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SARS-CoV-2 needs cholesterol to invade cells and form mega cells

SARS-CoV-2 needs cholesterol to invade cells and form mega cells

The researchers designed the cells to carry either a protein (green) from SARS-CoV-2 or its human target ACE2 (magenta). When they are close to each other, the cell membranes fuse. Researchers believe that such a process allows the virus to glide into cells. Credit: D. Sanders et al./bioRxiv.org

People taking cholesterol-lowering drugs may do better than others if they catch the new coronavirus. A new study suggests why: the virus relies on the fat molecule to cross the cell’s protective membrane.

To cause COVID-19, the SARS-CoV-2 virus must enter human cells – and it needs an accomplice. Cholesterol, the wax compound better known for clogging arteries, helps the virus open cells and infiltrate, according to the laboratory of Howard Hughes Medical Institute researcher Clifford Branguin.

Without cholesterol, the virus cannot penetrate the cell’s protective barrier and cause infection, the team wrote in a preprint published on bioRxiv.org on December 14, 2020. Work that recreates the early stages of infection in laboratory-grown cells is still there. has not gone through the peer review process.

“Cholesterol is an integral part of the membranes that surround cells and some viruses, including SARS-CoV-2. It makes sense that it must be so important for infection,” said Branguin, a biophysical engineer at Princeton University.

The finding may be the basis for the better health outcomes seen in patients with COVID-19 taking cholesterol-lowering drugs known as statins, he added. Although scientists have not yet established the responsible mechanism, this study and another published last fall suggest that the drugs prevent SARS-CoV-2 from entering cells by denying it cholesterol.

This finding about the importance of cholesterol could help scientists develop new measures to stop treatment with COVID-19 until most people are vaccinated, Branguin said. The work may also shed light on a strange feature of the disease: the formation of giant, composite cells found in the lungs of patients with COVID-19. In their experiments, the scientists saw that such mega cells appeared under the microscope.

Many cells can fuse to produce mega cells (green) or syncytium, similar to those found in the lungs of patients with COVID-19. Credit: D. Sanders et al./bioRxiv.org

Imitation of a viral infection

In normal times, Branguin’s team studies the physical forces that organize molecules in cells. But in the spring of 2020, his lab, like many others around the world, shifted its focus, training its biological experience on SARS-CoV-2. They began to study how viral and human proteins interact and how this interaction allows SARS-CoV-2 to enter cells. “We’re not a virology lab, we’ve never worked in this space before, so we started thinking about the tools and approaches we developed that we could use,” he says.

Brangwynne’s lab often works with cells grown in a laboratory. To mimic SARS-CoV-2 infection, his team designed such cells to sport one of two molecules, either the viral “protein” or the human ACE2 protein. (To cause infection, the virus must fuse its membrane with the cell’s membrane. This process begins when the protein proteins meet their cellular target, ACE2.)

In the lab, researchers observed how cells grown in the lab interacted with these proteins. First, small tentacles emerged from ACE2 cells and adhered to push proteins onto nearby cells. At these points, the two cell membranes fuse to form openings, allowing the contents of the cells to mix. Eventually, the two cells fused together, much like the way scientists expect a virus to fuse with a cell to infect it.

Researchers, including Princeton’s David Sanders, Chanel Jumper and Paul Ackermann, have tried to disrupt this cell fusion. Using an automated system, they tested the effects of about 6,000 compounds, as well as more than 30 pinches of spike protein. These experiments and others suggest that if the SARS-CoV-2 membrane is free of cholesterol, the virus cannot enter its target cell.

This is not the first evidence of cholesterol. A previous study by a group at the University of California, San Diego, found that the body’s immune response to the virus produced a compound that depleted cholesterol – but in this case from the cell’s own membrane, not the virus.

Credit: Howard Hughes Medical Institute

“Cholesterol is very well studied as an important factor in a large number of viral infections,” said Peter Casson, a scientist at the University of Virginia who studies the physical mechanisms of the viral disease. “Interestingly, the role of cholesterol in virus penetration varies greatly in viruses.” It is not clear how cholesterol supports SARS-CoV-2, but understanding this process may provide clues to the biology of the infection, said Casson, who was not involved in the study.

The obvious beneficial effect of statins extends to other viral infections. Some studies show that these drugs damage the flu virus by depriving it of cholesterol, Casson said. But this may not be the only way drugs can change the course of viral infections, he said. “It’s a little complicated because statins also modify the immune response.”

Mysterious mega cells

While Branguin was experimenting, his team noticed something strange. The cells continue to swallow each other, scattering their contents like eggs cracked in a bowl. The combined cells, known as syncytium, that appeared under the microscope resemble those found in healthy tissues, such as muscles and the placenta, and in some viral diseases.

“People already knew that the COVID-19 virus would create syncytium, but the researchers were able to visualize the process beautifully,” said Jennifer Lipinkot-Schwartz, senior group leader at Janelia’s research campus at HHMI, which was not involved in the study. “Cell fusion in itself is a really under-studied field in biology.”

The experiments probably illustrate how mega cells found in patients’ lungs are formed, she said. “Syncytium formation can be very harmful in the case of COVID, where it can destroy lung tissue and lead to death.”

Branguin says it is not yet clear whether syncytia plays a major role in the development of COVID-19. But his team writes that finding the contribution of cholesterol can help scientists fight the disease. “Our findings highlight the potential benefits of statins and others [similar] treatment. ”

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More information:
David W. Sanders et al. SARS-CoV-2 requires cholesterol for virus penetration and pathological syncytium formation, bioRxiv (2020). DOI: 10.1101 / 2020.12.14.422737

Provided by the Howard Hughes Medical Institute

Quote: SARS-CoV-2 needs cholesterol to invade cells and form mega cells (2021, January 22), extracted on January 22, 2021 from https://phys.org/news/2021- 01-sars-cov-cholesterol-invade-cells- mega.html

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