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).
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7 Comments
““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.”
Of course, everything they learn about how this virus works can (and probably will) be used by other researchers to make a new and improved, more efficient, better gain of function SARS-CoV3, and 4.
“… although the pandemic is over”
Gee, when did that happen?
And here I was thinking that people were still dying, and millions were suffering from long COVID, but its “over” ??? 🤮
Based on official US statistics from 2017 (minimally) there never was a Covid-19 pandemic, just public officials placing the blame for mortality due to preexisting conditions, comorbidities and inherently more susceptible people on Sars-CoV-2. All-in-all, the total number of US deaths alleged to be due to Covid-19 never exceeded (www.worldometers.org) the number we could expect due to excessive medical errors alone, as reported by Johns Hopkins researchers in May of 2016. As to so-called “long COVID,” as only a now eighty year old lay investigator who never got Covid-19 or vaccinated, my best guess is it’s due to mistreatment of those preexisting chronic conditions and/or toxic unnecessary vaccines. More details at: https://odysee.com/@charlesgshaver:d?view=about
Please stop spreading misinformation. The pandemic was and is very real, a lot of people died and became disabled because if the virus, and it’s still happening. Long Vacc is real, but only about 0,02% of people get it, while about 10% of peple get Long Covid after an infection.
I know it would be nice to get back to the 2019’s normal, but the best thing we can do is to adapt to today’s normal.
As the now longest lived of my immediate family with only one younger of four siblings still alive, if you lost someone(s) to only ‘alleged’ Covid-19 during an only ‘alleged’ pandemic I can feel your pain. However, backed up with official statistics, the fact of the matter is that thousands, not hundreds, of Americans died daily of mostly cheaply and easily prevented chronic diseases while the US Government misspent $Trillions on a phony pandemic. Did you even bother to learn more details linked-to in my comments?
(sarcasm) Don’t you know? The WHO declaring the end if the medical emergency is the exact same as the pandemic being over, but at the same time, the WHO declaring the outbreak of mpox as a medical emergency doesn’t mean mpox is now a pandemic (/sarcasm)
Huge numbers of “prestigious” researchers actually believe the primary culprit is not the Wuhan flu and its offspring but the bioweapons masquerading as vaccines which Bill Gates told us was the only way out of the hole Darpa and the US DoD had dug for us.