Fighting pathogens is the power of the tour that must occur with speed and accuracy. A team of CEMM researchers and Medeni Vienna led by Christophe Bock and Matthias Farlik investigated how macrophage immune cells, the body's first responders, master this challenge. Their research, Cell System (doi:10.1016/j.cels.2025.101346) provides time-resolved analysis of the molecular processes that these cells unfold when they encounter a variety of pathogens. They have developed a new method that combines gene editing and machine learning to identify key regulators of macrophage immune responses.
Macrophages (Greek for “big eater”) deserve their name. Their job is to recognize invasive pathogens such as bacteria and viruses, engulf them and break them down into biochemical components. Macrophages are also messengers. It mobilizes other immune cells, causes inflammation, and releases various signals to present digested pathogen fragments on its surface, leading to the adaptive immune system and leading to long-term immunity.
Macrophages encountering pathogens are subject to great pressure. If they are too late or unresponsive, the infection can be fatal. However, the immune response of overshoot is similarly damaging. A regulated immune response must be initiated within a very short period of time. It triggers a cascade of biochemical reactions, activating thousands of genes, producing substances tailored to the specific pathogens encountered.
Regulatory networks have been discovered
To understand how macrophages coordinate this numerous task, a team led by Christoph Bock (CEMM Principal Investigator and Professor in Medenivienna) and Matthiasphalik (CEMM Principal Investigator in Mednivienna) exposed macrophages from mice to various immune stimuli from macrophages. They established a molecular timeline for how intracellular changes can be tracked and regulatory programs can be developed step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step by step
The team then identified regulatory proteins that regulate these programs and used CRISPR genome editing to generate hundreds of gene knockouts and single-cell RNA sequences to characterize genetically perturbed cells. This innovative method has revealed a network of dozens of regulators who share the responsibility to trigger the most appropriate immune response. The identified regulators include many “normal suspects,” including the JAK-STAT signaling pathway, but also splicing and chromatin regulators whose roles in immune regulation are poorly understood.
How complicated is it to share with sponges, jellyfish and corals in this ancient part of our immune system. Advances in CRISPR screening technology allow us to systematically study the underlying regulatory programs. ”
Christophe Bock, Sr. Author
sauce:
CEMM Research Centre for Molecular Medicine, Austrian Academy of Sciences
Journal Reference:
Traxler, P., et al. (2025). Integrated time series analysis and high content CRISPR screening depict the dynamics of macrophage immunoregulation. Cell System. doi.org/10.1016/j.cels.2025.101346.
