SARS-CoV-2 manipulates the host cell's RNA to weaken the immune response

SARS-CoV-2 manipulates the host cell's RNA to weaken the immune response

Researchers at the Federal University of São Paulo (UNIFESP) in Brazil have found 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 entering the host cell, which is common with other viruses, SARS-CoV-2 acts on a second front by manipulating the host cell's genetic material in a way never seen before in other pathogens.

The study, published in the journalNucleic acid research Molecular medicineand supported by FAPESP through a thematic project and a postdoctoral fellowship, describes how the virus interacts in an unprecedented way with the RNA of infected lung cells.

SARS-CoV-2 is no fun. It interacts with the host cell in an extremely sophisticated and direct way and manipulates its genetic material like no other pathogen. We found that the virus's RNA interacts with different types of RNA in the infected cell through a sophisticated pairing mechanism, disrupting the function of the cell's machinery and blocking the production of interferon, one of the most important antiviral defenses."

Marcelo Briones, coordinator of the Center for Medical Bioinformatics of the São Paulo Medical Faculty (EPM-UNIFESP) and coordinator of the research

Although this is a fundamental biological study, Briones says the discovery could impact our understanding of the disease and the development of vaccines and treatments in the future. "This changes our understanding of the virus and RNA viruses and paves the way for new prevention and treatment strategies. We have shown that SARS-CoV-2 protects itself through methylation, that is, by modifying its RNA with a methyl group. In theory, this could allow the development of antiviral drugs that inhibit the enzymes responsible for this RNA modification," Briones explains to Agência FAPESP.

Weakened immune response

SARS-CoV-2 is an RNA virus, which means it has no DNA genome and has a high mutation capacity. "This does not mean that they are simpler viruses, quite the opposite. Our study showed that RNAs interact with both invading virus molecules and with 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 found that SARS-CoV-2 exposes its RNA to the cellular environment once it enters cells, promoting associations with a specific type of RNA - long non-coding RNAs (lncRNAs) - to evade the initial immune response of human cells. The virus quickly makes connections with lncRNAs such as UCA1, GAS5 and NORAD upon entering the cell. These lncRNAs are important regulators of interferon signaling, which is a key component of innate antiviral defense.

This process results in a chemical change that scientists call N⁶-methyl adenosine (m⁶A) methylation. This process destabilizes RNA structures and hinders the classical pairing between the amino acid bases adenine (A) and uracil (U). “Our main hypothesis is that methylation destabilizes double-stranded RNA structures and promotes Hoogsteen-type pairings, which are less stable and can disrupt interactions between RNAs and consequently interferon signaling, impairing the immune response,” explains Briones.

He adds that this structural change shortens 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, which has a complex pattern of reduced expression and increased methylation. It interacts directly with both the viral genome and with components of the interferon signaling pathway," explains the researcher.

The study used Oxford Nanopore sequencing technology, which allows direct, real-time analysis of long RNA or DNA fragments. This technology works by monitoring changes in an electrical 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 examined material belongs. Using machine learning techniques, the researchers measured the overall increase in methylation in cells. The mathematicians Fernando Antoneli and Nilmar Moretti were involved in the work.

Briones says the next steps will be to validate the computer analysis data experimentally. “Laboratory work is now beginning to confirm the mechanisms we observed,” concludes the researcher.

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