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
Two New Books From Frank Boehm, NA Founder – To be Released Dec. 2025
Molecular Manufacturing: The Future of Nanomedicine This book explores the revolutionary potential of atomically precise manufacturing technologies to transform global healthcare, as well as practically every other sector across society. This forward-thinking volume examines [...]
What could the future of nanoscience look like?
Society has a lot to thank for nanoscience. From improved health monitoring to reducing the size of electronics, scientists’ ability to delve deeper and better understand chemistry at the nanoscale has opened up numerous [...]
Scientists Melt Cancer’s Hidden “Power Hubs” and Stop Tumor Growth
Researchers discovered that in a rare kidney cancer, RNA builds droplet-like hubs that act as growth control centers inside tumor cells. By engineering a molecular switch to dissolve these hubs, they were able to halt cancer [...]
Platelet-inspired nanoparticles could improve treatment of inflammatory diseases
Scientists have developed platelet-inspired nanoparticles that deliver anti-inflammatory drugs directly to brain-computer interface implants, doubling their effectiveness. Scientists have found a way to improve the performance of brain-computer interface (BCI) electrodes by delivering anti-inflammatory drugs directly [...]
After 150 years, a new chapter in cancer therapy is finally beginning
For decades, researchers have been looking for ways to destroy cancer cells in a targeted manner without further weakening the body. But for many patients whose immune system is severely impaired by chemotherapy or radiation, [...]
Older chemical libraries show promise for fighting resistant strains of COVID-19 virus
SARS‑CoV‑2, the virus that causes COVID-19, continues to mutate, with some newer strains becoming less responsive to current antiviral treatments like Paxlovid. Now, University of California San Diego scientists and an international team of [...]
Lower doses of immunotherapy for skin cancer give better results, study suggests
According to a new study, lower doses of approved immunotherapy for malignant melanoma can give better results against tumors, while reducing side effects. This is reported by researchers at Karolinska Institutet in the Journal of the National [...]
Researchers highlight five pathways through which microplastics can harm the brain
Microplastics could be fueling neurodegenerative diseases like Alzheimer's and Parkinson's, with a new study highlighting five ways microplastics can trigger inflammation and damage in the brain. More than 57 million people live with dementia, [...]
Tiny Metal Nanodots Obliterate Cancer Cells While Largely Sparing Healthy Tissue
Scientists have developed tiny metal-oxide particles that push cancer cells past their stress limits while sparing healthy tissue. An international team led by RMIT University has developed tiny particles called nanodots, crafted from a metallic compound, [...]
Gold Nanoclusters Could Supercharge Quantum Computers
Researchers found that gold “super atoms” can behave like the atoms in top-tier quantum systems—only far easier to scale. These tiny clusters can be customized at the molecular level, offering a powerful, tunable foundation [...]
A single shot of HPV vaccine may be enough to fight cervical cancer, study finds
WASHINGTON -- A single HPV vaccination appears just as effective as two doses at preventing the viral infection that causes cervical cancer, researchers reported Wednesday. HPV, or human papillomavirus, is very common and spread [...]
New technique overcomes technological barrier in 3D brain imaging
Scientists at the Swiss Light Source SLS have succeeded in mapping a piece of brain tissue in 3D at unprecedented resolution using X-rays, non-destructively. The breakthrough overcomes a long-standing technological barrier that had limited [...]
Scientists Uncover Hidden Blood Pattern in Long COVID
Researchers found persistent microclot and NET structures in Long COVID blood that may explain long-lasting symptoms. Researchers examining Long COVID have identified a structural connection between circulating microclots and neutrophil extracellular traps (NETs). The [...]
This Cellular Trick Helps Cancer Spread, but Could Also Stop It
Groups of normal cbiells can sense far into their surroundings, helping explain cancer cell migration. Understanding this ability could lead to new ways to limit tumor spread. The tale of the princess and the [...]
New mRNA therapy targets drug-resistant pneumonia
Bacteria that multiply on surfaces are a major headache in health care when they gain a foothold on, for example, implants or in catheters. Researchers at Chalmers University of Technology in Sweden have found [...]
Current Heart Health Guidelines Are Failing To Catch a Deadly Genetic Killer
New research reveals that standard screening misses most people with a common inherited cholesterol disorder. A Mayo Clinic study reports that current genetic screening guidelines overlook most people who have familial hypercholesterolemia, an inherited disorder that [...]
