Today, we’re joined by Ivan Kairatov, a leading biopharma expert whose recent work has uncovered a startling new mechanism used by SARS-CoV-2. His team’s research reveals how the virus doesn’t just evade the immune system but actively commandeers the host’s cellular machinery in a way never before observed. Throughout our conversation, we will explore this unprecedented viral tactic, delving into the specific chemical modifications the virus employs to weaken our defenses, the central role of a particular long non-coding RNA, the innovative technology that made this discovery possible, and what it all means for the future of antiviral treatments.
Your study describes SARS-CoV-2’s manipulation of host RNA as “never before seen.” Could you walk us through the specifics of this sophisticated pairing mechanism and how it differs from the immune evasion tactics used by other common viruses?
It’s a fantastic question because it gets to the heart of what makes this virus so insidious. Many viruses are skilled at evading the immune system before they even get inside a host cell. But what we discovered is that SARS-CoV-2 fights a war on two fronts. Once inside, it engages in this incredibly sophisticated and direct manipulation of the cell’s own genetic material. We observed its RNA forming a very specific pairing with different types of RNA within the infected lung cell. This isn’t just a random interaction; it’s a targeted strike designed to disrupt the entire cellular machinery and, most critically, to block the production of interferon, which is one of our body’s primary alarm bells against viral invaders. This level of direct genetic meddling is what sets it apart and what we’ve truly never documented in other pathogens.
The article highlights N⁶-methyladenosine (m⁶A) methylation and “Hoogsteen-type pairings” as key to weakening the immune response. Can you detail the step-by-step process of how this chemical modification destabilizes lncRNAs and ultimately blocks the production of interferon?
Absolutely. Imagine the host cell’s RNA as a finely tuned machine with specific parts that have to fit together perfectly. As soon as SARS-CoV-2 invades, it exposes its RNA and triggers a chemical modification process called N⁶-methyladenosine, or m⁶A, methylation on the host’s long non-coding RNAs (lncRNAs). Our main hypothesis is that adding this methyl group acts like a wrench in the works. It destabilizes the normal, strong double-stranded RNA structures, specifically hindering the classic pairing between the bases adenine and uracil. This forces the RNA into what we call “Hoogsteen-type pairings,” which are far less stable. This structural instability means the lncRNAs can’t bind effectively to their targets, like microRNAs, for the necessary amount of time, severely weakening their regulatory function and, as a result, crippling the interferon signaling pathway that is so vital to a proper immune response.
You identified the lncRNA UCA1 as a “central player” in this process. What makes UCA1 so critical, and can you elaborate on the complex pattern of its reduced expression and increased methylation you observed during your analysis?
UCA1 turned out to be the linchpin in this entire viral strategy. It’s not just another piece on the board; it’s a central player because of its unique position. We found that UCA1 interacts directly with both the viral genome itself and key components of our own interferon pathway. This gives the virus a direct line to disrupt our defenses. The pattern we uncovered was fascinatingly complex. In infected cells, we saw a marked reduction in the overall amount of UCA1 being expressed. But simultaneously, the UCA1 that was still present showed a significant increase in methylation. It’s a devastating one-two punch: the virus not only reduces the number of these critical regulatory molecules but also sabotages the ones that remain, ensuring our antiviral response is thoroughly compromised.
The research combined Oxford Nanopore sequencing with machine learning. Could you explain how this specific technology allowed you to directly analyze RNA modifications in real-time and what unique insights this approach provided over traditional methods?
This technology was absolutely crucial; we couldn’t have made this discovery without it. Traditional sequencing methods often require you to chop up RNA into tiny fragments, and you lose a lot of crucial information in that process. Oxford Nanopore sequencing, however, let us analyze long, intact strands of RNA in real-time. The technology works by threading a single nucleic acid molecule through a tiny protein nanopore and measuring the resulting disruptions in an electrical current. The signal is then decoded to give us the sequence. The true breakthrough for our work was that this method is sensitive enough to detect the chemical modifications, like methylation, directly on the RNA molecule as it passes through. By feeding this incredibly rich, real-time data into our machine learning models, we could quantify the overall increase in methylation across all the RNA in the cell, painting a complete picture of the viral takeover that would have been impossible to see otherwise.
What is your forecast for the development of new treatments based on this discovery? Considering you’ve shown SARS-CoV-2 protects itself via methylation, what are the biggest hurdles and the most promising pathways to developing antivirals that can inhibit these enzymes?
My forecast is one of cautious optimism. While this is fundamental biology, it truly changes our understanding of RNA viruses and opens a very promising new avenue for treatment. The most direct pathway forward is to develop antivirals that specifically inhibit the enzymes responsible for this RNA methylation. If the virus is essentially building a chemical shield to protect itself and disable our defenses, then a drug that prevents the construction of that shield could be incredibly effective. The biggest hurdle will be specificity. Our own cells use methylation for normal, healthy functions, so the challenge is to design an inhibitor that can distinguish and block the viral-induced process without causing collateral damage to the host cell. It’s a difficult balance to strike, but now that we know the mechanism, we can begin the bench work to validate our findings and screen for compounds that could become the next generation of antivirals.
