Researchers have discovered that SARS-CoV-2 manipulates the human immune system by forcing cells to produce non-functional proteins, hindering the body’s antiviral defenses.
This groundbreaking study by teams from prestigious Brazilian universities highlights potential targets for new COVID-19 treatments, emphasizing the importance of restoring normal RNA processing in infected cells.
SARS-CoV-2’s Immune Evasion Strategies
To evade the human host’s immune response, SARS-CoV-2, the coronavirus that causes COVID-19, uses the machinery of defense cells to induce the expression of unproductive isoforms of key antiviral genes – variant forms of genes that result from disrupted splicing or transcription processes and do not code for functional (protective) proteins. This is a key finding of a study conducted by researchers at the Albert Einstein Jewish Brazilian Hospital (HIAE), the University of São Paulo (USP), and the Federal University of Minas Gerais (UFMG). An article on the study, which offers a foundation for the development of novel therapeutic strategies to combat COVID-19, was published in the International Journal of Molecular Science.
Other viruses, including coronaviruses, also distort protein production by disrupting messenger RNA (mRNA) splicing, but SARS-CoV-2 goes further by blocking expression of interferons, a family of proteins that help the immune system fight infection, and modulating specific immune cells. A lack of precise details regarding this process has been a major hindrance to the development of novel options to treat COVID-19.
Investigating Unstable mRNA and Protein Dysfunction
In the study, which was funded by FAPESP, the researchers set out to confirm the hypothesis suggested in the scientific literature that production of unstable mRNA isoforms can give rise to non-functional proteins.
To do this, they conducted an integrative analysis that combined several transcriptomic and proteomic datasets to arrive at a detailed characterization of the infected host cell landscape, both in vitro and in vivo.
Insights From Molecular Analysis and Findings
They found that infection by SARS-CoV-2 induced predominant expression of unproductive splicing isoforms in key genes linked to the immune system and antiviral response (IFN signaling genes, ISGs, class I MHC genes, and splicing machinery genes such as IRF7, OAS3, HLA-B, and HNRNPH1). These genes also produced fewer “normal” proteins, which in turn were more susceptible to attack by viral proteins.
On the other hand, inflammatory cytokine and chemokine genes (such as IL6, CXCL8, and TNF) mainly produced productive splicing isoforms in response to the infection.
“Although more than 50 papers on COVID-19 transcriptomics have been published, this is the first time this viral strategy has been demonstrated at the molecular level. Moreover, we used only publicly available data,” said Glória Regina Franco, full professor in the Institute of Biological Sciences (ICB) at UFMG and last author of the article.
“By demonstrating the molecular interaction between SARS-CoV-2 and the host’s splicing machinery, we provide fundamental information on potential targets for antiviral medications and immunomodulatory interventions. Our findings can be used to orient therapies that restore normal RNA processing during viral infections, for example,” said Helder Takashi Imoto Nakaya, a senior researcher at HIAE, a professor at USP’s School of Pharmaceutical Sciences (FCF), and penultimate author of the article.
Long COVID and Future Pandemics
Although the COVID-19 pandemic is over, new publications on the subject are always important, Nakaya said. “Novel coronaviruses can cause severe pandemics. The emergence of SARS-CoV-3, SARS-CoV-4, and so on, is perfectly plausible. The more we find out about the way these viruses work, the better,” he added.
More research on the damage caused by the virus at the molecular level is also important in light of the widespread reports of long COVID, a problem faced by millions of people worldwide and increasingly neglected.
Reference: “SARS-CoV-2 Selectively Induces the Expression of Unproductive Splicing Isoforms of Interferon, Class I MHC, and Splicing Machinery Genes” by Thomaz Lüscher Dias, Izabela Mamede, Nayara Evelin de Toledo, Lúcio Rezende Queiroz, Ícaro Castro, Rafael Polidoro, Luiz Eduardo Del-Bem, Helder Nakaya and Glória Regina Franco, 22 May 2024, International Journal of Molecular Sciences.
DOI: 10.3390/ijms25115671
Researchers at Indiana University and Michigan State University in the United States also took part in the study. Besides FAPESP, the funders included CAPES (the Brazilian Ministry of Education’s Coordination for the Improvement of Higher Education Personnel), CNPq (the National Council for Scientific and Technological Development, an arm of the Ministry of Science, Technology and Innovation), and the Research Pro-Rectorate of the Federal University of Minas Gerais (PRPq-UFMG).
