Illustration of a SARS-CoV-2 viral particle entering a cell. The particle passes through a cell membrane, made of two layers of lipids. A PNNL-OHSU team has shown how lipids are key to the virus’ ability to replicate. (Illustration by Michael Perkins/Pacific Northwest National Laboratory)
The virus that causes COVID-19 takes massive control of the body’s fat processing system, creating cellular deposits of fat that allow the virus to hijack the body’s molecular machinery and cause disease. After scientists at Oregon Health and Science University and the Department of Energy’s Pacific Northwest National Laboratory discovered the important role of fat for SARS-CoV-2, they used weight-loss drugs and other compounds targeting the fat to try to stop the virus in the cell. culture. Severed from its fatty fuel, the virus stopped replicating within 48 hours.
The researchers, who published their findings in Nature Communications, caution that the results are in cell cultures, not people; Much more research remains to see if such compounds hold promise for people diagnosed with COVID. However, scientists call the work a significant step toward understanding the virus.
Fikadu Tafesse, Ph.D. (OHSU)
“This is exciting work, but it is the beginning of a very long journey,” he said. Fikadu Tafesse, Ph.D., the study’s corresponding author and an assistant professor of molecular microbiology and immunology in the OHSU School of Medicine. “We have an interesting observation, but we have a lot more to learn about the mechanisms of this disease.”
fat as fuel
The team embarked on the study based on observations that people with a high body mass index and conditions such as cardiovascular disease and diabetes are more susceptible to the disease.
The team studied the effect of SARS-CoV-2 on more than 400 lipids, or fats, in two different human cell lines. The scientists found a massive change in lipid levels, with some fats increasing as much as 64-fold. In one cell line, the virus altered almost 80% of the fats; in the other, levels of just over half were changed.
The most affected lipids were triglycerides, those little packets of fat that most patients try to keep to a minimum. Triglycerides are crucial to our health as they allow us to store energy and maintain healthy membranes in our cells.
Turns out those oily grease stains are also critical for the COVID-19 virus.
Jennifer Kyle, Ph.D. (PNNL)
“Lipids are an important part of every cell. They literally hold us together by keeping our cells intact and are a major source of energy storage for our bodies,” he said. Jennifer Kyle, Ph.D., PNNL biomedical scientist who specializes in lipid measurement. “They are an attractive target for a virus.”
When we need energy, cells break down triglycerides into useful raw material: three fatty acids that are contained in each triglyceride molecule.
The team found that SARS-CoV2 doesn’t just increase the amount of triglycerides in our cells. The virus also changes much of our fat-processing system, changing the body’s ability to use fat for fuel.
The scientists went further and looked at the effects on lipid levels of 24 of the 29 virus proteins. The painstaking lab work was done at OHSU, and the cells were then shipped to PNNL for measurement and analysis.
cut off fuel supply
The team identified a handful of viral proteins whose effect on triglyceride levels was particularly strong. Based on the findings, the team searched databases and identified several compounds that could have the potential to mess up the body’s fat-processing system. Several proved to be effective in stopping virus replication in the laboratory.
An approved weight-loss drug, Orlistat, a lipase inhibitor that prevents triglycerides from being broken down into fatty acids, stopped viral replication. An experimental compound known as GSK2194069 also stopped the virus. These and other compounds worked against all SARS-CoV2 variants tested: alpha, beta, gamma and delta.
“As the virus replicates, it needs a continuous supply of energy. More triglycerides could provide that energy in the form of fatty acids. But we don’t know exactly how the virus uses these lipids to its advantage,” said Tafesse, whose team has also observed lipid changes as a result of Zika virus and HIV.
The research is the result of an ongoing collaboration between OHSU and PNNL. Four years ago, the institutions launched what is now known as the Pacific Northwest Biomedical Innovation Laboratory, or PMedIC, where scientists and clinicians work together to bring together basic science and clinical expertise to explore diseases and develop innovative therapies.
The effort combines PNNL’s basic research, particularly the ability to measure and interpret levels of molecules such as lipids, proteins, and metabolites, with OHSU’s extensive experience with science and human disease. The collaboration has led to several research projects and has produced results relevant to Zika virus, kidney failure, and Alzheimer’s disease.
Authors of the PNNL article include Kyle, Thomas Metz, Lisa Bramer Y Joon-Yong Lee. OHSU authors are Tafesse, first author Scotland Farley, Hans Leier, Jules Weinstein, Timothy Bates Y Carsten Schultz.
The work was funded by the National Institute of Environmental Health Sciences (U2CES030170). PNNL also supported the work. The team performed the lipid mass spectrometry measurements at EMSL, the Environmental Molecular Sciences Laboratory, a DOE Office of Science user facility located at PNNL.
Source: news.ohsu.edu