The virus that causes COVID-19 makes a massive takeover of the body’s fat processing system, creating fat cell stores that allow the virus to sequester the body’s molecular machinery and cause disease.
After scientists discovered the important role of fat for SARS-CoV-2, they used weight-loss drugs and other fat-targeted compounds to try to stop the virus in cell culture. Cut off from its fatty fuel, the virus stopped replicating within 48 hours.
The authors of the recent article in Nature Communications warn that the results are in cell culture, not in people; Much more research remains to be seen if these compounds are promising for people diagnosed with COVID. But scientists, from the University of Oregon University of Health and Science and the Department of Energy’s Northwest Pacific National Laboratory, say the work is an important step toward understanding the virus.
This is an exciting job, but it is the start of a very long journey. We have an interesting observation, but we have much more to learn about the mechanisms of this disease. “
Fikadu Tafesse, corresponding author of the study and adjunct professor of molecular microbiology and immunology, Oregon Health & Science University
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 in two different human cell lines. Scientists found a massive change in lipid levels, with some fats increasing up to 64 times. In a cell line, nearly 80 percent of the fats were altered by the virus; on the other, levels of just over half were modified.
The most affected lipids were triglycerides, those small packets of fat that most patients try to minimize. Triglycerides are crucial to our health as they allow us to store energy and keep the membranes of our cells healthy.
It turns out that these greasy fat stains are also critical for the COVID virus.
“Lipids are an important part of every cell. They literally keep us together by keeping our cells intact and are an important source of energy storage for our bodies,” said Jennifer Kyle, a biomedical scientist at PNNL specialized in measurement. of lipids. “They are an attractive target for a virus.”
When we need energy, cells break down triglycerides into a useful raw material: three fatty acids contained in each triglyceride molecule.
The team found that SARS-CoV2 not only increases the number of triglycerides in our cells. The virus also changes much of our fat processing system, changing the body’s ability to use fat as fuel.
The scientists went further, observing the effects of 24 of the virus’s 29 proteins on lipid levels. The meticulous laboratory work was done at OHSU, and then the cells were sent to PNNL for measurement and analysis.
Cut off the fuel supply
The team identified a handful of viral proteins whose effect on triglyceride levels was especially strong. Based on the findings, the team searched databases and identified several compounds that could have the potential to disrupt the body’s fat processing system. Several have been shown to be effective in preventing the virus from reproducing in the laboratory.
An approved weight loss drug, Orlistat, a lipase inhibitor, stopped viral replication. An experimental compound known as GSK2194069 also stopped the virus. These and other compounds worked against all tested SARS-CoV2 variants: alpha, beta, gamma, and delta.
“As the virus replicates, it needs a continuous supply of energy,” said Tafesse, whose team has also seen changes in lipids as a result of the Zika virus and HIV. “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.”
The research is the result of a continuous connection between OHSU and PNNL. Four years ago, institutions launched a collaboration now known as the Pacific Northwest Biomedical Innovation Co-Laboratory, or PMedIC, where scientists and physicians work together to bring together basic science and clinical experience to explore disease and develop innovative therapies. .
The effort combines basic PNNL research, especially the ability to measure and interpret levels of molecules such as lipids, proteins, and metabolites, with OHSU’s extensive experience with human disease science. The collaboration has generated several research projects and produced relevant results for Zika virus, renal failure and Alzheimer’s disease.
Source:
DOE / Pacific Northwest National Laboratory
Magazine reference:
Farley, SE, et al. (2022) A global lipid map reveals conserved host-dependent factors among SARS-CoV-2 variants. Communications of nature. doi.org/10.1038/s41467-022-31097-7