies of highly dynamic cellular processes such as cytokinesis in iPSCs. This work represents the first step towards a genome-wide endogenous tag library in human stem cells.
-
- Biochemistry and Chemical Biology
- Cell Biology
Mediator of ERBB2-driven Cell Motility 1 (MEMO1) is an evolutionary conserved protein implicated in many biological processes; however, its primary molecular function remains unknown. Importantly, MEMO1 is overexpressed in many types of cancer and was shown to modulate breast cancer metastasis through altered cell motility. To better understand the function of MEMO1 in cancer cells, we analyzed genetic interactions of MEMO1 using gene essentiality data from 1028 cancer cell lines and found multiple iron-related genes exhibiting genetic relationships with MEMO1. We experimentally confirmed several interactions between MEMO1 and iron-related proteins in living cells, most notably, transferrin receptor 2 (TFR2), mitoferrin-2 (SLC25A28), and the global iron response regulator IRP1 (ACO1). These interactions indicate that cells with high MEMO1 expression levels are hypersensitive to the disruptions in iron distribution. Our data also indicate that MEMO1 is involved in ferroptosis and is linked to iron supply to mitochondria. We have found that purified MEMO1 binds iron with high affinity under redox conditions mimicking intracellular environment and solved MEMO1 structures in complex with iron and copper. Our work reveals that the iron coordination mode in MEMO1 is very similar to that of iron-containing extradiol dioxygenases, which also display a similar structural fold. We conclude that MEMO1 is an iron-binding protein that modulates iron homeostasis in cancer cells.
