SARS-CoV-2 requires cholesterol to invade cells and form megacells

People who use cholesterol-lowering drugs may do better than others if they get the new coronavirus. A new study suggests why: the virus depends on the fatty molecule to get past the protective membrane of the cell.

To cause COVID-19, the SARS-CoV-2 virus must enter human cells – and it needs an accomplice. Cholesterol, the waxy compound better known for clogging arteries, helps the virus open cells and slip in, reports Howard Hughes Medical Institute researcher Clifford Brangwynne.

Without cholesterol, the virus cannot get past the protective barrier of a cell and cause infection, the team writes in a pre-print posted on December 14, 2020 on bioRxiv.org. has not yet undergone the scientific examination process of peer review.

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

The finding may underlie the better health outcomes seen in COVID-19 patients using cholesterol-lowering drugs, known as statins, he adds. Although scientists have not yet determined the responsible mechanism, this study and another published last fall suggest that the drug SARS-CoV-2 may end up in the cells by denying cholesterol.

This discovery of the importance of cholesterol could help scientists develop new stop-gap measures to treat COVID-19 until most people are vaccinated, Brangwynne says. The work may also shed light on a strange feature of the disease: the formation of giant, composite cells found in the lungs of COVID-19 patients. In their experiments, the scientists looked at similar megacells.

Mimicking a viral infection

In normal times, Brangwynne’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 and trained their biological expertise on SARS-CoV-2. They began investigating how viral and human proteins interact, and how the interaction can penetrate SARS-CoV-2 into cells. “We are not a laboratory for virology, we have never worked in this space, so we started thinking about the tools and approaches we developed,” he says.

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

In the laboratory, the researchers observed how cells were linked to these proteins in the laboratory. First, small tentacles appeared from cells with ACE2 and pinned to stimulate proteins on nearby cells. At these points, the two cellular membranes fused and formed openings, causing the contents of the cells to mix. Eventually, the two cells fused – similar to how scientists expect the virus to fuse with a cell to infect it.

The researchers, including David Sanders, Chanelle Jumper and Paul Ackerman of Princeton, tried to disrupt the cell mix. Using an automated system, they tested the effects of about 6,000 compounds, as well as more than 30 adaptations to the vein protein. These experiments and others have suggested that if SARS-CoV-2’s membrane does not have cholesterol, the virus cannot enter its target cell.

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

“Cholesterol has been studied very well 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 greatly between viruses.” It is not clear how cholesterol helps SARS-CoV-2, but understanding the process may provide clues about the biology of 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, Kasson said. But that may not be the only way drugs can change the course of viral infections, he says. “It’s a bit complicated because statins also alter the immune response.”

Mysterious megacells

While Brangwynne’s experiments were going on, his team noticed something strange. The cells kept engulfing each other and wasting their contents like eggs bursting into a bowl. The composite cells, known as syncytia, that appear under the microscope resemble those found in healthy tissues, such as muscle and placenta, and in some viral diseases.

“People already knew that the COVID-19 virus would create syncytia, but the researchers were able to visualize the process nicely,” said Jennifer Lippincott-Schwartz, a senior group leader at HHMI’s Janelia Research Campus, who was not involved in the research. not. “Cell-cell fusion is itself a real under-studied field in biology.”

The experiments probably illustrate how megacells occur in patients’ lungs, she says. “The formation of syncytia can be very harmful in the case of COVID, where it can destroy lung tissues and lead to death.”

Brangwynne says it is not yet clear whether syncytia plays an important role in the progress of COVID-19. But, his team writes, the discovery of cholesterol’s contribution could help scientists fight the disease. “Our findings highlight the potential usefulness of statins and other [similar] treatments. ”