To suppress the immune response, SARS-CoV-2 stimulates the production of proteins without protective function

To evade the human host’s immune response, SARS-CoV-2, the coronavirus that causes COVID-19, exploits the machinery of defense cells to induce the expression of unproductive isoforms of key antiviral genes. These are variants of genes that result from impaired splicing or transcription processes and do not encode functional (protective) proteins.

This is a key finding of a study conducted by researchers from the Albert Einstein Jewish Brazilian Hospital (HIAE), the University of São Paulo (USP) and the Federal University of Minas Gerais (UFMG). The study, which provides a basis for the development of novel therapeutic strategies to combat COVID-19, was published in International Journal of Molecular Sciences.

Other viruses, including coronaviruses, also disrupt protein production by interrupting the splicing of messenger RNA (mRNA). But SARS-CoV-2 goes further by blocking the expression of interferons, a family of proteins that help the immune system fight infection, and modulates specific immune cells. The lack of precise details about this process has been a major obstacle to developing new treatments for COVID-19.

The aim of the study was to confirm the hypothesis put forward in the scientific literature that the production of unstable mRNA isoforms can lead to the formation of non-functional proteins.

To this end, they performed an integrative analysis combining multiple transcriptomic and proteomic datasets to obtain a detailed characterization of the infected host cell landscape both in vitro and in vivo.

They found that SARS-CoV-2 infection induced predominant expression of unproductive splice isoforms in key genes associated with the immune system and antiviral response (IFN signaling genes, ISGs, MHC class I 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 vulnerable to attack by viral proteins.

On the other hand, genes for inflammatory cytokines and chemokines (such as IL6, CXCL8, and TNF) produced mainly productive splice isoforms in response to infection.

“Although more than 50 articles have been published on transcriptomics in COVID-19, this is the first time that this viral strategy has been demonstrated at the molecular level. In addition, we only used publicly available data,” said Glória Regina Franco, full professor at the Institute of Life Sciences (ICB) of the UFMG and last author of the article.

“By revealing the molecular interaction between SARS-CoV-2 and the host splicing apparatus, we provide fundamental information about potential targets for antiviral drugs and immunomodulatory interventions. Our findings can be used, for example, to target therapies that restore normal RNA processing during viral infections,” said Helder Takashi Imoto Nakaya, principal investigator at HIAE, professor in the School of Pharmaceutical Sciences (FCF) at USP, and penultimate author of the article.

Long COVID and future pandemics

Even though the COVID-19 pandemic is over, new publications on the topic are still important, Nakaya said. “Novel coronaviruses can cause severe pandemics. The emergence of SARS-CoV-3, SARS-CoV-4, etc. is quite plausible. The more we learn about how these viruses work, the better,” he added.

In view of the numerous reports on Long COVID – a problem that affects millions of people worldwide and is increasingly neglected – more intensive research into the damage the virus causes at the molecular level is important.

Researchers from Indiana University and Michigan State University in the USA were also involved in the study.