Home Cellular science Cellular quality control system identified as culprit in coronavirus infection

Cellular quality control system identified as culprit in coronavirus infection



While studying an illness caused by a close cousin of the virus behind COVID-19, a team of scientists have identified a compound that shows potential for relieving symptoms of coronavirus infections.

The team, from the Department of Energy’s Pacific Northwest National Laboratory and the University of North Carolina at Chapel Hill, studied the virus that causes Middle East respiratory syndrome, which is caused by a coronavirus. MERS is much less common, but much more deadly, than COVID-19.

The team set out to learn more about how the virus that causes MERS damages the lungs and harms patients. In lab studies, the team analyzed tens of thousands of measurements of proteins, molecular messengers, and other signals that occur after infection. They have identified a molecular process, which is part of the body’s quality control machinery, which plays a central role in damage from coronavirus infection.

Next, the team searched a large database of compounds and identified one, known as AMG PERK 44, that stopped the virus from replicating in human tissues in the lab. They also found that the compound had a potent effect on mice infected with the virus. The compound stimulated lung function and reduced lung damage and weight loss in mice, especially male mice.

The broad fight against respiratory diseases

Battelle, which operates PNNL, and UNC have filed a patent on the use of a PERK inhibitor to treat coronavirus infections. But scientists say it’s far too early to know if the compound could help patients. It is not currently used as a medicine.

Rather, they say that the results of their study, published in the journal mBio, are very useful as part of a larger effort to learn more about respiratory disease.

“Studies like this help us learn more about how deadly respiratory viruses work – how they do what they do, why they attack certain parts of the lung and not others,” the PNNL virologist said. Amy Sims, one of the first two co-authors of the article, with PNNL scientist Hugh Mitchell.

“Studying how these viruses work helps us understand why patients have the symptoms they do and, ultimately, how to treat or prevent the disease,” Sims added.

Sims has been studying coronaviruses for over 20 years. She and her collaborators began this study eight years ago, before the outbreak of the coronavirus that causes COVID-19. Years after Sims and his colleagues designed the study, its findings could be relevant to the millions of people who have been infected with SARS-CoV-2, the virus that causes COVID-19.

“Consider how quickly a vaccine to protect against COVID-19 was created and how quickly new drugs were found to treat the disease,” Sims said. “The success is not because scientists started from scratch when the virus emerged. They were able to draw on years and years of research to understand how the immune system works and how it responds to coronaviruses. You never know when some knowledge will prove crucial in the future.

Emergency response – for damaged proteins

The team’s studies led to proteins, molecules that are the workhorses of the body’s cells. Proteins perform a myriad of functions to keep organisms, like humans, alive and healthy. The body keeps a close eye, making sure that its proteins are intact and functioning.

When the body begins to produce proteins that are substandard for some reason, including infection, the protein repair machinery in a cell’s endoplasmic reticulum goes into emergency response mode. The organism can function as a sorting center for damaged proteins during times of stress. When inundated with misfolded proteins, the unfolded protein response, or UPR, kicks in. UPR temporarily stops all cellular activity related to making new proteins. This gives the cell time to make the necessary repairs to the misfolded proteins.

If too many proteins are damaged and the protein repair and folding mechanisms cannot recover, the system triggers other proteins to kill the cell.

It is this system that the PNNL-UNC team discovered to be very active in certain lung cells when the body responds to an infection with MERS.

For the present study, manipulation of lung tissue and mice was performed at UNC, in a lab led by one of the world’s top coronavirus researchers, Ralph Baric. PNNL scientists measured and interpreted large amounts of data on molecular messages. Sims worked in the Baric lab at UNC and joined PNNL early last year; the two institutions have worked together for years.

“Coronavirus infections cause complex disease phenotypes, and new strategies are needed to unravel host pathways that contribute to the development of serious and potentially fatal consequences,” said Baric.

Besides Sims and Mitchell, PNNL authors include Katrina Waters, lead author of the article, and Jennifer Kyle, Kristin Burnum-Johnson, Richard D. Smith and Thomas Metz. From UNC, authors include Lisa Gralinski, Mariam Lam, Mr. Leslie Fulcher, Ande West and Scott Randell, as well as lead authors Ralph Baric and Timothy Sheahan.

The work was funded by the National Institute of Allergy and Infectious Diseases, PNNL and others. The measurements were performed using mass spectrometry at EMSL, the Environmental Molecular Sciences Laboratory, a user facility of the DOE Office of Science at PNNL. NIH funding came from NIH / NIAID U19 grants AI109761, U19100625, and NIH U19-AI106772-01, as well as core support to the Marsico Lung Institute at UNC (via the CF BOUCHE15RO Foundation grant and NIH P30DK065988).

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