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

To evade the human host immune response, SARS-CoV-2, the coronavirus that causes COVID-19, uses the defense cell mechanism 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 encode functional (protective) proteins.

This is one of the main conclusions of a study conducted by researchers from the Albert Einstein Brazilian Jewish 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 new therapeutic strategies to combat COVID-19, is published in the journal International Journal of Molecular Sciences.

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

In this study, the researchers sought to confirm the hypothesis suggested in the scientific literature that the production of unstable mRNA isoforms can give rise to non-functional proteins.

To do this, they conducted an integrative analysis combining multiple transcriptomic and proteomic datasets to arrive at a detailed characterization of the infected host cellular landscape, both in vitro and in vivo.

They found that SARS-CoV-2 infection induced a predominant expression of unproductive splicing isoforms in key genes related to 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 were in turn more susceptible to attack by viral proteins.

In contrast, inflammatory cytokine and chemokine genes (such as IL6, CXCL8, and TNF) predominantly produced productive splice isoforms in response to infection.

“Although more than 50 articles on COVID-19 transcriptomics have been published, this is the first time that this viral strategy has been demonstrated at the molecular level. Furthermore, we have only used publicly available data,” said Glória Regina Franco, full professor at 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 splicing machinery, we provide fundamental insights into potential targets for antiviral drugs and immunomodulatory interventions. Our findings can be used to guide therapies that restore normal RNA processing during viral infections, for example,” said Helder Takashi Imoto Nakaya, principal investigator at HIAE, professor in the School of Pharmaceutical Sciences (FCF) at USP and penultimate author of the paper.

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 serious pandemics. The emergence of SARS-CoV-3, SARS-CoV-4, etc., is perfectly plausible. The more we know about how these viruses work, the better,” he added.

It is also important to conduct more research into the damage caused by the virus at the molecular level, in light of the many reports of long COVID, a problem facing millions of people around the world and increasingly overlooked.

Researchers from Indiana University and Michigan State University in the United States also participated in the study.