The innate immune system serves as the body’s primary defense mechanism against pathogens and foreign substances. One crucial aspect of this system is the presence of pattern recognition receptors, which are responsible for identifying non-self RNA molecules, such as those from viruses and bacteria, and initiating an immune response.
A recent study conducted by a team of researchers from Ludwig Maximilian University (LMU) has shed light on how certain modifications to RNA can evade these pattern recognition receptors. This discovery is significant for the development of RNA therapeutics and mRNA vaccines. The research findings were published in the prestigious journal Cell.
The key players in recognizing foreign RNA are toll-like receptors TLR7 and TLR8, located within endolysosomes, specialized cell organelles. However, before these receptors can identify the RNA, it needs to be broken down by specific enzymes within the endolysosomes. This is where modified RNA comes into play, as it can bypass this recognition process.
The researchers found that RNA molecules containing pseudouridine, a modification commonly found in vertebrate RNA, are less susceptible to enzymatic breakdown within endolysosomes. Additionally, the receptors fail to recognize fragments of RNA containing pseudouridine. This mechanism explains why modified RNA does not trigger an excessive inflammatory response.
Pseudouridine has been known to reduce immune responses to synthetic mRNA since 2005, laying the foundation for the development of RNA-based drugs and vaccines. For instance, some COVID-19 mRNA vaccines incorporate a related modification called N1-methylpseudouridine, which also evades immune detection. Understanding the molecular basis of these modifications is crucial for the widespread use of RNA technology.
The researchers’ findings provide valuable insights for the targeted development of RNA-based therapies. They are currently investigating the role of pseudouridine in preventing the recognition of the body’s own RNA. This knowledge could lead to further advancements in the field of RNA therapeutics and vaccine development.
For more information on this study, readers can refer to the published paper in Cell by Marleen Bérouti et al., titled “Pseudouridine RNA avoids immune detection through impaired endolysosomal processing and TLR engagement.” The DOI for this publication is 10.1016/j.cell.2025.05.032.
This groundbreaking research was conducted by the Ludwig Maximilian University of Munich, showcasing the institution’s commitment to advancing scientific knowledge and medical innovation. Readers interested in accessing the original article can find it on the Cell journal website.
In conclusion, the study’s findings on how modified RNA evades the innate immune system have significant implications for the development of RNA-based therapies and vaccines. This research paves the way for future advancements in the field and underscores the importance of understanding the immune evasion mechanisms of RNA modifications.
