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Researchers from Würzburg and Marburg identify a long non-coding RNA as a key regulator of macrophages
Macrophages are considered the “scavenger cells” of the immune system, but some pathogens exploit these very cells as hiding places. Researchers from the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg and Philipps-Universität Marburg have now discovered a mechanism that helps immune cells to balance their response to infection: a long non-coding ribonucleic acid called SAILR, which acts as an apoptosis regulator. The findings were published recently in the journal PNAS.
Macrophages are a key component of the human immune system and help the body fight off infections: as soon as a pathogen invades, the macrophages engulf and “digest” it. Hence, macrophages are often referred to as “scavenger cells”. However, some intracellular pathogens such as Salmonella manage to outwit macrophages and even multiply inside them. How these immune cells maintain the balance between self-preservation and effective pathogen clearance has not yet been fully elucidated. Researchers at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg, a site of the Braunschweig Helmholtz Centre for Infection Research (HZI) in cooperation with Julius-Maximilians-Universität Würzburg (JMU), have now, together with scientists from Philipps-Universität Marburg, identified a factor that plays an important role in this balancing act: a long non-coding ribonucleic acid, or lncRNA for short.
“We have identified an RNA molecule specific to humans called SAILR,” says Alexander Westermann, an affiliated scientist at HIRI and a professor at JMU. He is the first author of the study published in the Proceedings of the National Academy of Sciences (PNAS). In resting macrophages, SAILR binds to the “survival protein” 14-3-3β and helps keep the cells alive. During a bacterial infection, however, SAILR is rapidly silenced. As a result, macrophages are more likely to die, which eliminates the safe havens where bacteria can multiply inside the cell. “This makes SAILR an RNA-based kill switch,” concludes Westermann.
“Until now, it was generally assumed that macrophages primarily upregulate defense mechanisms to combat pathogens, rather than triggering their own destruction,” explains Leon Schulte, a professor at the University of Marburg and corresponding author of the study. “It was therefore completely unexpected that an infection would actively suppress a factor that promotes cell survival,” adds HIRI Director Jörg Vogel, in whose lab the study was initiated.
A biomarker for severe infections
SAILR directly connects macrophage survival to the interaction between host and pathogen. This links a fundamental molecular mechanism to human disease. It suggests that the RNA molecule may be useful as a diagnostic marker or therapeutic target for severe infections and inflammation. Clinical research already points in this direction: In severe cases of COVID-19 or sepsis, SAILR levels in blood cells drop significantly. In the future, SAILR could help predict the severity of an infection. “In the long term, SAILR could potentially be used as a biomarker for severe disease progression, for instance, through blood tests,” says Schulte.
However, SAILR is not only of interest as a marker but also as a potential therapeutic target: “The prospect of specifically modulating SAILR—for example, by lowering it to eliminate infected macrophages or stabilizing it to limit tissue damage—could prove promising. This could lead to new RNA-based therapies for sepsis and other severe inflammatory conditions by enabling targeted control of macrophage survival,” Vogel suggests.
At the same time, the findings offer new perspectives on the development of the human immune system: SAILR is present only in primates and thus represents an evolutionarily recent form of immune regulation absent from standard experimental models. “This highlights why certain infection mechanisms can only be replicated to a limited extent in the laboratory and could help tailor drugs and testing systems more specifically to humans,” says Westermann.
Research at the interface of RNA, immunity, and infection
This work opens up new avenues of research at the interface between RNA biology, immunity, and infection. Future studies could investigate in greater detail how RNA-protein interactions in immune cells regulate inflammatory processes and host-pathogen interactions. At the same time, non-coding RNAs are coming into sharper focus as potential key regulators of the immune response.
Collaborations
This study is a collaboration between the HIRI, the JMU, and the Philipps-Universität Marburg. Additional collaborators include the Academy of Athens (Greece), the NUCLEATE – Cluster for Nucleic Acid Sciences and Technologies, the Friedrich Schiller University Jena, the German Center for Lung Research (DZL), the German Center for Infection Research, the Harvard T.H. Chan School of Public Health (Boston, USA), the Hellenic Institute for the Study of Sepsis (Athens, Greece), Jena University Hospital, Johannes Gutenberg University Mainz, Justus Liebig University Giessen, the Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, the National and Kapodistrian University of Athens, the Universities of Giessen and Marburg Lung Center (UGMLC), the University Hospital of Giessen and Marburg (UKGM), and the University Hospital Würzburg.
Funding
This work was supported by the German Research Foundation, the Hessian Ministry of Science and Research, Arts and Culture, the Fritz Thyssen Foundation, and the Federal Ministry of Research, Technology and Space. The authors also received support from a Gottfried Wilhelm Leibniz Prize, the German Excellence Initiative through the Graduate School of Life Sciences at JMU, and funding from the UGMLC, the DZL, the UKGM, the Foundation for Pathobiochemistry and Molecular Diagnostics, and the Federal Ministry of Health. This study also used data generated by the Blueprint Consortium, which was funded by the European Union’s Seventh Framework Programme.
Helmholtz Institute for RNA-based Infection Research:
The Helmholtz Institute for RNA-based Infection Research (HIRI) is the first institution of its kind worldwide to combine ribonucleic acid (RNA) research with infection biology. Based on novel findings from its strong basic research program, the institute’s long-term goal is to develop innovative therapeutic approaches to better diagnose and treat human infections. HIRI is a site of the Braunschweig Helmholtz Centre for Infection Research (HZI) in cooperation with the Julius-Maximilians-Universität Würzburg (JMU) and is located on the Würzburg Medical Campus. More information at https://www.helmholtz-hiri.de.
Helmholtz Centre for Infection Research:
Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and its other sites in Germany are engaged in the study of bacterial and viral infections and the body’s defense mechanisms. They have a profound expertise in natural compound research and its exploitation as a valuable source for novel anti-infectives. As member of the Helmholtz Association and the German Center for Infection Research (DZIF) the HZI performs translational research laying the ground for the development of new treatments and vaccines against infectious diseases. https://www.helmholtz-hzi.de/en
Media contact:
Luisa Härtig
Manager Communications
Helmholtz Institute for RNA-based Infection Research (HIRI)
Josef-Schneider-Str. 2 / D15
97080 Würzburg | Germany
+49 931 31 86688
luisa.haertig@helmholtz-hiri.de
Westermann AJ, Schock A, Ashour DAD, Wende S, Skevaki C, Mack E, Schmeck B, Linne U, Herrmann T, Antonakos N, Florou H, Giamarellos-Bourboulis EJ, Weis S, Vogel J, Schulte LN (2026) A human-specific long noncoding RNA regulator of antigen-presenting cell viability and antimicrobial defense. PNAS, DOI: 10.1073/pnas.2520205123
https://doi.org/10.1073/pnas.2520205123
https://www.helmholtz-hzi.de/en/media-center/newsroom/news-detail/kill-switch-fo... Press release on HZI website
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