Metabolic changes in lung epithelial cells infected with SARS-CoV-2.

Key Messages

This lab study examines the changes in gene activity in primary lung epithelial cells after SARS-CoV-2 infection and gene activity in biopsied lung tissue from COVID-19 patients.

SARS-CoV-2 was used to infect primary human bronchial epithelial cells and lung tissue was biopsied from COVID-19 patients. A method called “RNA analysis” was used to identify increased gene activity in the infected cells and lung biopsies.

The findings revealed the increased gene activity in infected lung cells resulted in changes to the metabolism of cholesterol and other lipids.

Drugs that are known to target lipid, glucose, and mitochondrial metabolism were used to treat the lung cells infected with the SARS-CoV-2 virus.

The drug fenofibrate reduced the accumulation of phospholipids which are components of the cell membrane that are hijacked for viral replication. The drug also decreased glucose breakdown, helping to starve the virus of energy.

A 5-day treatment of the infected cells with fenofibrate lowered the viral load (i.e. the amount of virus in the cells) without affecting cell viability.

Increased levels of cholesterol and lipids are essential for SARS-CoV-2 replication. Fenofibrate reduces the availability of cholesterol and other lipids by activating PPARα, a protein which is a key regulator of lipid metabolism. PPARα could prove to be an important drug target for the fight against COVID-19.

SSRN Electronic Journal

Publication Date: July 14, 2020
Peer Reviewed: No
Publication Type: Original | Preclinical

The SARS-CoV-2 Transcriptional Metabolic Signature in Lung Epithelium

Avner Ehrlich, Skyler Uhl, Konstantinos Ioannidis, Matan Hofree, Benjamin R. tenOever, Yaakov Nahmias


Viruses are efficient metabolic engineers that actively rewire host metabolic pathways to support their lifecycle. Charting SARS-CoV-2 induced metabolic changes in lung cells could offer insight into COVID-19 pathogenesis while presenting new therapeutic targets. Here we show that the transcriptional response SARS-CoV-2 in primary lung epithelial cells and biopsies of COVID-19 patients is predominantly metabolic. This transcriptional signature was dominated by changes to lipid metabolism and the induction of IRE1 and PKR pathways of endoplasmic stress in a process regulated by several viral proteins. Transcriptional regulatory analysis of these changes reveals small clusters of transcription factors modulating key enzymes in each pathway. The upregulation of glycolysis and the dysregulation of the citric acid cycle was mediated by NFκB and RELA. While the upregulation of fatty acid and cholesterol synthesis showed a more complex control conditionally modulated by ER-stress activated PPARγ, C/EBP, and PPARα. Viral protein ORF3a appeared to interact with all three pathways suggesting both direct and indirect modulation of host metabolism. Finally, we show that PPARα-agonist fenofibrate reversed the metabolic changes induced by SARS-CoV-2 blocking viral replication. Taken together, our data suggest that elevated lipid metabolism may underlie aspects of COVID-19 pathogenesis, offering new therapeutic avenues in targeting this critical pathway on which the virus relies.

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). This work was additionally funded by generous support from the Marc Haas Foundation, the National Institutes of Health, and DARPA’s PREPARE Program (HR0011-20-2-0040). The views, opinions, and/or findings expressed are those of the author and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. government (BRT).

Ethical Approval: Experiments using samples from human subjects were conducted in accordance with local regulations and with the approval of the institutional review board at the Icahn School of Medicine at Mount Sinai under protocol HS#12-00145.