Researchers at the Federal University of São Paulo (UNIFESP) in Brazil have discovered that SARS-CoV-2, the virus that causes COVID-19, uses a sophisticated tactic to evade the human body's defense system. In addition to its ability to evade the immune system before invading the host cell, which is common to other viruses, SARS-CoV-2 acts on a second front by manipulating the host cell's genetic material in a way never before seen in other pathogens.
The study, published in the journal Nucleic Acids Research Molecular Medicine and supported by FAPESP through a Thematic Project and a postdoctoral fellowship , describes how the virus interacts with the RNA of infected lung cells in an unprecedented way.
"SARS-CoV-2 doesn't mess around. It interacts with the host cell in an extremely sophisticated and direct manner, manipulating its genetic material like no other pathogen does. We discovered that, through a very sophisticated pairing mechanism, the virus's RNA interacts with different types of RNA in the infected cell, interfering with the functioning of the cellular machinery and blocking the production of interferon, one of the main antiviral defenses," explains Marcelo Briones , coordinator of the Center for Medical Bioinformatics at the São Paulo Medical School (EPM-UNIFESP) and coordinator of the research.
According to Briones, although this is a fundamental biology study, the discovery may influence our understanding of the disease and the development of vaccines and treatments in the future. "This changes our understanding of the virus and of RNA viruses and paves the way for new prevention and treatment strategies. We've shown that SARS-CoV-2 protects itself through methylation, that is, by modifying its RNA with a methyl group. In theory, this could enable the development of antivirals that inhibit the enzymes responsible for this RNA modification," Briones explains to Agência FAPESP.
Weakened immune response
SARS-CoV-2 is an RNA virus, meaning it does not have a DNA genome, and it has a high capacity for mutation. "This doesn't mean that they're simpler viruses; quite the contrary. Our study showed that RNAs interact with both invading virus molecules and molecules that are extremely important for the immune response, which is extremely interesting from a fundamental biology point of view," he says.
In their work, Cristina Peter and Caio Cyrino identified that SARS-CoV-2 exposes its RNA to the cellular environment as soon as it penetrates cells, promoting connections with a specific type of RNA – long non-coding RNAs (lncRNAs) – to circumvent the initial immune response of human cells. The virus quickly establishes connections with lncRNAs, such as UCA1, GAS5, and NORAD, upon invading the cell. These lncRNAs are important regulators of interferon signaling, which is a key component of innate antiviral defense.
During this process, a chemical modification occurs that the scientists call N⁶-methyladenosine (m⁶A) methylation. This process destabilizes RNA structures and hinders the classic pairing between the amino acid bases adenine (A) and uracil (U). "Our main hypothesis is that methylation destabilizes double-stranded RNA structures, promoting Hoogsteen-type pairings, which are less stable and can interfere with interactions between RNAs and, consequently, with interferon signaling, which impairs the immune response," Briones explains.
He adds that this structural change reduces the binding time of lncRNAs to their main targets, such as microRNAs (miRNAs), thereby weakening their regulatory function. "In the study, we identified the lncRNA UCA1 as a central player exhibiting a complex pattern of reduced expression and increased methylation. It interacts directly with both the viral genome and components of the interferon pathway," the researcher explains.
The study used Oxford Nanopore sequencing technology, which allows for the direct, real-time analysis of long fragments of RNA or DNA. This technology works by monitoring changes in an electric current as nucleic acids – the molecules that make up genetic material – pass through a protein nanopore. The resulting signal is decoded to determine the specific RNA sequence.
This result can then be immediately compared to a genetic sequencing database to identify various pieces of information, such as the species to which the material being studied corresponds. Using machine learning techniques, the researchers measured the overall increase in methylation in cells. Mathematician Fernando Antoneli and Nilmar Moretti participated in the work.
Briones says that the next steps will be to validate the computational analysis data experimentally. "Now the bench work begins to confirm the mechanisms we observed," the researcher concludes.
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe .
