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Researchers from NDM’s Wellcome Centre for Human Genetics and the Queen Mary University have found evidence of how the normally protective response of the immune system to infection can go wrong in sepsis, offering exciting possibilities for the development of more targeted therapies for this deadly condition.

The team have previously shown how differences in the levels of messages from genes (RNA abundance) in white blood cells can identify a specific group of sepsis patients with the poor outcome that fail to mount an appropriate protective immune response.

In their recently published Nature Immunology study, researchers from NDM’s Wellcome Centre for Human Genetics, Queen Mary University, Kennedy Institute of RheumatologyEmergency Medicine Research Oxford, Wellcome Sanger Institute, Oxford University Hospitals NHS Foundation Trust and NIHR Oxford Biomedical Research Centre showed how the sepsis response in these patients involves neutrophils, cells which act as the first responders in the fight against infection, that are immature and not functioning normally. The team also found evidence of likely problems in the emergency production of cells by the bone marrow based on differences in circulating blood stem and progenitor cells. They did this by studying patients with sepsis using new ways of analysing the regulation of genes in cells at single-cell resolution.

This work provides an opportunity to identify patients with specific mechanism of immune dysfunction in sepsis and clues to how to treat it. For example, their work implicates the involvement of specific chemical messengers and regulators such as STAT3 and CEBPB, and the possibility of using drugs targeting the interleukin 6 receptor and granulocyte colony-stimulating factor for specific patients with sepsis.

Prof Julian Knight, Professor of Genomic Medicine and senior author of the study said: “Sepsis is a devastating condition where better therapies are urgently needed but this has been limited by a lack of precision in understanding what is going wrong and in whom. Here we have shown the importance of neutrophil dysfunction in the maladaptive response to infection and that this is a particular problem in a subset of patients with sepsis, providing the opportunity for more targeted therapies in those individuals.”

Sepsis is recognised to be a highly heterogeneous condition, and understanding specific disease subtypes or ‘immune endotypes’ is recognised as an important next step by researchers in the field to develop targeted therapies. In the paper, the team identified the specific cell types and gene programs characterizing the sepsis response signature (SRS) of the subgroup of patients that they had previously reported. The cellular resolution achieved in understanding the unique immune response signatures of SRS consolidated these signatures as discrete disease endotypes.

"The understanding of sepsis immune endotypes is a significant step forward in the field of sepsis research," said Andrew Kwok, DPhil student at the Wellcome Centre for Human Genetics, and the lead author of the study. "With knowledge of the drivers of poor outcome endotypes, we can develop therapies for those patients specifically, targeting the specific mechanism underlying the endotype. This has the potential to revolutionize the way we treat sepsis and save countless lives."