....and potentially how to evaluate circulating strains for pandemic probability
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There are many lingering mysteries from the COVID-19 pandemic. For instance, why does SARS-CoV-2, the virus behind the disease, cause severe symptoms in some patients, while many other coronaviruses don’t? 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 beginning of answers. In a study published today in the journal Proceedings of the National Academy of Sciences, a UCLA-led multidisciplinary research team explores one way that COVID-19 turns the immune system — which is crucial for keeping people alive — against the body itself, with potentially deadly results.
Using an artificial intelligence system they developed, the study authors scanned the entire collection of proteins produced by SARS-CoV-2 and then performed an exhaustive series of validation experiments. The scientists found that certain viral protein fragments, generated after the SARS-CoV-2 virus is broken down into pieces, can mimic a key component of the body’s machinery for amplifying immune signals. Their discoveries suggest that some of the most serious COVID-19 outcomes can result from these fragments overstimulating the immune system, thereby causing rampant inflammation in widely different contexts such as cytokine storms and lethal blood coagulation.
...
The research team found SARS-CoV-2 fragments can imitate 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, only shorter. These immune peptides can spontaneously assemble into new structures with double-stranded RNA, a special form of a molecule essential for building proteins from DNA, typically found in viral infections or released by dying cells.
The resultant hybrid complex of the immune peptides and double-stranded RNA kicks off a chain reaction that triggers an immune response.
In addition to their AI analysis, the researchers used state-of-the-art methods for elucidating nanoscale biological structures and conducted cell- and animal-based experiments. Compared to 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 that, additional experiments with multiple cell types all consistently show that fragments of the SARS-CoV-2 coronavirus prompt an amplified inflammatory response compared to those from a common cold coronavirus. Likewise, experiments with mice show that fragments from SARS-CoV-2 lead to huge immune response, especially in the lungs.
The findings could influence treatment for COVID-19 and efforts to identify and surveil future coronaviruses capable of causing pandemics.
“We may be able to look at the protein composition of this year’s coronavirus strains and figure out whether they’re potentially pandemic-capable or just going to cause the common cold,” Wong said.
Wong and his colleagues concentrated on three SARS-CoV-2 fragments. Using a technique for analyzing detailed molecular structures called synchrotron X-ray diffraction, they found that, like the innate immune peptide, the SARS-CoV-2 fragments can organize double-stranded RNA into structures that stimulate the immune system.
“We saw that the various forms of debris from the destroyed virus can reassemble into these biologically active ‘zombie’ complexes,” Wong said. “It is interesting that the human peptide being imitated 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 conditions.”
Viral protein fragments may unlock mystery behind serious COVID-19 outcomes
‘Zombie’ virus fragments continue to cause inflammation after the virus is destroyed.
There are many lingering mysteries from the COVID-19 pandemic. For instance, why does SARS-CoV-2, the virus behind the disease, cause severe symptoms in some patients, while many other coronaviruses don’t? 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 beginning of answers. In a study published today in the journal Proceedings of the National Academy of Sciences, a UCLA-led multidisciplinary research team explores one way that COVID-19 turns the immune system — which is crucial for keeping people alive — against the body itself, with potentially deadly results.
Using an artificial intelligence system they developed, the study authors scanned the entire collection of proteins produced by SARS-CoV-2 and then performed an exhaustive series of validation experiments. The scientists found that certain viral protein fragments, generated after the SARS-CoV-2 virus is broken down into pieces, can mimic a key component of the body’s machinery for amplifying immune signals. Their discoveries suggest that some of the most serious COVID-19 outcomes can result from these fragments overstimulating the immune system, thereby causing rampant inflammation in widely different contexts such as cytokine storms and lethal blood coagulation.
...
The research team found SARS-CoV-2 fragments can imitate 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, only shorter. These immune peptides can spontaneously assemble into new structures with double-stranded RNA, a special form of a molecule essential for building proteins from DNA, typically found in viral infections or released by dying cells.
The resultant hybrid complex of the immune peptides and double-stranded RNA kicks off a chain reaction that triggers an immune response.
In addition to their AI analysis, the researchers used state-of-the-art methods for elucidating nanoscale biological structures and conducted cell- and animal-based experiments. Compared to 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 that, additional experiments with multiple cell types all consistently show that fragments of the SARS-CoV-2 coronavirus prompt an amplified inflammatory response compared to those from a common cold coronavirus. Likewise, experiments with mice show that fragments from SARS-CoV-2 lead to huge immune response, especially in the lungs.
The findings could influence treatment for COVID-19 and efforts to identify and surveil future coronaviruses capable of causing pandemics.
“We may be able to look at the protein composition of this year’s coronavirus strains and figure out whether they’re potentially pandemic-capable or just going to cause the common cold,” Wong said.
Wong and his colleagues concentrated on three SARS-CoV-2 fragments. Using a technique for analyzing detailed molecular structures called synchrotron X-ray diffraction, they found that, like the innate immune peptide, the SARS-CoV-2 fragments can organize double-stranded RNA into structures that stimulate the immune system.
“We saw that the various forms of debris from the destroyed virus can reassemble into these biologically active ‘zombie’ complexes,” Wong said. “It is interesting that the human peptide being imitated 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 conditions.”
