Molecular Trickery
By Julia Moióli, São Paulo Research Foundation
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| Colorized scanning electron micrograph of a cell (purple) infected with the Omicron strain of SARS-CoV-2 virus particles (green), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID |
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).
