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

People who take cholesterol-lowering drugs may do better than others if they get the new coronavirus. A new study indicates why: the virus depends on the fat molecule to pass through the cell’s protective membrane.

To cause COVID-19, the SARS-CoV-2 virus must force its way into people’s cells – and it needs an accomplice. Cholesterol, the waxy compound best known for clogging arteries, helps the virus open cells and slide inward, reports Clifford Brangwynne, a researcher at the Howard Hughes Medical Institute.

Without cholesterol, the virus cannot sneak through a cell’s protective barrier and cause infection, the team writes in a preprint published on bioRxiv.org on December 14, 2020. The work, which recreated the initial stage of infection in cells grown in the laboratory, has not yet gone through the peer review scientific verification process.

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

The finding may underlie the better health outcomes seen in patients with COVID-19 taking cholesterol-lowering drugs known as statins, he adds. 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 discovery of the importance of cholesterol may help scientists develop new interim measures to treat COVID-19 until most people are vaccinated, says Brangwynne. The work may also shed light on a strange feature of the disease: the formation of giant compound cells found in the lungs of patients with COVID-19. In their experiments, the scientists saw similar megacells emerging under the microscope.

Mimicking a viral infection

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

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

In the laboratory, the researchers observed the interaction of cells grown in the laboratory with these proteins. First, tiny tentacles emerged from cells with ACE2 and fixed on peak proteins in nearby cells. At these points, the two cell membranes fused and the openings formed, allowing the cell contents to mix. Eventually, the two cells merged – similar to how scientists expect the virus to merge with a cell to infect it.

The researchers, including David Sanders, Chanelle Jumper and Paul Ackerman, from Princeton, tried to stop this cell fusion. Using an automated system, they tested the effects of about 6,000 compounds, as well as more than 30 adjustments to the peak protein. These experiments and others suggested that if the SARS-CoV-2 membrane lacks cholesterol, the virus cannot enter the target cell.

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

“Cholesterol has been very well studied as an important factor in a large number of viral infections,” says Peter Kasson, a scientist at the University of Virginia who studies the physical mechanisms of viral diseases. “The interesting thing is that the role of cholesterol in viral entry varies widely among viruses.” It is unclear exactly how cholesterol helps SARS-CoV-2, but understanding this process may offer clues about the biology of the infection, says Kasson, who was not involved in the research.

The apparent beneficial effect of statins also extends to other viral infections. Some research suggests that these drugs harm the flu virus by depriving it of cholesterol, says Kasson. But that may not be the only way that drugs can change the course of viral infections, he says. “It’s a little bit complicated because statins also change the immune response.”

Mysterious Mega Cells

While Brangwynne’s experiments were running, his team noticed something strange. The cells continued to swallow each other, spreading their contents like broken eggs in a bowl. The composite cells, known as syncytia, 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 will create syncytia, but the researchers were able to visualize the process beautifully,” said Jennifer Lippincott-Schwartz, senior group leader at HHMI’s Janelia Research Campus, who was not involved in the research. . “Cell-cell fusion is in itself a very little studied area in biology.”

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

Brangwynne says it is still unclear whether or not syncytia play an important role in the progression of COVID-19. But, his team writes, the discovery of the contribution of cholesterol may help scientists fight the disease. “Our findings underscore the potential usefulness of statins and other [similar] treatments. ”