News
Hidden Scars: How COVID Lockdowns Altered Teen Brains Forever
Research from the University of Washington revealed that COVID-19 lockdowns led to accelerated cortical thinning in adolescents, impacting brain development significantly. This effect was more pronounced in females than males, raising concerns about long-term brain health. The study [...]
Simple Blood Test To Detect Dementia Before Symptoms Appear
UCLA researchers have identified placental growth factor (PlGF) as a potential blood biomarker for early detection of cognitive impairment and dementia. High PlGF levels correlate with increased vascular permeability, suggesting its role in the development [...]
Investing Goldman Sachs asks ‘Is curing patients a sustainable business model?’
Goldman Sachs analysts attempted to address a touchy subject for biotech companies, especially those involved in the pioneering “gene therapy” treatment: cures could be bad for business in the long run. “Is curing patients [...]
The risks of reversed chirality: Study highlights dangers of mirror organisms
A groundbreaking study evaluates the feasibility, risks, and ethical considerations of creating mirror bacteria with reversed chirality, highlighting potential threats to health and ecosystems. In a recent study published in Science, a team of researchers [...]
Alarming Mutation in H5N1 Virus Raises Pandemic Red Flags
NIH-funded study concludes that the risk of human infection remains low A recent study published in Science and funded by the National Institutes of Health (NIH) has found that a single alteration in a protein on the surface [...]
Scientists Discover Genetic Changes Linked to Autism, Schizophrenia
The Tbx1 gene influences brain volume and social behavior in autism and schizophrenia, with its deficiency linked to amygdala shrinkage and impaired social incentive evaluation. A study published in Molecular Psychiatry has linked changes in brain [...]
How much permafrost will melt this century, and where will its carbon go?
Among the many things global warming will be melting this century—sea ice, land glaciers and tourist businesses in seaside towns across the world—is permafrost. Lying underneath 15% of the northern hemisphere, permafrost consists of [...]
A Physics Discovery So Strange It’s Changing Quantum Theory
MIT physicists surprised to discover electrons in pentalayer graphene can exhibit fractional charge. New theoretical research from MIT physicists explains how it could work, suggesting that electron interactions in confined two-dimensional spaces lead to novel quantum states, [...]
Inside the Nano-Universe: New 3D X-Ray Imaging Transforms Material Science
A cutting-edge X-ray method reveals the 3D orientation of nanoscale material structures, offering fresh insights into their functionality. Researchers at the Swiss Light Source (SLS) have developed a groundbreaking technique called X-ray linear dichroic orientation tomography [...]
X-chromosome study reveals hidden genetic links to Alzheimer’s disease
Despite decades of research, the X-chromosome’s impact on Alzheimer’s was largely ignored until now. Explore how seven newly discovered genetic loci could revolutionize our understanding of the disease. Conventional investigations of the genetic contributors [...]
The Unresolved Puzzle of Long COVID: 30% of Young People Still Suffer After Two Years
A UCL study found that 70% of young people with long Covid recovered within 24 months, but recovery was less likely among older teenagers, females, and those from deprived backgrounds. Researchers emphasized the need [...]
Needle-Free: New Nano-Vaccine Effective Against All COVID-19 Variants
A new nano-vaccine developed by TAU and the University of Lisbon offers a needle-free, room-temperature-storable solution against COVID-19, targeting all key variants effectively. Professor Ronit Satchi-Fainaro’s lab at Tel Aviv University’s Faculty of Medical and [...]
Photoacoustic PDA-ICG Nanoprobe for Detecting Senescent Cells in Cancer
A study in Scientific Reports evaluated a photoacoustic polydopamine-indocyanine green (PDA-ICG) nanoprobe for detecting senescent cells. Senescent cells play a role in tumor progression and therapeutic resistance, with potential adverse effects such as inflammation and tissue [...]
How Dysregulated Cell Signaling Causes Disease
Cell signaling is crucial for cells to communicate and function correctly. Disruptions in these pathways, caused by genetic mutations or environmental factors, can lead to uncontrolled cell growth, improper immune responses, or errors in [...]
Scientists Develop Super-Strong, Eco-Friendly Plastic That Bacteria Can Eat
Researchers at the Weizmann Institute have developed a biodegradable composite material that could play a significant role in addressing the global plastic waste crisis. Billions of tons of plastic waste clutter our planet. Most [...]
Building a “Google Maps” for Biology: Human Cell Atlas Revolutionizes Medicine
New research from the Human Cell Atlas offers insights into cell development, disease mechanisms, and genetic influences, enhancing our understanding of human biology and health. The Human Cell Atlas (HCA) consortium has made significant [...]
