Viral protein fragments could reveal the mystery of the serious consequences of COVID-19

Many mysteries remain regarding the COVID-19 pandemic. For example, why does SARS-CoV-2, the virus that causes the disease, cause severe symptoms in some patients, while many other coronaviruses do not? And what causes strange symptoms to persist even after the infection has been cleared from a person’s system?

The world may now have the beginnings of answers. In a study published in the journal Proceedings of the National Academy of SciencesA multidisciplinary research team led by UCLA is exploring one way COVID-19 turns the immune system — which is crucial to keeping people alive — against the body itself, with potentially deadly results.

Using an artificial intelligence system they developed, the study authors analyzed the entire collection of proteins produced by SARS-CoV-2, then performed an exhaustive series of validation experiments.

Scientists have discovered that certain viral protein fragments, generated after the SARS-CoV-2 virus breaks down, can mimic a key part of the body’s machinery to amplify immune signals.

Their findings suggest that some of the most severe consequences of COVID-19 may result from overstimulation of these fragments of the immune system, thereby causing widespread inflammation in very different contexts, such as cytokine storms and life-threatening blood clotting.

The study was led by corresponding author Gerard Wong, professor of bioengineering in the UCLA Samueli School of Engineering and the Department of Chemistry and Biochemistry and the Department of Microbiology, Immunology and Molecular Genetics at the ‘UCLA College.

“What we found deviates from the standard picture of viral infection,” said Wong, who is also a member of the California NanoSystems Institute at UCLA. “The textbooks tell us that once the virus is destroyed, the diseased host ‘wins’ and different virus fragments can be used to train the immune system for future recognition. COVID-19 reminds us that it’s not that simple.

“For comparison, if one assumed that once food is digested into its molecular components its effects on the body cease, that would be very liberating; I wouldn’t have to worry about the half dozen jelly donuts I just made. eat. However, this simple image is not correct.

The research team found that SARS-CoV-2 fragments can mimic innate immune peptides, a class of immune molecules that amplify signals to activate the body’s natural defenses. Peptides are chains of amino acids like proteins, but shorter.

These immune peptides can spontaneously assemble into new structures with double-stranded RNA, a special form of molecule essential for building proteins from DNA, typically found in viral infections or released from dying cells .

The resulting hybrid complex of immune peptides and double-stranded RNA sets off a chain reaction that triggers an immune response.

In addition to their AI analysis, the researchers used cutting-edge methods to elucidate biological structures at the nanoscale and conducted experiments on cells and animals.

Compared to the relatively harmless coronaviruses that cause the common cold, the team found that SARS-CoV-2 harbors many more combinations of fragments that can better mimic human immune peptides.

Consistent with this, additional experiments with multiple cell types all consistently show that fragments of the SARS-CoV-2 coronavirus cause an amplified inflammatory response compared to those of a common cold coronavirus. Likewise, experiments in mice show that fragments of SARS-CoV-2 cause a huge immune response, especially in the lungs.

The findings could influence the treatment of COVID-19 and efforts to identify and monitor future coronaviruses capable of causing pandemics.

“We may be able to look at the protein composition of this year’s coronavirus strains and determine whether they are potentially likely to cause a pandemic or whether they will just cause a cold,” Wong said.

Wong and colleagues focused on three fragments of SARS-CoV-2. Using a technique for analyzing detailed molecular structures called synchrotron X-ray diffraction, they discovered that, like the innate immune peptide, SARS-CoV-2 fragments can organize double-stranded RNA into structures that stimulate the system immune.

“We saw that the various forms of debris from the destroyed virus can reassemble to form these biologically active ‘zombie’ complexes,” Wong said. “Interestingly, the human peptide mimicked by the viral fragments has been implicated in rheumatoid arthritis, psoriasis and lupus, and that different aspects of COVID-19 are reminiscent of these autoimmune diseases.”

The scientists also measured all the genes expressed at the cellular level. By comparing with internationally curated databases, the team found that the gene expression profile of cells exposed to SARS-CoV-2 “zombie” complexes closely resembled that of COVID-19 itself. even.

“What is surprising about the gene expression result is that no active infection was used in our experiments,” Wong said. “We didn’t even use the entire virus, but only about 0.2 or 0.3 percent of it, but we saw this incredible level of agreement that is highly suggestive.”

The results may explain some peculiarities of COVID-19 infection.

For example, the fact that fragments of SARS-CoV-2 lead to excessive inflammation could help explain why some seemingly healthy people suffer from severe COVID-19. Normally, enzyme activity varies greatly between healthy individuals, with levels varying by as much as a factor of 10. It is ultimately the enzymes that are responsible for cutting the virus particles into smaller and smaller pieces.

Evidence that persistence of SARS-CoV-2 fragments may cause disease also bolsters emerging clues about treatments that may show promise.

“Our results suggest that we may be able to manage COVID-19 by inhibiting certain enzymes or enhancing others,” Wong said. “One could even imagine a strategy also based on mimicry, using biologically inactive decoys that resemble these viral fragments enough to compete for double-stranded RNA, but form complexes that do not activate the immune system. “

Residual viral fragments are known to exist in other viral infections, but their biological activities have not been systematically studied.

The collaborative effort for this study brought together a team from 24 departmental and institutional affiliations during a particularly challenging time in the pandemic. The first author is Yue Zhang, a former postdoctoral researcher at UCLA and current assistant professor at Westlake University in Hangzhou, China.