“Zombie” Virus Fragments – Scientists Discover How COVID-19 Causes Severe Symptoms

Fragments of the ‘zombie’ virus continue to cause inflammation even after the virus itself has been destroyed.

Numerous unanswered questions remain from the COVID-19First identified in 2019 in Wuhan, China, COVID-19, or Coronavirus disease 2019, (which was originally called "2019 novel coronavirus" or 2019-nCoV) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has spread globally, resulting in the 2019–22 coronavirus pandemic.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>COVID-19 pandemic. For example, what leads to the severe symptoms exhibited in some patients by SARS-CoV-2Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the official name of the virus strain that causes coronavirus disease (COVID-19). Previous to this name being adopted, it was commonly referred to as the 2019 novel coronavirus (2019-nCoV), the Wuhan coronavirus, or the Wuhan virus.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>SARS-CoV-2, the virusA virus is a tiny infectious agent that is not considered a living organism. It consists of genetic material, either DNA or RNA, that is surrounded by a protein coat called a capsid. Some viruses also have an outer envelope made up of lipids that surrounds the capsid. Viruses can infect a wide range of organisms, including humans, animals, plants, and even bacteria. They rely on host cells to replicate and multiply, hijacking the cell's machinery to make copies of themselves. This process can cause damage to the host cell and lead to various diseases, ranging from mild to severe. Common viral infections include the flu, colds, HIV, and COVID-19. Vaccines and antiviral medications can help prevent and treat viral infections.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>virus responsible for COVID-19, compared to the typically milder symptoms of other coronaviruses? Additionally, what are the underlying reasons for the persistence of unusual symptoms long after the virus has been eliminated from an individual’s body?

The world may now have the beginning of answers. In a study recently published in the journal Proceedings of the National Academy of Sciences, a UCLAThe University of California, Los Angeles (UCLA) is a public land-grant research university in Los Angeles, California. It is organized into the College of Letters and Science and 12 professional schools. It is considered one of the country's Public Ivies, and is frequently ranked among the best universities in the world by major college and university rankings.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>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.

Research Methodology and Findings

The study was led by corresponding author Gerard Wong, a professor of bioengineering at the UCLA Samueli School of Engineering and in the UCLA College’s chemistry and biochemistry department and microbiology, immunology, and molecular genetics department.

“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 after the virus is destroyed, the sick host ‘wins,’ and different pieces of virus can be used to train the immune system for future recognition. COVID-19 reminds us that it’s not this simple.

“For comparison, if one were to assume that after food gets digested into its molecular components, then its effects on the body are over, it would be very liberating; I wouldn’t have to worry about the half-dozen jelly donuts I just ate. However, this simple picture is not correct.”

The research team found that 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<div class="cell text-container large-6 small-order-0 large-order-1">
<div class="text-wrapper"><br />Amino acids are a set of organic compounds used to build proteins. There are about 500 naturally occurring known amino acids, though only 20 appear in the genetic code. Proteins consist of one or more chains of amino acids called polypeptides. The sequence of the amino acid chain causes the polypeptide to fold into a shape that is biologically active. The amino acid sequences of proteins are encoded in the genes. Nine proteinogenic amino acids are called "essential" for humans because they cannot be produced from other compounds by the human body and so must be taken in as food.<br /></div>
</div>” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>amino acids like proteins, only shorter. These immune peptides can spontaneously assemble into new structures with double-stranded RNARibonucleic acid (RNA) is a polymeric molecule similar to DNA that is essential in various biological roles in coding, decoding, regulation and expression of genes. Both are nucleic acids, but unlike DNA, RNA is single-stranded. An RNA strand has a backbone made of alternating sugar (ribose) and phosphate groups. Attached to each sugar is one of four bases—adenine (A), uracil (U), cytosine (C), or guanine (G). Different types of RNA exist in the cell: messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA).” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>RNA, a special form of a molecule essential for building proteins from DNADNA, or deoxyribonucleic acid, is a molecule composed of two long strands of nucleotides that coil around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth, and reproduction. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>DNA, typically found in viral infections or released by dying cells.

A theater marquee notes the shuttering of businesses and public activity during the COVID-19 pandemic. Credit: Edwin Hooper/Unsplash

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 nanoscaleThe nanoscale refers to a length scale that is extremely small, typically on the order of nanometers (nm), which is one billionth of a meter. At this scale, materials and systems exhibit unique properties and behaviors that are different from those observed at larger length scales. The prefix "nano-" is derived from the Greek word "nanos," which means "dwarf" or "very small." Nanoscale phenomena are relevant to many fields, including materials science, chemistry, biology, and physics.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>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.

Implications of the Study

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.”

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

“What’s astonishing about the gene expression result is there was no active infection used in our experiments,” Wong said. “We did not even use the whole virus — rather only about 0.2% or 0.3% of it — but we found this incredible level of agreement that is highly suggestive.”

The findings may account for some peculiarities of COVID-19 infection.

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

Evidence that persistence of SARS-CoV-2 fragments may drive illness also reinforces emerging clues about which treatments may show promise.

“Our results suggest 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, by using biologically inactive decoys that look enough like these viral fragments to compete for double-stranded RNA, but form complexes that don’t activate the immune system.”

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

Reference: “Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes” by Yue Zhang, Vanthana Bharathi, Tatsuya Dokoshi, Jaime de Anda, Lauryn Tumey Ursery, Nikhil N. Kulkarni, Yoshiyuki Nakamura, Jonathan Chen, Elizabeth W. C. Luo, Lamei Wang, Hua Xu, Alison Coady, Raymond Zurich, Michelle W. Lee, Tsutomu Matsui, HongKyu Lee, Liana C. Chan, Athena A. Schepmoes, Mary S. Lipton, Rui Zhao, Joshua N. Adkins, Geremy C. Clair, Lance R. Thurlow, Jonathan C. Schisler, Matthew C. Wolfgang, Robert S. Hagan, Michael R. Yeaman, Thomas M. Weiss, Xinhua Chen, Melody M. H. Li, Victor Nizet, Silvio Antoniak, Nigel Mackman, Richard L. Gallo and Gerard C. L. Wong, 2 February 2024, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2300644120

The collaborative effort for this study brought together a team with 24 departmental and institutional affiliations during a particularly challenging time of the pandemic. The first author is Yue Zhang, a former UCLA postdoctoral researcher and current assistant professor at Westlake University in Hangzhou, China. Additional UCLA-based co-authors are doctoral students Jaime de Anda, Jonathan Chen and Elizabeth Luo; HongKyu Lee of Harbor-UCLA Medical Center; Liana Chan, assistant adjunct professor of medicine at the David Geffen School of Medicine at UCLA; Michael Yeaman, professor of medicine at the Geffen School of Medicine and director of the Institute for Infection and Immunity at the Lundquist Institute at Harbor-UCLA Medical Center; and Melody Li, assistant professor of microbiology, immunology and molecular genetics.

The study’s senior authors include Rich Gallo and Victor Nizet of UC San Diego Silvio Antoniak and Nigel Mackman of the University of North Carolina at Chapel Hill. Co-authors are also affiliated with Harvard Medical School, the Stanford Synchrotron Radiation Lightsource and the Pacific Northwest National Laboratory.

The study was supported by the National Science Foundation, the National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>National Institutes of Health, the Department of Energy, and institutional funding sources that include the UCLA W. M. Keck Foundation COVID-19 Research Award Program.